Evolution of Immunosuppression in Renal Transplantation

THE EVOLUTION OF Immunosuppression in Renal Transplantation 1
Target Audience
This educational monograph is directed toward physicians who are involved in renal transplantation,
and/or evaluate and treat patients before and after kidney transplants.
Program Overview
Transplantation is associated with high costs in human terms and medical expenses. It is important to
continue to improve the outcomes—patient and graft survival, graft function, and quality of life—for
kidney transplant patients, who generally wait years for transplants.
Posttransplant immunosuppression regimens involve a balancing act. The therapeutic goal—prevention

of rejection—is weighed against the risks of immunodeficiency complications—infection, cancer—and
non-immune toxicities, such as anemia, hypertension, hyperlipidemia, diabetes, and nephrotoxicity.
Immunosuppression can seldom, if ever, produce permanent unresponsiveness to donor antigens; organ
transplant recipients require adequate immunocompetence for life. New agents and new regimens offer
hope for the future of reduced risk of immunodeficiency complications and non-immune toxicity. New
non-depleting protein drugs—monoclonal antibodies and fusion proteins—offer promise of a more
favorable balance.
There is a significant unmet educational need among the renal transplant team and the referring
nephrologists: the need to more fully understand optimal regimens for enhancing graft and patient
survival posttransplant, and the need to react to adverse changes in their status. The primary objective
of this monograph is to meet the medical education needs of physicians and allied health professionals
who care for patients undergoing transplantation. This will permit knowledge of potential improvements
in patient care to be delivered to those who may benefit.
Learning Objectives
Upon completion of this activity, participants should be better able to:
1. Define the key issues in immunosuppression in transplantation
2. Describe the evolution and successes of immunosuppression over the past 10 years
3. Discuss the unmet needs in immunosuppression for transplantation
4. Identify the potential of selective immunosuppression candidates in development to meet these
needs
Faculty
Philip F. Halloran, MD, PhD, OC

Professor of Medicine
Division of Nephrology and Transplantation Immunology
Director, Alberta Transplant Institute
Canada Research Chair in Transplant Immunology
University of Alberta
Edmonton, Alberta, Canada
Sundaram Hariharan, MD
Chief of Nephrology
Professor of Medicine
Medical College of Wisconsin
Milwaukee, WI
Stuart Knechtle, MD
Ray D. Owen Professor of Transplantation
University of Wisconsin–Madison
Madison, WI
Thomas C. Pearson, MD, DPhil

Livingston Professor of Surgery
Department of Surgery
Emory University School of Medicine
Atlanta, GA
Mohamed H. Sayegh, MD
Warren E. Grupe and John P. Merrill Chair in Transplantation Medicine
Professor of Medicine and Pediatrics
Harvard Medical School
Director, Transplantation Research Center
Brigham and Women’s Hospital
Boston, MA
Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners,
managers, and other individuals who are in a position to control the content of CME activities. All relevant
conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity
of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its
learners with high-quality CME activities and related materials that promote improvements or quality in
health care and not a specific proprietary business interest or a commercial interest.
The faculty reported the following financial relationships or relationships to products or devices they or
their spouse/life partner have with commercial interests related to the content of this CME activity:
Name of Faculty or Presenter Reported Financial Relationship

Philip F. Halloran, MD, PhD, OC Has no relationships to report
Sundaram Hariharan, MD Consulting Fees: Bristol-Myers Squibb, Novartis AG
Speakers’ Bureaus: Wyeth, Fujisawa
Stuart Knechtle, MD Ownership Interest: Bristol-Myers Squibb
Thomas C. Pearson, MD, DPhil Has no relationships to report
Mohamed H. Sayegh, MD Consulting Fees: Genzyme
The planners and managers reported the following financial relationships or relationships to products
or devices they or their spouse/life partner have with commercial interests related to the content of this
CME activity:
Name of Faculty or Presenter Reported Financial Relationship

Trace Hutchison, PharmD Has no relationships to report
Jan Hixon, RN, BA, MSN Has no relationships to report
Linda Graham, RN Has no relationships to report
Christine de Vries Has no relationships to report
Physician Continuing Medical Education

Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship
of the Postgraduate Institute for Medicine and DRIVE Medical Consulting & Communications. The
Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education
for physicians.
Credit Designation
The Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.25
category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only
those credits that he/she actually spent in the activity.
Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that
are not indicated by the FDA. The Postgraduate Institute for Medicine (PIM), DRIVE Medical Consulting
& Communications (DRIVE), and Bristol-Myers Squibb (BMS) do not recommend the use of any agent
outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily
represent the views of PIM, DRIVE, or BMS. Please refer to the official prescribing information for each
product for discussion of approved indications, contraindications, and warnings.
Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance patient
outcomes and their own professional development. The information presented in this activity is not
meant to serve as a guideline for patient management. Any procedures, medications, or other courses of
diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without
evaluation of their patients’ conditions and possible contraindications on dangers in use, review of
any applicable manufacturer’s product information, and comparison with recommendations of other
authorities.
Media
Printed Monograph
Method of Participation
There are no fees for participating and receiving credit for this activity. During the period November 2005
through November 2006, participants must:
1. Read the learning objectives and faculty disclosures.
2. Study the educational activity.
3. Complete the Post-Test by recording the best answer to each question on the Answer Key on
the Post-Test and Evaluation Form.
4. Complete the Evaluation Form.
5. Mail or fax the Post-Test and Evaluation Form to the Postgraduate Institute for Medicine.
A statement of credit will be issued only upon receipt of a completed Post-Test and Evaluation Form and
will be mailed to you within 3 weeks.
Postgraduate Institute for Medicine

367 Inverness Parkway
Suite 215
Englewood, CO 80112
Fax: (303) 790-4876
Introduction
The primary objective in contemporary transplant immunosuppression is safe control of rejection.
This requires that we achieve a balance between immunosuppression and its potential complications:
immunodeficiency complications (infection, certain cancers) and non-immune toxicity. In the past
decade, new immunosuppressive drugs have improved this balance and improved outcomes after renal
transplantation. However, some of these newer drugs require frequent therapeutic drug monitoring, and
many are associated with acute and chronic toxicities.
New biologic agents have been developed to address these problems, including monoclonal antibodies
and fusion proteins. These agents are not immunogenic, have long half-lives and prolonged biologic
effects, thus allowing intermittent administration, and have minimal non-immune toxicity. The equivalent
potency, and greater specificity and selectivity of the new biologic agents render them less toxic than
earlier immunosuppressive drugs. They present opportunities to replace the drugs that are associated
with most of the long-term, non-immune toxicities, such as the corticosteroids and the calcineurin
inhibitors. This monograph reviews the evolution of immunosuppressive strategies and assesses the
ability of new drugs to approach an improved balance.
The immune response to a kidney transplant

Organ transplantation between genetically non-identical individuals typically results in immunologic
rejection of the organ through T-cell-dependent mechanisms, including T-cell-mediated rejection and/or
antibody-mediated rejection.
Organ transplantation activates the innate immune system and antigen presentation. Following
transplantation, dendritic cells of both donor and host origin in the graft and surrounding tissues become
activated and move to T-cell areas of secondary lymphoid organs, where the antigen-bearing dendritic
cells engage alloantigen-reactive naïve T cells and central memory T cells.
The alloimmune response in the lymphoid tissues can be represented by the 3-signal model, as depicted
in Figure 1.1 The Major Histocompatibility Complex (MHC) class I and II antigens on the surface of the
dendritic cells engage and trigger T cells with cognate T-cell receptors. This constitutes “signal 1,”
transduced through the CD3 complex.
Dendritic cells provide costimulation, or “signal 2,” delivered when CD80 and CD86 on the surface of
dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction pathways: the
calcium-calcineurin pathway, the RAS–mitogen-activated protein (MAP) kinase pathway, and the nuclear
factor-kB pathway.
These pathways activate transcription factors that trigger the expression of many new molecules,
including interleukin-2, CD154, and CD25. Interleukin (IL)-2 activates the “target of rapamycin (TOR)”
pathway to provide “signal 3,” which is the trigger for cell proliferation. Lymphocyte proliferation also
requires nucleotide synthesis. Proliferation and differentiation lead to a large number of effector T cells.
Within days of receiving a transplant, the patient’s immune response generates the agents of allograft
rejection: effector T cells and alloantibodies.
Activated CD4+T cells produce IL-2, which helps activated CD8+T cells to clonally expand and develop
effector functions (eg, expression of interferon [IFN]-g, perforin, and granzyme A and B). They lose their
homing molecules for lymphoid organs and acquire homing molecules for inflamed sites. They home
to the graft, create inflammation, and attract more effector T cells and monocytes, which then become
activated macrophages.
Allograft rejection is mediated by the activated T cells and macrophages that accumulate in the
transplanted organ. The migration of these cells into the organ is aided by endothelial changes in
stressed, infected, or injured tissue by adhesion molecules and chemokine receptors expressed by
lymphocytes that have been activated by antigen in the lymph node.
Cytokines and chemokines produced during this process play critical roles in determining the content
of the infiltrate and its patterns of activation. The mechanism of tissue injury is probably related to a
delayed-type hypersensitivity mechanism, in which T cells and activated macrophages release products
Figure 1: The 3-Signal Model of the Immune Response and Sites of Possible
Immunomodulation
Belatacept
(LEA29Y)
Within days posttransplant, the patient’s immune response generates the agents of allograft rejection:
effector T cells and alloantibodies. The T-cell response when engaged by antigen-presenting cells in the
lymphoid organs can be represented by the 3-signal model. Also shown are the sites of action of some of the
approved immunosuppressive drugs and those currently in clinical trials, and those showing promising results
in preclinical studies. In this illustration, the IL-2 is shown acting on the IL-2-producing cell; however, in the
generation of effector T cells, the IL-2 from the activated CD4+T cells may act principally on the receptors of the
CD8+ effector T-cell precursors to promote their clonal expansion and differentiation. © 2004 Massachusetts
Medical Society. Used with permission.1
Host exposure to intact MHC alloantigens displayed on donor APCs (direct allorecognition) results in acute
rejection because of substantial expansion of T cells of multiple specificities. Alternatively, host exposure
to donor alloantigens that have been processed and presented by host APCs (indirect allorecognition)
leads to the activation of a limited T-cell repertoire with restricted ability to recognize graft targets. This
process contributes to chronic rejection.
Challenges and the Future of Immunosuppression

There are 3 possible strategies for effecting immunosuppression: lymphocytes can be depleted,
lymphocyte traffic can be diverted, or lymphocyte response pathways can be blocked. Each of the 3 signals
of the immune cascade has been used as a target of inhibition in the search for the improved balance
in immunosuppression. Any of these actions can produce the desired therapeutic effect of suppressing
graft rejection, but excessive lymphocyte depletion or blocking heightens the risk of immunodeficiency
consequences. Moreover, all of the small-molecule drugs carry significant non-immune toxicity. This
monograph will discuss the efficacy and safety of these approaches.
Another area of challenge in transplantation is the treatment of subgroups of recipients with high
immunologic risk (African Americans, retransplants, and recipients with high-panel reactive antibodies),
high medical risks (older age, diabetes, and vascular disease), or high donor risk (expanded criteria donor
[ECD] kidneys, older donors). All of these reduce the chances of successful transplantation.
Interest is shifting toward the preservation of function and prevention of complications in the many
patients with transplants performed in previous years. Global immunosuppression has improved acute
graft survival in recent years but the disease phenotypes that emerge as risks to long-term survival must
now be understood. Prevention of late graft loss and premature patient death due to immune and non-
immune toxicities of immunosuppressive agents is a major emerging issue in transplantation.
Emerging opportunities to improve outcomes include the development of precisely targeted, selective
immunosuppressive agents with more favorable safety profiles. New immunosuppressive strategies
exploit normal mechanisms of T-cell activation. For example, intervening to inhibit costimulatory signals
(signal 2) to reduce T-cell activation may allow control of the alloimmune response without compromising
the patient. This monograph describes recent developments in this evolution of immunosuppression in
renal transplantation.
A Decade of Evolution and Progressive Successes

Immunosuppressive trends for solid organ transplantation have undergone a significant shift over the past
decade. In 1990, most regimens used corticosteroids in combination with the calcineurin inhibitor (CNI),
cyclosporine, and the antimetabolite, azathioprine (AZA).2,3 By June 2001, many new immunosuppressive
agents had become available, including tacrolimus and improved formulations of cyclosporine, such as
cyclosporine micro-emulsion. New immunosuppressants, including mycophenolate mofetil (MMF) and
mycophenolate sodium, the TOR inhibitor sirolimus, antibody agents, such as antithymocyte globulin,
and the IL-2 receptor antibodies, daclizumab and basiliximab, were added to the armamentarium. 3
Because T cells play a central role in graft rejection, most of these immunosuppressive drugs target
T cells, with the most successful drugs acting in the early phases of T-cell activation. Cyclosporine
and tacrolimus, for example, prevent T cells from producing cytokines critical for T-cell proliferation,
such as interleukin-2. Sirolimus (rapamycin) blocks signal transduction via the interleukin-2 receptor.
Azathioprine and mycophenolate, both inhibitors of purine synthesis, also inhibit T-cell proliferation.
Monoclonal antibodies directed at T cells, such as OKT3 (muromonab-CD3), act by depleting T cells and
blocking the T-cell antigen receptor.
These advances have led to improvement in survival for both patients and grafts, but there are still
problems with these agents. Immunosuppression with these drugs is nonspecific and is associated with
a substantial risk of opportunistic infections and cancer. These drugs also have side effects, such as the
nephrotoxic effects of cyclosporine and tacrolimus and the diabetogenic effects of tacrolimus. Table 1
summarizes immunosuppressive therapies currently in clinical use.
Table 1: Immunosuppressive Therapies in Clinical Use
AGENT BRAND APPROVED USE BACKGROUND & MECHANISM OF ACTION
I. Corticosteroids prednisone Multiple Multiple Exhibit a wide range of effects on almost every phase of the immune
methylprednisolone and inflammatory responses, playing a role in the treatment of many
diseases. Specifically, corticosteroids inhibit antigen presentation,
cytokine production, and proliferation of lymphocytes.4,5
II. Small Molecule Drugs
1. Inhibitors of nucleotide syntheses
cyclophosphamide Cytoxan®, Neosar®, Solid tumors, Cyclophosphamide DNA crosslinking impairs DNA replication and
others sarcomas, multiple transcription, ultimately leading to either cell death or altered cellular
myeloma, leukemias6 function, preventing clonal expansion of T cells.
mycophenolate mofetil MMF inhibits inosine monophosphate dehydrogenase, a key enzyme in
CellCept®, Prophylaxis of organ
(MMF) purine synthesis, thereby preventing proliferation of both T cells and
® rejection9
mycophenolate sodium Myfortic B cells and inhibiting antibody production.9
2. Antimetabolites
Prophylaxis of organ A derivative of 6-mercaptopurine, azathioprine inhibits DNA and RNA
azathioprine Imuran®, Azasan®
rejection7 synthesis, leading to decreased immune cell proliferation.1,8
3. Immunophilin-Binding Drugs
a. Calcineurin Inhibitors: CNIs interact with binding proteins to inhibit calcineurin activity, which inhibits IL-2, a critical link in the proliferation of helper T cells.
THE EVOLUTION OF Immunosuppression in Renal Transplantation
tacrolimus (or FK506) Prograf® Prophylaxis of organ The prodrug of tacrolimus binds to an immunophilin FK-binding protein
rejection10 12 (FKBP12), the active drug-protein complex then blocks calcineurin
phosphatase activity, suppressing lymphokine transcription and T-cell
activation.10
Sandimmune®, Prophylaxis of organ Cyclosporine binds to calcineurin near its active site, making the site
cyclosporine (or
Neoral®, Gengraf®, rejection, and chronic unavailable to dephosphorylate large substrates, suppressing T-cell
cyclosporine A)
others organ rejection10 activation and cytokine production.11
b. TOR Inhibitors
Prophylaxis of organ Sirolimus and everolimus inhibit T-cell activation and proliferation
sirolimus Rapamune® rejection12 and also inhibit antibody production. Specifically, this class engages
FKBP12 to create complexes that engage and inhibit the target of
rapamycin (TOR); however, sirolimus and everolimus do not affect
Prophylaxis of organ calcineurin activity.12
rejection (Approved This class also inhibits p70S6 kinase, proliferation signal inhibitor
7
everolimus Certican® outside the United blocking growth factor-driven proliferation of cells.13
States)13
III. Protein Drugs
1. Depleting Antibodies (against T cells, B cells, or both)
a. Polyclonal antibodies
antithymocyte Thymoglobulin® Treatment of organ Cytotoxic antibodies directed against antigens expressed on T-cells
globulin (rabbit) rejection14 mediate T-cell effects via inhibition of proliferative responses.14
antithymocyte globulin Atgam® Prophylaxis and

(equine) treatment of acute
rejection14
b. Monoclonal antibodies
alemtuzumab Campath® Treatment of Alemtuzumab binds to CD52, an antigen present on essentially all B
relapsed B-cell and T lymphocytes, a majority of monocytes, macrophages, and NK
chronic lymphocytic cells. The proposed mechanism is antibody-dependent lysis of cells
leukemia15 following cell surface binding.15
rituximab Rituxan® Treatment of relapsed Rituximab is a chimeric (murine/human) monoclonal antibody

or refractory follicular directed against the CD20 antigen on the surface of B cells, which
CD20-positive B-
regulates an early step in the activation of differentiation. It is a

cell non-Hodgkin’s selective B-cell-depleting agent.16
lymphoma16
2. Non-Depleting Antibodies
a. Monoclonal antibodies
muromonab-CD3 Orthoclone® Treatment of acute Muromonab-CD3 is a murine monoclonal antibody to the CD3
(OKT3) allograft rejection in antigen of T cells. Binding of muromonab-CD3 to T cells results in early
transplant patients17 activation, which leads to cytokine release, followed by blocking T-cell
functions.1,17
basiliximab, Simulect®, Prophylaxis of organ Basiliximab and daclizumab are anti-CD25 monoclonal antibodies that
daclizumab Zenapax® rejection18,19 act as IL-2 receptor antagonists by selectively blocking IL-2 receptors
on activated T lymphocytes, impairing the response of the immune
system to antigenic challenges.18,19
8
Immunosuppressive agents available today include a variety of drugs for primary immunosuppression as well as for maintenance therapy.
Immunosuppressive Strategies in Current Practice

The original transplant immunosuppressive drug was azathioprine (AZA), the mainstay until about 1983.
AZA is associated with leukopenia, bone marrow depression, and macrocytosis, and requires blood-
count monitoring. When cyclosporine was introduced, AZA became a second-line drug, sometimes
used in combination regimens (cyclosporine and AZA). Corticosteroid use remained universal. In the
period 1983 to1995, immunosuppressive strategies were based on cyclosporine, AZA, glucocorticoids,
antithymocyte and antilymphocyte globulin, and muromonab CD3 (OKT3). Although the use of these
therapies significantly improved graft outcomes over earlier regimens, their burden of toxicity was
substantial, and rejection rates were high.
The modern era in immunosuppression emerged after 1995 with the use of tacrolimus and
mycophenolate. Sirolimus, introduced in 1999, also contributed to this evolution. Today, most patients
have a low probability of rejection and early graft loss. However, many issues remain.
The small-molecule immunosuppressive agents (CNI, TOR inhibitors, and purine synthesis inhibitors)
do not saturate their targets at clinically tolerable doses and, therefore, require careful dosing and
monitoring. Cyclosporine is a calcineurin inhibitor and can cause nephrotoxicity, hemolytic-uremic
syndrome, hypertension, neurotoxicity, posttransplantation diabetes mellitus, and hyperlipidemia, and,
therefore, requires monitoring. Tacrolimus confers superior control of rejection with fewer adverse effects.
The incidence of hypertension and hyperlipidemia is lower with tacrolimus than with cyclosporine, while
posttransplantation diabetes mellitus and neurotoxicity incidence is higher. Some experience indicates
that polyoma virus complications may be more frequent with tacrolimus, especially combined with
mycophenolate mofetil (MMF). Sirolimus causes hyperlipidemia and increases the nephrotoxicity of
calcineurin inhibitors when used in combination. It also is associated with thrombocytopenia, delayed
wound healing, delayed graft function, mouth ulcers, pneumonitis, and interstitial lung disease. The
adverse effects of MMF include gastrointestinal symptoms (mainly diarrhea), neutropenia, and mild
anemia.
Depleting protein immunosuppressive agents destroys T cells, B cells, or both. T-cell depletion may
produce severe systemic symptoms, related to the release of cytokines, and increases the risks of infection,
posttransplant lymphoproliferative disease, and possible late rejection. Recovery of immune functions
may take months or years. OKT3 produces the most profound cytokine-release syndrome (fever, chills,
hypotension). Polyclonal antibody antithymocyte globulin produces less cytokine-release syndrome, but
produces thrombocytopenia, leukopenia, and serum sickness.1 The monoclonal antibody, alemtuzumab
(anti-CD52), binds to CD52 on all T and B cells and produces prolonged depletion. Alemtuzumab has been
associated with myeloid hematologic toxicities, comprising long-lasting lymphocytopenia and transient
neutropenia and thrombocytopenia, and a heightened risk of fever or infection.20 The monoclonal
antibody, rituximab, is B-cell-depleting; however, this depletion does not affect most plasma cells, which
lack CD20.
The non-depleting, anti-CD25 monoclonal antibodies, daclizumab and basiliximab, target semi-redundant
T-cell activation pathways and reduce immune responsiveness without depleting or compromising
immune function. However, they are only moderately effective and are used in combination regimens,
where they reduce rejection by about one third. 1
The direction of development in immunosuppression is toward the long-term use of non-lymphocyte–

depleting proteins that effectively inhibit T-cell proliferation by selectively binding to and blocking
costimulation signals to prevent rejection, while avoiding the toxicities and immune compromise
associated with toxic, small-molecule drugs. The fusion protein, belatacept (LEA29Y), now in Phase 3
clinical trials, illustrates this development. Belatacept is a second-generation cytotoxic-T-lymphocyte-
associated antigen 4 (CTLA-4) fusion protein that binds to CD80 and CD86 and inhibits signal 2 in the
T-cell activation pathway. In Phase 2 clinical trials, it was shown to be as effective as cyclosporine at
preventing rejection, without the toxicities associated with cyclosporine.1
Table 2: Potential Immunosuppressive Drug Protocols

INDUCTION THERAPY
Anti-CD25 antibody (basiliximab, daclizumab)
Polyclonal antithymocyte globulin
Anti-CD25 antibody + Polyclonal antithymocyte globulin
Alemtuzumab (experimental)
MAINTENANCE THERAPY
CNI + MMF + - prednisone
Cyclosporine + sirolimus +
- prednisone
Sirolimus + MMF + - prednisone
Sirolimus +
- prednisone
Tacrolimus monotherapy
TREATMENT OF ACUTE REJECTION

Glucocorticosteroids
If unresolved:
Muromonab-CD3 or ATG
Immunosuppressive therapy includes antibody induction therapy during the peritransplant period, primary
and adjunctive maintenance immunosuppression, and treatment for acute graft rejection.1
Optimizing Immunosuppressive Regimens

Current immunosuppressive strategies (see Table 2) generally rely on combinations of agents and
are designed to meet 3 different needs: antibody induction therapy during the peritransplant period,
primary and adjunctive maintenance immunosuppression, and treatment for acute graft rejection.
Hundreds of potential combinations exist, and many new protocols have emerged, often including a
reduced reliance on glucocorticoids and calcineurin inhibitors. However, controlled clinical trials have
not been conducted on many of these combinations, and their use relies on clinical experience and varies
by transplant center.
Antibody Induction Therapy

Antibody-based induction immunotherapy is used in the early transplant period to reduce the early
immune system activity against the transplanted organ and to condition the system to adapt to the
graft. Induction with depleting or nondepleting antibodies is used for the majority of kidney transplant
recipients. During this period, the use of antibody-based therapy allows for avoidance or dose reduction
of calcineurin inhibitors, possibly reducing the risk of early nephrotoxicity and delayed graft function, and
provides better prevention of early acute rejection.
Nondepleting anti-CD25 monoclonal antibodies are widely administered early in the posttransplant
period because they are moderately effective but almost free of side effects. The anti-CD25 monoclonal
antibodies, daclizumab and basiliximab, are approved for induction therapy.3 The depleting antibodies
—usually polyclonal anti-lymphocyte antibodies—are now more commonly used than monoclonal
anti-CD3, especially in situations of high immunologic risk. The choice of depleting polyclonal antibody
preparations is shifting away from equine antithymocyte globulin to rabbit antithymocyte globulin.
Recently, alemtuzumab (anti-CD52) also has been used extensively as a depleting strategy in some
programs.
Maintenance Immunosuppression
Maintenance immunosuppression is designed to suppress the alloimmune response, to provide a safe
level of long-term graft survival and function with a very low rejection rate, to give an acceptable rate of
side effects, and to lower the incidence of chronic rejection over the long term. In primary maintenance
immunosuppressive therapy, many patients continue to receive corticosteroids; however, steroid-free
regimens remain an important therapeutic goal. Mycophenolate mofetil (MMF), with or without sirolimus
and prednisone, is the most widely employed maintenance immunosuppressive agent in solid organ
transplantation, and has replaced the use of AZA, except in the UK and some developing countries.3
Antirejection Treatment
The need for treatment for acute rejection episodes within 1 year of kidney transplantation has improved
from 18% in 2000 to 15% in 2002. Historically, acute rejection was shown to be one of the strongest
prognostic factors for long-term graft survival following renal transplantation. As posttransplant
immunosuppressive therapy has evolved, there has been a corresponding reduction in the rate of early
acute graft-rejection episodes. Factors that may contribute to graft failure during the first year post-
transplant include acute rejection, primary nonfunction, graft thrombosis, recurrent kidney disease, or
the death of a patient with a functioning graft. Some events in the first year also are associated with
a lower probability of long-term graft survival. For example, a recent analysis reemphasized that the
functional response of the acute rejection episode to therapy is important with respect to the impact
on graft survival. Acute rejection episodes that do not respond well to treatment are possible markers
for an increased risk of subsequent late rejection and graft failure.21 T-cell-mediated rejection accounts
for most rejection episodes but antibody-mediated rejection is recognized with increasing frequency.3
Antibody-mediated rejection is treated with some of the same strategies as T-cell-mediated rejection
because the antibody response requires T-cell help, particularly as it develops. However, it is also treated
with plasmapheresis, IVIG, and rituximab. Table 3 details potential therapeutic options.
Table 3. Immunosuppressive Agents for Treating Acute Graft Rejections

POTENTIAL IMMUNOSUPPRESSIVE
TYPE OF ACUTE REJECTION
THERAPY ALTERNATIVES
T-cell-Mediated Rejection Steroids

Anti-T-cell Agents (muromonab-CD3,
antithymocyte globulins)
Antibody-Mediated Rejection Steroids

Anti-T-cell Agents (muromonab-CD3,
antithymocyte globulins)
Plasmapheresis
IVIG
Rituximab
Therapy of the acute rejection is tailored toward the type of rejection.
Steroids are the mainstay of initial therapy for acute rejection episodes, although their actions are
multiple on macrophages and T cells and are not well understood. The anti-inflammatory properties of
steroids are also believed to be therapeutically beneficial in these episodes. A typical steroid dose is 3 to
10 mg/kg per day for 3 to 5 days, which is then tapered to a maintenance dose. This strategy is effective
in reversing acute rejection in approximately 60% to 75% of episodes.22
Muromonab-CD3 targets the CD3 complex on the surface of mature T cells, thus inhibiting the
alloimmune response. In first acute rejection episodes, this agent achieves reversal in approximately
94% of episodes. It is used to treat steroid-resistant rejection and often used as the first-line agent for
severe vascular rejections. The development of human anti-murine antibodies by the recipient, however,
can potentially reduce the efficacy of muromonab-CD3. These antibodies may preclude the use of
muromonab-CD3 by neutralizing the therapeutic effect.22
Antithymocyte globulin binds circulating T and B lymphocytes, which are then removed from the
circulation via the reticuloendothelial system. In acute rejection episodes, antithymocyte globulin has
efficacy similar to that of muromonab-CD3 and is also often used for steroid-resistant acute rejections.22
Preferential use of this agent to treat acute rejection as compared with muromonab-CD3 has become
more common in recent years.3
Strategies to Refine Immunosuppressive Therapy

Corticosteroid-Sparing Regimens
The toxicity of long-term steroid exposure has created a growing interest in steroid avoidance and
minimization protocols. Some of the potential benefits of the withdrawal or avoidance of steroids
include normal growth in children, improved lipid profiles, improved blood pressures, better glycemic
control, and lower risk of bone disease. Compared with protocols that discontinue steroids after the
initial posttransplant period, a steroid-free protocol may avoid the increased risk of infection, body
disfigurement, and other steroid-induced side effects. It may also avoid the long-term risks of steroid
use and the increased risk of rejection when the steroids are withdrawn.23 However, recent data have
demonstrated that the risk of rejection is higher in patients withdrawn from steroids on a cyclosporine-
plus-steroid protocol. Long-term observation is needed to determine the long-term safety of steroid
avoidance and withdrawal.
The availability of tacrolimus has allowed for the development of protocols that have achieved high rates
of successful steroid withdrawal after 6 months of therapy. More recently, studies involving rapid steroid
withdrawal over 1 to 2 weeks in patients receiving tacrolimus have shown similar graft survival rates
compared with patients withdrawn after 3 to 6 months. MMF has also been widely used in steroid-free
protocols, although the long-term effects remain to be determined. As the complexity and diversity of
current protocols increase, we are likely to see more widespread use of steroid-free protocols; however,
it is unlikely that randomized trials of long duration will be undertaken to assess the safety of these
protocols.
Calcineurin Inhibitor-Sparing Regimens

Due to the risk of both acute and chronic nephrotoxicity occurring with CNI therapy, the development
of protocols free of these agents is an ongoing part of the evolution of immunosuppressive therapy in
renal transplantation. It is possible that sirolimus in combination with MMF and steroids may potentially
offer a regimen that provides good long-term immunosuppression with less nephrotoxicity. The use
of a completely CNI-free regimen may prevent or delay the onset and progression of chronic allograft
nephropathy (CAN) by minimizing immune injury and drug-induced nephrotoxicity, which in turn may
lead to a cycle of tissue injury, interstitial fibrosis, ischemia, and pathologic tissue remodeling. 24
The initial use of sirolimus in CNI-free regimens demonstrated improved kidney function at 1 year, but
the overall merits of CNI-free protocols compared with other protocols such as tacrolimus and MMF is not
known.25 Similarly, more recently, investigators comparing basiliximab, MMF, and prednisone plus either
cyclosporine or sirolimus, found that at 2 years, the sirolimus-treated group had better renal function, less
scarring and atrophy, and lower expression of genes associated with injury and fibrogenesis.24 However,
the control group was the relatively toxic combination of cyclosporine and sirolimus.
The early withdrawal of cyclosporine from a sirolimus-cyclosporine-steroid regimen has been shown
to improve renal function and, ultimately, results in better graft survival—again, as compared with
continuation of the relatively toxic combination of cyclosporine and sirolimus.26
Follow-up results at 4 years from a study of 430 eligible patients randomized at 3 months posttransplant
to either remain on the sirolimus-cyclosporine-steroid therapy or to have cyclosporine withdrawn
demonstrate the feasibility of this strategy. In this trial, differences in acute rejection and mortality were
not significant; however, the patients who were withdrawn from cyclosporine had significantly better
graft survival, improved calculated GFR and improved mean arterial blood pressure. To be generalized,
such studies should include comparison with less toxic control therapies.
Depleting Regimens
Experimental depleting induction regimens have used alemtuzumab, an anti-CD52 antibody for
the protein induction phase, followed by sirolimus and tapering prednisone for maintenance
immunosuppression.27 However, the long-term consequences of severe depletion are unknown, and
clinical observations suggest a possible increase in antibody-mediated rejection with this regimen.
Alemtuzumab can cause more profound depletion of lymphocytes than monocytes. The resultant
imbalance of lymphocytes and monocytes after alemtuzumab treatment of a renal-transplant recipient
may lead to an acute rejection dominated by monocytes.28
Remaining Issues and Unmet Needs in Immunosuppression in

Transplantation
Despite many advances in solid organ transplantation over the last decade, clinical barriers and challenges
to optimal immunosuppressive therapy still remain. Although short-term outcomes provided by current
approved and available immunosuppressive combination therapies have continued to improve, the
consequences of their prolonged administration have become the subject of growing problems, such
as drug toxicities, late graft deterioration, and adverse events, which significantly affect both patient and
graft survival.
Toxicities of Immunosuppressive Therapy

Immunosuppressive therapy may be accompanied by undesired consequences, including immuno-
deficiency and drug-specific, non-immune toxicities.
Immunodeficiency Toxicities
Suppression of the transplant recipient’s normal immune functions establishes a state of
immunodeficiency and heightens the risk of severe infections, including cytomegalovirus (CMV),
Epstein-Barr virus (EBV), human polyoma virus (BK virus), pneumocystis, and granulomatous infections.
In addition, these infections occasionally translate to tumors, such as posttransplant lymphoproliferative
disease and skin cancers. Cancers and infections remain common, and their occurrence is significantly
increased in transplant recipients compared with the general population.
The use of more immunoselective drugs can reduce these risks. The understanding of the immune
cascade and the identification of selective target blockers can be translated to clinical practice. Research
efforts continue to focus on selective immunosuppressive agents with specific target sites that have
minimal risk of immunodeficiency toxicities. For example, selective inhibitors such as anti-CD25 antibody
(signal-3 blocker) or belatacept (signal-2 blocker) have little effect on the risk of infection and post-
transplant lymphoproliferative disease and may achieve a better balance of immunosuppression and
immunocompetence.
Non-Immune Toxicities
A wide range of side effects accompany the small-molecule immunosuppressive agents. Five of the most
prevalent are the “ABCDN group”: anemia, blood pressure elevation, cholesterol elevation, diabetes, and
nephrotoxicity. The goal of immunosuppressive research is not to trade one set of toxicities for another—
for example, by exchanging sirolimus hypercholesterolemia and anemia for tacrolimus nephrotoxicity—
but to reduce them all. The goal is to achieve a reduction in the total burden of non-immune toxicities.
The non-immune side effects of immunosuppressive therapy have become more serious concerns
because they can be indirectly linked to organ or tissue damage and even cardiovascular events and/
or death. Non-immune toxicities are agent-specific, arising from each drug’s mechanism of action.
Immunosuppressive agents target molecules that act both in the immune cascade and in non-immune
tissues.1 For example, cyclosporine and tacrolimus therapies are associated with hypertension (HTN),
diabetes, and dyslipidemias at 1 year posttransplantation and are seen in as many as 40% of patients
undergoing these therapies.29 The majority of non-immune toxic effects of current immunosuppressive
therapy are shown in Table 4.
Table 4: Non-immune Toxic Effects of Immunosuppressive Therapy
AGENT TOXICITIES MONITORING CONSIDERATIONS1

I. Corticosteroids prednisone Cataracts, hypertension (HTN), hyperglycemia, osteoporosis,
methylprednisolone cushingoid habitus, hyperlipidemia, impaired growth
II. Small Molecule Drugs
1. Inhibitors of nucleotide syntheses
cyclophosphamide Leukopenia, thrombocytopenia, alopecia, skin rashes, nausea, vomiting,

abdominal cramps, diarrhea, oral ulceration, infections, others.30
mycophenolate mofetil Diarrhea, nausea, neutropenia, thrombocytopenia mild anemia, nausea, Blood level monitoring not required, but
(MMF) diarrhea1,9 may improve efficacy; absorption reduced by
mycophenolate sodium cyclosporine1
2. Antimetabolites
azathioprine Severe leukopenia and/or thrombocytopenia, macrocytic anemia, and Blood count monitoring required1
severe bone marrow depression.7
3. Immunophilin-Binding Drugs
a. Calcineurin Inhibitors As a class, CNIs exhibit dose-dependent nephrotoxicity31
tacrolimus (or FK506) Nephrotoxicity, HTN, neurotoxicity, hepatotoxicity, hyperlipidemia, Trough monitoring required1
hyperglycemia, posttransplant diabetes10
cyclosporine (or Nephrotoxicity, HTN, neurotoxicity, hepatotoxicity, hyperlipidemia, Trough monitoring or checking levels 2 hours
cyclosporine A) gingival hyperplasia, hyperglycemia, posttransplant diabetes, gout32 after administration required1
b. TOR Inhibitors
sirolimus Hyperlipidemia, increased CNI toxicity at full dose of CNI, Lipid monitoring required, recipients whose
everolimus thrombocytopenia, delayed wound healing, interstitial lung disease, risk of rejection is low to moderate can stop
leg edema.1,12 Use for 3–10 days has been reported to produce a cyclosporine 2-4 months post-transplant1
profound and durable lymphopenia lasting greater than 1 year.33
14
III. Protein Drugs
1. Depleting Antibodies (against T cells, B cells, or both)
a. Polyclonal antibodies
antithymocyte Cytokine-release syndrome (fever, chills, hypotension),

globulin (rabbit) thrombocytopenia, leukopenia, serum sickness1,14
antithymocyte globulin
(equine)
b. Monoclonal antibodies
alemtuzumab Mild cytokine-release syndrome, neutropenia, anemia, idiosyncratic

pancytopenia, autoimmune thrombocytopenia, thyroid disease1,15
rituximab Infusion reactions, uncommon hypersensitivity reactions1,67

2. Non-Depleting Antibodies
a. Monoclonal antibodies
muromonab-CD3 Severe cytokine-release syndrome, pulmonary edema, acute renal Free OKT3 levels and CD3 monitoring are used.
(OKT3) failure, GI disturbances, changes in CNS system.1 Long-term use of
this agent has been associated with increased risk of posttransplant
lymphoproliferative disease.34
basiliximab, GI disturbances, uncommon hypersensitivity reactions1,18,19 No monitoring required1

daclizumab
In general, non-immune toxicity is agent-specific and is often related to the mechanism of action.
15
In addition to individual agent toxicities, combination therapy can potentiate non-immune toxicity.
For example, sirolimus combined with cyclosporine or tacrolimus potentiates nephrotoxicity. Thus,
one strategy is to investigate combinations in attempts to avoid the toxicities seen with CNIs.35 One
trial indicated that sirolimus potentiates tacrolimus nephrotoxicity and the sirolimus combination
produced greater renal dysfunction and hypertension than did MMF plus tacrolimus.36 In clinical
practice, the toxicity of a target-of-rapamycin (TOR) inhibitor and calcineurin inhibitor combination can
be reduced by withdrawing 1 of the drugs,37 but long-term safety and efficacy of such protocols remains
to be established. Similarly, increased GI toxicity has been noted with MMF and tacrolimus combination
therapy.
Calcineurin Inhibitor (CNI) Nephrotoxicity

Nephrotoxicity as a result of the use of CNIs is seen in most renal transplant cases on long-term follow-
up.31 After 2 years of CNI treatment, structural changes of tubular atrophy and interstitial fibrosis have
been documented in 75% to 90% of CNI-treated patients;24,38 and in all cases by 10 years posttransplant.
These pathologic renal changes exacerbate scarring and atrophy and contribute to loss of function.38
Among recipients of non-renal transplants, renal insufficiency and permanent renal failure are prevalent
among patients who receive continuous CNI therapy. The mechanism of CNI nephrotoxicity may be due
to an impact of calcineurin on the renal vasculature, manifested early as increased vascular resistance and
later by structural changes such as arteriolar nodular hyalinosis.24,38
A randomized prospective trial comparing CNI-free to CNI-based immunosuppression found that the
CNI-free group had better renal function, a diminished prevalence of atrophy and fibrosis, and down-
regulated expression of genes associated with fibrogenesis. The investigators in this trial concluded that
in terms of renal function and histologic integrity of renal allografts at 2 years posttransplant, superior
results were achieved with the CNI-free regimen (sirolimus plus MMF plus steroids) than with continuous
use of cyclosporine with MMF and steroids.24 However, this was a small study and requires confirmation.
The ongoing evolution of immunosuppressive therapy will include options for reducing these and other
non-immune toxicities of CNIs, such as posttransplant diabetes, hyperlipidemia, hypertension, and
anemia. Options include choosing more selective drugs, avoiding toxic combinations, and maintaining
vigilance for toxic effects and reacting to reduce them.1 Special efforts should be made to identify specific
patient populations who are at heightened risks; for example, the older obese patient at risk of diabetes.
Immunosuppressive Strategies for Specific Patient Populations

High-risk patients need to be identified prior to renal transplantation in order to implement the most
appropriate immunosuppressive regimens individualized for a given patient. These risks can be either
immunologic or medical, both of which require special management.
High Immunologic Risk

Patients who are younger and female, and those with African-American heritage have a higher
immunologic risk, which impacts treatment decisions. In addition, numerous transplant-related and
posttransplant variables elevate immunologic risk and affect the immunosuppressive strategy selected.
The graft-related risks include the use of grafts from deceased donors or from donors over 55 years of age.
The recipient risk factors include patients undergoing retransplant, or who have a high number of panel
reactive antibodies (PRAs) or positive B- and T-cell cross matches, and those who experience delayed
graft function posttransplant.39
Based on clinical observations, immunosuppressive protocols for African-American recipients, recipients

of secondary grafts, and recipients with high PRA levels should be tailored to be more intensive and given
in higher doses. Similarly, children’s immune systems are relatively aggressive, and they require higher-
dose immunosuppression compared with elderly patients. Patients requiring a more aggressive approach
may receive standard triple immunosuppressive therapy, including CNI, steroids, and antimetabolites.
Conversely, some patients may require lower levels of immunosuppression; individualized approaches
for those at specific risks may include steroid avoidance and CNI-elimination protocols. Some of the
specific strategies used for different patient populations are summarized in Table 5.
Table 5. Immunosuppressive Strategies for Specific Patient Populations
RISK FACTOR CONSIDERATIONS OR ALTERATIONS

TO IMMUNOTHERAPY
High Immunologic Risk
African Americans Standard triple immunosuppressive therapy, including CNI,

steroids, and antimetabolites
High Panel-Reactive Antibodies Standard triple immunosuppressive therapy, including CNI,

steroids, and antimetabolites
Positive Cross Match Induction antibody therapy with thymoglobulin, MMF, and
tacrolimus, plasmapheresis, rituximab, and IVIG
High Medical Risk
Diabetes Avoid steroids, CNIs, or sirolimus
Hyperlipidemia Avoid steroids, CNIs, or sirolimus
Vascular Disease Steroid withdrawal or avoidance
Older Donor CNI withdrawal or avoidance
Immunosuppressive protocols are tailored based on an individual patient’s immunologic and medical risks.
High Medical Risk

Renal transplant patients can either present with or develop a number of concomitant medical conditions
that will impact immunotherapy decisions. Beyond the first year posttransplant, infections and malignancy
account for approximately 10% to 12% of all deaths in renal graft recipients, while cardiovascular disease
accounts for approximately 30% of deaths.40 In fact, renal dysfunction itself is a cardiovascular risk factor,
given its association with hypertension, anemia, and lipid disorders. Similarly, diabetes, which is present
in 40% to 50% of renal transplant patients, is also an important clinical issue that contributes to the risk
of cardiovascular disease and hypertension. Older patients present with a number of concurrent medical
conditions, possible reduced performance status, and additional cardiovascular and circulatory issues.
Patients with more medical risk factors also require tailored immunosuppressive regimens; for example,
for patients with vascular disease, steroids may be withdrawn or avoided.
Issues of Chronic Rejection

Newer immunosuppressive therapy regimens in renal transplantation have reduced the incidence of
acute rejection. However, long-term graft survival has not improved. While 1-year graft survival rates now
exceed 90%, this falls to 65% to 70% at 5 years and to under 50% at 10 years.39 The clinical challenge is to
prevent and treat the long-term complications of renal transplantation, including suboptimal allograft
function, premature death, cardiovascular disease, and bone disease.
Several different causes can be identified for progressive loss of graft function. The development of
antibodies specific for donor MHC molecules is hypothesized as a factor contributing to chronic rejection.
Other factors include transplant glomerulopathy, recurrent or persistent renal disease, hypertension,
proteinuria, and infection, as well as CNI toxicity. Long-term graft survival may be negatively impacted by
such factors as older recipients and donors, prolonged wait times, by uncontrolled, late, silent rejections,
or by over-immunosuppression (leading to infections such as BK virus), or by a combination of these
factors. Changes in the immunosuppressive therapy may slow the progression of chronic allograft
nephropathy (CAN) if such changes are able to halt an ongoing immune response or, when CNI toxicity
is a significant contributor to the process, when CNIs are withdrawn. The mainstays of treatment for graft
preservation, however, include control of blood pressure, treatment of hyperlipidemia, and management
of diabetes.22 Specific clinical situations and posttransplant complications create a need to further
individualize therapy; some of these options are reviewed in Table 6.
Table 6: Modification of Immunosuppressive Therapies

POSTTRANSPLANT SITUATION POTENTIAL MANAGEMENT STRATEGIES
Chronic Rejection Blood pressure control, ACE-I, ARB
Deteriorating Graft Blood pressure control, ACE-I, ARB, Non-CNI

immunosuppressive regimen
Posttransplant Complications:
Diabetes Avoid / decrease steroids or CNIs
Hyperlipidemia Avoid / decrease steroids, CNIs, or sirolimus
CMV Infection Reduce dose intensity, decrease antiproliferative agents
BKV Nephritis Reduce dose intensity
EBV (PTLD) Reduce dose intensity, rituximab, chemotherapy
Specific graft situations and posttransplant complications create a need to further individualize therapy.
Optimizing outcomes requires long-term follow-up by knowledgeable caregivers who recognize and
react to change.1 Identifying progression of renal injury is best conducted using serial assessment of renal
function and histology, as graft injury is likely a dynamic process with a limited ability for recovery from
irreversible changes.41 A major challenge regarding long-term immunosuppression is the need for the
development of inexpensive and noninvasive tools to define and monitor responses along the spectrum
of immunity.40 For example, tests such as microarray analysis of gene expression in biopsy specimens
could be used to more precisely determine the immunologic basis of rejection in a particular patient. This
ability would change clinical management as well as the design of clinical trials.
New biologic agents, including monoclonal antibodies and fusion proteins, have been developed to
address many of these problems. These precisely targeted, selective immunosuppressive agents are not
immunogenic, have long half-lives and prolonged biologic effects allowing intermittent administration,
and have a favorable safety profile with minimal non-immune toxicities. These agents exploit normal
mechanisms of T-cell activation; for example, by inhibiting costimulatory signals to block T-cell activation.
They may replace the drugs associated with most of the long-term non-immune toxicities, such as the
corticosteroids and CNIs.
Investigational Immunosuppressive Agents in Clinical Trials in Renal

Transplantation
Research continues to focus not only on the development of new immunosuppressive agents, but also
on individualizing immunosuppression based on genotyping (or pharmacogenomics), on establishing
new biomarkers, and on gaining better understanding of immune regulation in transplant rejection. The
ultimate objective is to develop clinically applicable immunologic tolerance protocols. Several clinical
trials currently under way include protocols for extensive sample collection and analysis in order to
develop predictive biomarkers and incorporate them into clinical practice.
The adverse side effects of available immunosuppressive therapeutics are due in large part to their
nonselective mechanisms of action, as most clinically approved immunosuppressive maintenance
drugs target signaling pathways and/or enzymes with wide-ranging cellular distribution.42 To refine
immunosuppressive therapy, research is being focused on the development of more selective agents
with unique or novel mechanisms of action. A number of products in the pipeline for immunosuppressive
therapy, including both small molecules and biologics, are summarized in Table 7.
Table 7: Investigational Agents in Clinical Trials in Transplantation

AGENT CURRENT STATUS MECHANISM OF ACTION
Biologics
LEA29Y Bristol-Myers Squibb

(belatacept) One Phase 2 trial completed: Efficacy and Inhibition of T-cell costimulation
Safety as Part of a Quadruple Drug Regimen in pathway by blocking CD28, its
First Renal Transplant Recipients43; two Phase homologue CTLA4, and their ligands
3 trials ongoing: BENEFIT including recipients CD80 and CD86. Infusion.
of cadaveric or living donor kidneys and
BENEFIT-EXT including recipients of kidneys
from extended criteria donors44
Efalizumab Genentech Anti-CD11, a monoclonal antibody,

(anti-CD11a) Phase 2 trial in renal transplantation; blocking T-cell adhesion, trafficking, and
islet trial ongoing activation. Subcutaneous injection.
Non-Biologics / Small Molecules
FTY720 Novartis Induces rapid and reversible

(fingolimod) Phases 2 and 3 ongoing; sequestration of lymphocytes into
Completed two Phase 1 and two secondary lymphoid organs, thereby
Phase 2 trials45 preventing their migration to sites of
inflammation. Oral agent.45,46
FK778 Astellas Pharma US, Inc. Inhibits pyrimidine synthesis, blocking

Phase 2 ongoing proliferation of T and B cells. Oral agent.
CP-690,550 Pfizer Tyrosine kinase JAK3 inhibitor,

Phase 2 trial in kidney transplantation; inhibiting cytokine-induced signaling
Phase 2 trial in rheumatoid arthritis and proliferation. Oral agent.
A number of small molecule and biologic agents, designed to be used in short courses for induction, for
treatment of acute rejection, or for prolonged immunosuppression, are in clinical trials.
Figure 2. Sites of Action of Experimental Immunosuppressants
Belatacept
(LEA29Y)
CP-690,550
FK778
FTY720
The development of an immune response and full activation of T cells requires 2 distinct but synergistic signals.
The investigational agent belatacept (LEA29Y) inhibits signal 2 in the immunologic cascade. Other new agents
block or stimulate different receptors involved in the immune response: FTY720 is an S1P-R agonist; FK778 inhibits
pyrimidine synthesis; CP-690,550 blocks cytokine-induced proliferation at JAK3. Adapted from Halloran PF.1 © 2004
Massachusetts Medical Society. Used with permission.
Biologic Products
Belatacept (LEA29Y)
The development of an immune response and full activation of T cells requires 2 distinct but synergistic
signals, as demonstrated in Figure 2. The first signal, delivered through the T-cell antigen receptor, is
provided by the antigen itself and is responsible for the specificity of the immune response. The second,
or costimulatory, signal is not antigen-specific, and many T-cell molecules may serve as receptors for
costimulatory signals. The best characterized costimulatory pathway includes CD28, its homologue
CTLA4, and their B7 ligands CD80 and CD86.47, 48
Initial immunosuppressive drug development in this area focused on a recombinant fusion protein CTLA-
4-Ig, which has shown promise in the treatment of autoimmune diseases, such as rheumatoid arthritis.49
When tested in transplantation, this compound suppressed rejection and induced tolerance in rodents
but was less effective in primates. A rational design concept was used to create a modified version of
CTLA4-Ig, which produced LEA29Y (belatacept). The restricted distribution of belatacept’s target (the B7
ligands, CD80 and CD86) makes the drug highly immunoselective, thus allowing effective maintenance
immunosuppression with little morbidity or toxicity.47
Belatacept is designed for use as an agent of chronic maintenance immunosuppression because it

acts extracellularly on a specific target, which may limit systemic non-specific toxicities.47 This strategy
aims to protect the transplanted organ against acute and chronic rejection and to sustain better long-
term function, with more favorable effects on lipids, CV end points, and diabetes as compared with
corticosteroids and calcineurin inhibitors. Belatacept may also allow the minimization and/or avoidance
of those drugs.
Another important property of belatacept is its ability to inhibit T-cell-dependent antibody responses,
especially since the development of anti-donor antibodies contributes to late kidney transplant
deterioration, including some cases of transplant glomerulopathy, and constitutes a major barrier
to retransplantation.47 Belatacept may have the potential to reduce the incidence of sensitization in
recipients whose grafts do fail, and permit them to receive another transplant.
Figure 3. Trial Design and Consent/enroll

Belatacept Dosing Regimen
Identify ‘higher’ or ‘lower’ risk patient
‘Low-risk group’ ‘Higher risk group’

Patients receiving first renal transplant Patients receiving > 2nd renal transplant
History of panel-reactive antibodies <20% History of panel-reactive antibodies >20%
Low risk of AR (investigator determined) Higher risk of AR (investigator determined)
Randomize to treatment arm (1:1:1)

(High-risk patients limited to 10% of total number of patients)
LEA29Y LEA29Y CsA

‘More intensive’ regimen ‘Less intensive’ regimen (dosed as per protocol)
0—3 months 0—1 month Initial daily dose
10 mg/kg on Days 10 mg/kg on Days 1, 15, 29 7 ± 3 mg/kg
1, 5, 15, 29, 43, 57, 71, 85 2—3 months 0—1 month
4—6 months 10 mg/kg on Days 57, 85 Adjusted to 150-400 ng/mL
10 mg/kg on Days 113, 141, 169 4—12 months 1—12 months
7—12 months 5 mg/kg every 4 or 8 weeks Adjusted to 150-300 ng/mL
5 mg/kg every 4 or 8 weeks
A study of 218 renal transplant recipients compared 2 LEA29Y-based CNI-free maintenance regimens to a
cyclosporine-based regimen.47
A recently published randomized study of 218 renal transplant recipients compared 2 belatacept-based,
CNI-free maintenance regimens to a cyclosporine A-based maintenance regimen, as shown in Figure
3.43 This evaluation demonstrated that the belatacept-based CNI-free regimens were equivalent to the
cyclosporine-based regimen in terms of efficacy for acute rejection prophylaxis at 6 months’ follow-
up. The observed acute rejection rates of 6% to 7% with belatacept, mycophenolate, steroids, and
basiliximab in this trial compare favorably to reported rates of 8% to 17% in clinical trials of cyclosporine,
mycophenolate mofetil, steroids, and basiliximab, and are lower than the reported rate of 47% in a clinical
trial using mycophenolate mofetil, steroids, and basiliximab alone in low-risk transplant recipients.
At 12 months’ follow-up, patient cardiovascular metabolic profiles were favorable with belatacept
treatment as compared to cyclosporine therapy, and renal function, as measured by GFR, was significantly
higher in patients receiving the belatacept regimens. Measured GFR was approximately 9 to 13 mL/
minute higher in recipients of belatacept as compared with recipients of cyclosporine. Underscoring
the potential benefit of non-nephrotoxic therapy, differences in measured GFR favoring belatacept were
also observed in patients with impaired function with tubular atrophy and interstitial fibrosis (commonly
known as chronic allograft nephropathy).43 These early results suggest that belatacept will allow patients
to avoid the renal, cardiovascular, and metabolic toxicities of cyclosporine. Thus, costimulation blockade
offered by belatacept may offer a new, CNI-free paradigm for improving long-term outcomes in renal
transplant maintenance immunosuppression.
Anti-CD11a (efalizumab)
Efalizumab, already approved for use in the treatment of psoriasis, is a humanized IgG1 monoclonal
antibody that targets the CD11 chain of LFA1, which has been shown to block T-cell adhesion, trafficking,
and activation. In a Phase 1/2, open-label, dose-ranging, multicenter trial, efalizumab was administered
weekly for 12 weeks’ posttransplantation and used as chronic induction with a maintenance regimen of
full-dose or half-dose cyclosporine. At 3 months, 7.8% of patients had reversible rejection episodes and
at 6 months, 1 additional rejection episode occurred for a cumulative rejection rate of 10.4%. In a subset
of 10 patients who received the high-dose efalizumab (2 mg/kg) with full-dose cyclosporine, MMF, and
steroids, 3 patients developed posttransplant lymphoproliferative disease. The authors concluded that
while efalizumab appears to be an effective immunosuppressive agent, it should be used in a lower dose
(0.5 mg/kg) and with an immunosuppressive regimen that spares calcineurin inhibitors.44
Non-biologics/Small Molecules
FTY720 (fingolimod)
FTY720 is a synthetic structural analogue of myriocin, a metabolite of an ascomycete, with a novel
mechanism of action. FTY720 acts as an agonist of the S1P-R receptors, which in turn reduces the
recirculation of lymphocytes by sequestering them into secondary lymphoid organs without affecting
their function or properties. This reduces migration of effector cells to inflammatory tissues and graft
sites.45,46
In clinical trials to date, 2 Phase 2 trials in combination with cyclosporine have been completed with
FTY720, as well as 2 randomized, placebo-controlled Phase 1 trials in maintenance therapy.45,46,50 The
recently published first Phase 2A study of FTY720 in de novo renal transplantation47 found that at a dose
of 2.5 mg, FTY720 was as effective as MMF in combination with cyclosporine for the prevention of acute
rejection after renal transplantation, with the incidence of the composite end point of biopsy-confirmed
acute rejection, graft loss, or death to be 14.6% at Month 3 in these FTY720-treated patients. In addition,
FTY720 was observed to be well tolerated and not associated with the side effects commonly observed
with immunosuppressive therapies—the main difference in tolerability being a transient asymptomatic
bradycardia and an expected decrease in peripheral lymphocytes, which was reversible after treatment
discontinuation.44-46 The possible occurrence of retinal edema due to FTY720 is being investigated.46
FK778
FK778 is a synthetic malononitrilamide, derived from leflunomide, with both immunosuppressive and
anti-proliferative effects. FK778 inhibits both T-cell and B-cell functions by blocking pyrimidine synthesis.
Single- and repeat-dose Phase 1 studies have indicated oral bioavailability and no dose-limiting effects
at the levels tested. In a double-blind randomized Phase 2 study, 149 patients were given either
high- or low-level FK778 or placebo combined with tacrolimus and steroids. In this evaluation, both
active treatment arms showed efficacy of FK778 to reduce acute graft rejection. Anemia was the most
commonly reported adverse event and was dose-related. Currently, additional clinical studies of FK778
are under way in Europe and in the United States in liver and renal transplantation patients.51,52 Data from
preclinical and clinical trials to date indicate the potential for improvement in transplant outcomes based
on the ability of FK778 to prevent acute and chronic allograft rejection in organ transplant models, its
favorable myocardial profile, and its potential anti-viral activity.52 However, its relatively narrow window
between efficacy and toxicity has been a concern.53
CP-690,550
The tyrosine kinase JAK3 is required for the transduction of immune cell proliferative signals, and
inhibition of this signaling provides an opportunity to disrupt proliferation. JAK3, unlike other members
of this family, is expressed at high levels in natural killer cells and thymocytes and is inducible in T cells, B
cells, and myeloid cells but is not expressed in resting T cells.
In preclinical models, the JAK3 inhibitor CP-690,550 has resulted in strong immunosuppression and
significant improvement in allograft survival. Of note, this agent has activity beyond JAK3; it also affects
JAK2,54 which is required for signaling by erythropoietin receptors, thus creating the potential for anemia.
It may also be capable of over-immunosuppression similar to that seen with currently used clinical
immunosuppressants. The JAK3 inhibitor CP-690,550 is in Phase 2 trials.
Other Investigational Immunosuppressive Therapies

A number of additional agents already in use or under investigation for other indications also have
potential for use in renal transplantation. For example, 2 monoclonal antibodies, an anti-CD40 antibody
being investigated in Phase 1 trials for the treatment of non-Hodgkin’s lymphoma (Chiron/Xoma) and
an anti-IL-15 antibody being developed for the treatment of rheumatoid arthritis (Amgen) are potential
candidates for use in transplantation, as well. In addition, Thios Pharmaceuticals has planned to move TSI
(rPSGL-Ig), an agent previously evaluated in re-vascularization, into Phase 2 trials to prevent delayed graft
function (DGF) in renal transplantation.
Pharmacogenomics
In the future, pharmacogenomics may provide the information necessary to tailor individualized
immunosuppressive regimens, based on genotyping. This may prove especially relevant for the use of
drugs with high toxicities and narrow therapeutic indexes.55,56 For example, the CYP3A (cytochrome
P-450-3A) allele CYP3A5*1 is associated with increased CYP3A5 levels and is present in 70% to 80% of
African Americans but in only 5% to 10% of whites.57 African-American patients with this genotype may
metabolize drugs faster and require higher doses to achieve target blood concentrations than other
ethnic groups. There is also significant variability within ethnic groups, which makes the planning of
initial dosing difficult for drugs with a narrow therapeutic range.57 For example, CYP3A5 genotyping
can predict which patients may experience a delayed time to reach target levels of tacrolimus, which
is associated with earlier transplant rejection. Thus, genotyping for this allele could help reduce graft
rejection in the high-risk group of African-American patients.58
Assessing the Efficacy of Immunosuppressive Strategies

The evolution of immunosuppressive therapy in renal transplantation has resulted in a steady decline
in acute rejection rates and substantial improvements in short-term renal transplant survival.59 This
has created a paradox for investigators attempting to assess the efficacy of newer immunosuppressive
agents, as these traditional end points are becoming impractical due to fewer such events. Innovative
approaches for assessing the efficacy of new strategies are emerging in which alternative surrogate
markers, such as renal function, histologic findings, and immunologic markers in urine are being used or
considered to assess outcomes.59
As shown in Figure 4, benefits of agents developed in the 1980s, such as cyclosporine, were detected by
assessment of 1-year graft survival. In the 1990s, evaluation of novel immunosuppressants shifted from
graft failure to acute rejection, and agents such as MMF, tacrolimus, and sirolimus were evaluated on end
points surrounding 1-year acute rejection rates.59 As immunosuppressive therapies continue to evolve,
surrogate markers may play an increasingly important role as study end points.
Figure 4: Timeline and potential future end points in renal transplantation adapted from
Hariharan et al., 200359
ORIGINAL END POINTS:
Graft Loss
Death
Acute Rejection (Bx proven)
Rx Failure
RECENT ALTERNATIVE END POINTS:
Renal Function
Histology
Immune Markers
Composite End Point
FUTURE END POINTS:
MEASURED GFR
AGENTS AZATHIOPRINE, TACROLIMUS BELATACEPT

PREDNISONE CsA MMF SIROLIMUS
YEAR 1970 1975 1980 1985 1990 1995 2000 2005 FUTURE
Earlier agents were assessed based on 1-year graft survival. Subsequently, evaluation of immunosuppressants
shifted from graft failure to acute rejection, and most recently to end points surrounding 1-year acute rejection
rates. Agents currently in clinical trials, such as belatacept, rely on objective assessments of renal function such
as measured GFR .
Posttransplantation Monitoring
The identification of markers that, within a few months’ posttransplant, could predict long-term survival
would permit individualization of immunosuppressive therapy. These end points fall into 3 categories:
clinical, histologic, and immunologic, and should be combined with strategic monitoring of the
recipient’s general health.59
Clinical End Points

Serum creatinine – Short-term postttransplant renal function has been correlated with long-term
survival, and renal function can be estimated by the serum creatinine level. Serum creatinine at 6 and 12
months after renal transplantation has been shown to correlate with long-term graft survival.59
Calculated creatinine clearance – GFR is considered the best overall index of renal function in health
and disease. Because GFR is difficult to measure in clinical practice, most clinicians estimate the GFR from
the serum creatinine concentration. However, the accuracy of this estimate is limited because the serum
creatinine concentration is affected by factors other than creatinine filtration such as age, gender, and
body size. To circumvent these limitations, several formulas have been developed to estimate creatinine
clearance from serum creatinine concentration, and including age, sex, and body size variables. However,
these equations based on measured or estimated creatinine clearance systematically overestimate
GFR.60
Measured Glomerular Filtration Rate (GFR) - GFR is recognized as the more accurate assessment
of renal function and, despite the difficulty of obtaining this measure, it is emerging as an important
endpoint in clinical trials.41
Histologic End Points

Renal histologic findings can be observed before renal dysfunction, and as a result, this assessment has
become an attractive short-term end point. Until recently, renal histologic evaluation was practical only in
patients experiencing renal dysfunction.59 However, scheduled protocol renal biopsies, which can detect
silent tubulitis, have also recently been performed in recipients with stable renal function.61 However,
the significance of silent tubulitis is not clear. Although the additional costs associated with detecting
silent acute rejection and logistic issues present challenges to use of this end point, future studies should
consider incorporation of this evaluation.59
Non-specific atrophy and fibrosis – Some kidneys are lost with a slowly progressive but non-specific
phenotype, where extensive tubular atrophy and interstitial fibrosis occur. In effect, this represents loss of
nephrons. In some cases, this is related to a specific disease entity, such as recurrent glomerulonephritis. In
others, it is attributable to transplant glomerulopathy arising from alloantibody injury, and in some cases,
no specific disease entity can be identified, and the nephron loss probably reflects the cumulative effect
of multiple insults—donor age, brain death, ischemic damage at the time of transplant, T-cell- mediated
rejection, and toxicity from drugs. In such cases, the term “chronic allograft nephropathy” (CAN) has been
applied. The heterogeneity and non-specificity of CAN make it unsuitable as an end point to evaluate
new immunosuppressive agents. However, CNIs do produce tubular atrophy and interstitial fibrosis,
and protocols that avoid CNIs can develop objective assessments of these changes. Quantification is
facilitated by the use of indices such as the Banff Score Index.62
Immunologic Markers
Identification of reliable immunologic markers that could be detected before the development of
renal dysfunction would be a valuable addition to posttransplant monitoring.59 Potential options are as
follows:
Anti-HLA antibodies – The detection of anti-donor antibodies early after transplantation has been
correlated with immunologic injury and renal dysfunction, making this a potential marker to be evaluated
for measuring transplant outcome.59
T-cell responses to donor antigen – Measuring T-cell reactivity to donor cells or HLA peptides has been
successfully correlated with risks of acute and chronic rejection.63 These studies are also important to
incorporate in future clinical trials to minimize or withdraw immunosuppression.
Tissue, blood, and urine immune molecules – The immunologic acceptance of a graft can also
be evaluated using molecular markers of rejection/acceptance in blood, tissue, and urine cytokines.
Although the reproducibility and availability of such markers in clinical trials and practice remains a
challenge, they are attractive future end points due to their non-invasive nature.59
General Health
Screening for potential toxicities of immunodeficiency, including infections such as CMV, EBV,
Pneumocystis Carinii, BK virus, and malignancies (most commonly lymphomas and skin cancers), requires
routine posttransplant patient monitoring. Similarly, non-immune morbidities, such as cardiovascular
risk factors (hypertension, diabetes, and hyperlipidemia), are relevant events that adversely affect long-
term outcomes. As the rates of acute rejection and late graft failure decline, morbidity and assessments
of the recipient’s general health are becoming increasingly relevant to clinical practice.59
Immunosuppressive Therapy Compliance

Another issue in immunosuppressive therapy in renal transplantation is non-compliance with the
prescribed posttransplant medication. Risk factors for non-compliance include direct side effects
(cosmetic and others), inconvenient or burdensome regimens, financial concerns, the complexity of
the regimen, and the “pill burden” felt by some patients. Non-compliance models have found that age,
occupation, time since transplant, and certain medication-related beliefs to be predictive of the likelihood
of compliance. Donor type and history of diabetes and of infection also may affect compliance.64
Immunosuppressive regimens associated with improved compliance may improve long-term outcomes.
Parenteral administration of protein drugs could have advantages: supervised administration in clinics
could eliminate some forms of non-compliance. In addition, lack of side effects may make these drugs
more acceptable.
High-tech Immune Monitoring

A major challenge remains in the development of inexpensive and noninvasive tools to define and
monitor responses along the spectrum of immunity that ultimately lead to immune tolerance.65
Specifically, new biomarkers that allow early diagnosis of rejection at the molecular level must be
developed to enable treatment to be individualized rather than using set immunosuppressive protocols.
Furthermore, developing assays that define the phenotype of a potentially tolerant recipient is critical
to the success of immunosuppressive withdrawal. These assays will include T-cell alloreactivity assays,
humoral immune responses, and molecular profiling of intragraft events.
Immune Tolerance Strategies

In a sense, all transplantation is based on a form of adaptive tolerance, because the persistence of the
organ in the presence of immunosuppressive drugs induces partial unresponsiveness in most patients.
Thus, immunosuppressive drugs really only prevent graft injury for long enough that adaptations can
occur. Lower doses of immunosuppressants are then needed for life in most persons to stabilize these
adaptations.
Immunologic tolerance is defined as unresponsiveness to a specific antigen in an immunocompetent

person, usually induced by exposure to the antigen under special circumstances. In other words,
immunologic tolerance of the antigens of the graft would be achieved while retaining immune responses
against all other antigens. The hope is that patients can achieve “lifelong tolerance” to the transplanted
organ via manipulation of the recipient’s immunity during the very first weeks after transplantation. In
practice, proposed tolerance strategies often use conventional immunosuppressive therapies.66
To pursue this objective, the National Institutes of Health Immune Tolerance Network (www.immunetol-
erance.org) was established in 1999. Recently, various pilot clinical trials in transplantation, autoimmunity,
and allergies—designed to explore the biology of tolerance in humans—have been approved through
this venue, and these studies may shed light on how to achieve the goal of immune tolerance.66, 67
At present, however, no practical therapies are ready for the clinic, and it is by no means clear that
they ever will be. The human immune response is complex, and human genetic diversity is extensive.
Even the tolerance strategies that do exist make extensive use of immunosuppressive drugs. For the
present, immunosuppression is here to stay. However, withdrawal of immunosuppressive drugs may be

acceptable in selected patients who are well adapted to their graft, if assays to detect T-cell responses
and alloantibody responses at an early treatable stage could be developed.
Successful allogeneic stem cell transplantation (bone marrow transplantation) can achieve true tolerance.
However, this is a difficult and dangerous treatment across HLA differences, and it is not yet ready for
widespread use as a strategy to prepare patients for organ transplantation.
Conclusion
Advances in the understanding of the refined details of immunologic mechanisms have fostered
the development of new biologic agents that selectively intervene in this complex cascade. New
agents with favorable safety profiles and targeted mechanisms of inhibition reduce the non-immune
toxicities associated with earlier drugs and contribute to improved acute and chronic graft survival. As
a result of selective targeting, such as blocking costimulatory signals, these agents show a promising
ability to achieve a balance between immunosuppression and its complications. These agents are not
immunogenic, have long half-lives and prolonged biologic effects, allowing intermittent administration,
and have minimal non-immune toxicity. The equivalent potency with greater specificity and selectivity
of the new biologic agents render them less toxic than earlier immunosuppressive drugs. This evolution
toward individualized immunomodulation offers hope for continued improvements in acute and chronic
rejection. For patients who endure long waiting periods before transplantation, new agents promise to
improve their quality of life and protect the survival of graft and patient.
References
1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715-2729.
2. 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry
of Transplant Recipients: Transplant Data 1994-2003. Department of Health and Human Services, Health
Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD;
United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann
Arbor, MI.
3. Shapiro R, et al. Immunosuppression: evolution in practice and trends, 1993-2003. Am J Transplant. 2005;5(pt
2):874-886.
4. O’Malley BW. Mechanism of action of steroid hormones. N Engl J Med. 1971;284:370-388.
5. Thorn G. Clinical considerations in the use of corticosteroids. N Engl J Med. 1966;274:775-781.
6. Skeel RT. Handbook of Cancer Chemotherapy. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
7. Azasan® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
Healthcare; 2004:22,966.
8. Ahmed A, Mory R. Azathioprine. Int J Dermatol. 1981;20:461-467.
9. CellCept® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
Healthcare; 2004:2855.
10. Prograf® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
11. O’Keefe SJ, Tamura J, Kincaid RL. FK-506 and CsA-Sensitive Activation of the Interleukin-2 Promoter by
calcineurin. Nature. 1992;357(6380):692-694.
12. Rapamune® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
13. Dumont FJ. Everolimus. Curr Opin Investig Drugs. 2001;2:1220-1234.
14. Thymoglobulin® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
15. Campath® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
16. Rituxan® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
17. Orthoclone® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
18. Simulect® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
19. Zenapax® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
20. Ferrajoli A, et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer. 2003;98(4):
773-778.
21. Meier-Kreisch HU, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute
rejection rates over the most recent era. Am J Transplant. 2005;4:378-383.
22. Pellegrino B. Immunosuppression. eMedicine [serial online]. April 22, 2004;doc 1.
23. Birkeland SA. Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100
consecutive patients. Transplantation. 2001;71:1089-1090.
24. Flechner SM, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal
structure and function at two years. Am J Transplant. 2004;4(4):1776-1785.
25. Groth CG, et al. Sirolimus (rapamycin) based therapy in human renal transplantation: similar efficacy
and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.
Transplantation. 1999;67:1036-1042.
26. Oberbauer R, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal
allograft survival and renal function at 48 months after transplantation. Transplant Int. 2005;18(1):1422-1428.
27. Knechtle SJ, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a
pilot study. Am J Transplant. 2003;3:722-730.
28. Zhang PL, et al. Monocyte-mediated acute renal rejection after combined treatment with preoperative
Campath-1H (alemtuzumab) and postoperative immunosuppression. Ann Clin Lab Sci. 2004;34:209-213.
29. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the
management of organ transplantation. Drugs. 2000;59:323-389.
30. Cytoxan® Prescribing Information. Bristol-Myers Squibb, 2004.
31. Mayer AD, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the
prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group.
32. Sandimmune® Prescribing Information. In: Physicians’ Desk Reference 2005. 59th ed. Montvale, NJ: Thomson
33. Brennan DC, et al. A randomized double-blinded comparison of thymoglobulin versus Atgam for induction
immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999;67:1011-1018.
34. Swinnen LJ, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the
monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. 1990;323(25):1723-1728.
35. McAlister VC, et al. Sirolimus-tacrolimus combination immunosuppression. Lancet. 2000;355(9201):376-377.
36. Gonwa T, et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in
kidney transplantation: results at 6 months. Transplantation. 2003;75:1213-1220.
37. Johnson RWG, et al. Sirolimus allows early cyclosporine withdrawal in renal function and lower blood pressure.
38. Nankivell BJ, et al. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology.
Transplantation. 2004;78(4):557-565.
39. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after
renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342(9):605-612.
40. Sayegh MH, Carpenter CB. Transplantation 50 years later - progress, challenges, and promises. N Engl J Med.
2004;351(26):2761-2766.
41. Abramowicz D, et al. Cyclosporine Withdrawal Study Group. Cyclosporine withdrawal from a mycophenolate
mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized,
controlled study.Transplantation. 2002 Dec 27;74(12):1725-34.
42. Suthanthiran M, Strom TB. Immunobiology and immunopharmacology of organ allograft rejection. J Clin
Immunol. 1995;15(4):161-171.
43. Vincenti F, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353(8):
770-781.
44. Vincenti F. What’s in the pipeline? New immunosuppressive drugs in transplantation. Am J Transplant. 2002;2:
898-903.
45. Zemann B, et al. Sphingosine kinase type 2 is essential for lymphodepletion induced by the immunomod-
ulatory drug FTY720. Blood. 2005;[Epub ahead of print].
46. Dragun D, Fritxche L, Boehler T, Peters H, Budde K, Neumayer HH. FTY720: Early clinical experience. Transplant
Proc. 2004;36(supple 2s):544s-548s.
47. Larsen CP, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent
immunosuppressive properties. Am J Transplant. 2005;5:443-453.
48. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med.
1998;338(25):1813-1821.
49. Kremer JM, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion
protein CTLA4Ig. N Engl J Med. 2003;349(20):1907-1915.
50. Tedesco-Silva H, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A
study in de novo renal transplantation. Transplantation. 2005;79(1553):1560.
51. First RM, Fitzsimmons WE. New drugs to improve transplant outcomes. Transplantation. 2004;77(9):S88-S92.
52. Fitzsimmons WE, First RM. FK778, a synthetic malononitrilamide. Yonsei Med J. 2004;45(6):1132-1135.
53. Fawcett J, Johnson DW. FK778: a powerful immunosuppressive, but will it really be good for you?
54. Borie DC, O’Shea JJ, Changelian PS. Jak3 inhibition, a viable new modality of immunosuppression for solid
organ transplants. Trends Mol Med. 2004;10:532-539.
55. Fredericks S, Holt DW, MacPhee IA. The pharmacogenetics of immunosuppression for organ transplantation:
a route to individualization of drug administration. Am J Pharmacogenomics. 2003;3:291-301.
56. Cattaneo C, Perico N, Remuzzi G. From pharmacokinetics to pharmacogenomics: a new approach to tailor
immunosuppressive therapy. Am J Transplant. 2002;4:299-310.
57. MacPhee IA, et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome
p4503A5 and P-glycoprotein correlate with dose requirements. Transplantation. 2002;74(1486):1489.
58. MacPhee IA, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations
after kidney transplantation. Am J Transplant. 2004;4:914-919.
59. Hariharan S, McBride MA, Cohen EP. Evolution of endpoints for renal transplant outcome. Am J Transplant.
2003;3:933-941.
60. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular
filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study
Group. Ann Intern Med. 1999;130:461-70.
61. Gloor JM, et al. Subclinical rejection in tacrolimus-treated renal transplant recipients. Transplantation. 2002;73:
1965-1968.
62. Racusen L, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713-723.
63. Salama AD, et al. Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol. 2003;14(6):
1706-1708.
64. Greenstein S, Siegal B. Compliance and noncompliance in patients with a functioning renal transplant:
a multicenter study. Transplantation. 1998; 66:1718-1726.
65. Li B, et al. Noninvasive diagnosis of renal allograft rejection by measurement of messenger RNA for perforin
and granzyme B in urine. N Engl J Med. 2001;344:947-954.
66. Bluestone JA, Matthews JB, Krensky AM. The immune tolerance network: the “holy grail” comes to the clinic.
J Am Soc Nephrol. 2000;11:2141-2146.
Notes
Post-Test
ACCELMED® Monograph
The Evolution of Immunosuppression in Renal Transplantation
1) The overall objective of successful 6) Some strategies to reduce non-immune

immunosuppressive therapy is: toxicities of current immunosuppressive
a. immunosuppression: preventing immune therapy include:
rejection of the allograft a. The growing use of corticosteroid-sparing
b. maintaining immunocompetence: regimens
minimizing the risk of undesired b. The growing use of CNI-sparing regimens
consequences of immunosuppression such c. The anticipation of diabetes risks and
as certain infections and cancers choice of less diabetogenic agents
c. maintaining a balance of A and B d. A shift away from the use of cyclosporine
d. neither A nor B plus sirolimus
e. All of the above
2) Three different elements in immunosuppressive
therapy in renal transplantation are: 7) Basic toxicity problems with current
a. Antibody induction therapy, maintenance immunosuppressive strategies are:
immunosuppression, treatment of graft a. The growing use of corticosteroid-
rejection sparing regimens
b. Antibody induction therapy, graft b. The growing use of CNI-sparing regimens
enhancement, maintenance c. Immune and non-immune toxicities of
immunosuppression common immunosuppressive regimens
c. Primary and secondary maintenance d. A shift away from muromonab-CD3
immunosuppression, treatment of graft and equine antithymocyte globulin to
rejection rabbit antithymocyte globulin
d. Antibody induction therapy, management
of CNI toxicity, maintenance 8) An investigational agent in clinical trials in
immunosuppression transplantation immunosuppression that
e. None of the above provides selective costimulation blockade is:
a. XL-880
3) Agents in the class of calcineurin inhibitors are: b. sorafenib
a. Muromonab-CD3 c. efalizumab
b. Mycophenolate mofetil (MMF) d. belatacept
c. Cyclosporine and tacrolimus e. None of the above
d. Rituximab
e. None of the above 9) Potential surrogate markers for
immunosuppressive therapy in renal
4) Antibody induction immunosuppressive transplantation include:
therapy in current use includes: a. Posttransplant monitoring of serum
a. Polyclonal anti-lymphocyte antibodies and creatinine and creatinine clearance
anti-CD3 monoclonal antibodies b. Glomerular filtration rate (GFR)
b. Daclizumab or basiliximab c. Cystatin C
c. Alemtuzumab d. Renal histologic end points
d. A and B e. All of the above
e. A, B, and C
10) Immune tolerance strategies
5) Maintenance immunosuppressive therapy may a. Have been proven successful and are in
include: routine clinical practice
a. Cyclosporine or tacrolimus b. Exhibit significant drug-related toxicities
b. Adjunctive maintenance therapy with c. Have started pilot trials through the
glucocorticosteroids plus mycophenolate National Institutes of Health Immune
mofetil Tolerance Network
c. Adjunctive maintenance therapy with d. None of the above
azathioprine or sirolimus e. All of the above
d. All of the above
e. None of the above
Post-Test
Project ID: 3092 ES 16
Postgraduate Institute for Medicine (PIM) respects and appreciates your opinions. To assist us in evaluating the effectiveness
of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this
evaluation form. You must complete this evaluation form to receive acknowledgment of participation for this activity.
PLEASE ANSWER THE FOLLOWING QUESTIONS BY CIRCLING THE APPROPRIATE RATING:

5 = Outstanding 4 = Good 3 = Satisfactory 2 = Fair 1 = Poor
Extent to Which Program Activities Met the Identified Objectives

Upon completion of this activity, participants should be better able to:
• Define the key issues in immunosuppression in transplantation 5 4 3 2 1

• Describe the evolution and successes of immunosuppression over the past 10 years 5 4 3 2 1
• Discuss the unmet needs in immunosuppression for transplantation 5 4 3 2 1
• Identify the potential of selective immunosuppression candidates in development 5 4 3 2 1
to meet these needs
OVERALL EFFECTIVENESS OF THE ACTIVITY

The content presented:
Was timely and will influence how I practice 5 4 3 2 1
Will assist me in improving patient care 5 4 3 2 1
Fulfilled my educational needs 5 4 3 2 1
Avoided commercial bias or influence 5 4 3 2 1
IMPACT OF THE ACTIVITY

The information presented:
(check all that apply)
Reinforced my current practice/treatment habits Will improve my practice/patient outcomes
Provided new ideas or information I expect to use Enhanced my current knowledge base
Will the information presented cause you to make any changes in your practice?
Yes No
If yes, please describe any change(s) you plan to make in your practice as a result of this activity:
How committed are you to making these changes? 5 (Very committed) 4 3 2 1 (Not at all committed)
FUTURE ACTIVITIES
Do you feel future activities on this subject matter are necessary and/or important to your practice?
Yes No
Please list any other topics that would be of interest to you for future educational activities:
Post-Test
Project ID: 3092 ES 16
FOLLOW-UP
As part of our ongoing continuous quality-improvement effort, we conduct post-activity follow-up surveys to assess the impact of
our educational interventions on professional practice. Please indicate your willingness to participate in such a survey:
Yes, I would be interested in participating in a follow-up survey
No, I’m not interested in participating in a follow-up survey
Additional comments about this activity:
If you wish to receive acknowledgment of participation for this activity, please complete the post-test by selecting the best
answer to each question, complete this evaluation verification of participation, and fax to: (303) 790-4876.
POST-TEST ANSWER KEY (Insert Answer)
1 2 3 4 5 6 7 8 9 10
REQUEST FOR CREDIT
Name Degree
Organization Specialty
Address
City, State, Zip
Telephone Fax E-Mail
FOR PHYSICIANS ONLY

I certify my actual time spent to complete this educational activity to be:
I participated in the entire activity and claim 1.25 credits (physician).
I participated in only part of the activity and claim _____ credits.
Signature Date Completed
To receive credit for this program, please mail or fax the completed Post-test Answer Key and Evaluation Form to:
Postgraduate Institute for Medicine
367 Inverness Parkway, Suite 215
Englewood, CO 80112
Fax: (303) 790-4876

Evolution of Immunosuppression in Renal Transplantation

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Evolution of Immunosuppression in Renal Transplantation

Enviado por

Direitos autorais:

Formatos disponíveis

THE EVOLUTION OF Immunosuppression in Renal Transplantation 1

Posttransplant immunosuppression regimens involve a balancing act. The therapeutic goal—prevention

Philip F. Halloran, MD, PhD, OC

Thomas C. Pearson, MD, DPhil

Disclosure of Conflicts of Interest

Name of Faculty or Presenter Reported Financial Relationship

Name of Faculty or Presenter Reported Financial Relationship

Physician Continuing Medical Education

Disclosure of Unlabeled Use

Postgraduate Institute for Medicine

The immune response to a kidney transplant

Challenges and the Future of Immunosuppression

A Decade of Evolution and Progressive Successes

II. Small Molecule Drugs

1. Inhibitors of nucleotide syntheses

antithymocyte globulin Atgam® Prophylaxis and

rituximab Rituxan® Treatment of relapsed Rituximab is a chimeric (murine/human) monoclonal antibody

regulates an early step in the activation of differentiation. It is a

Immunosuppressive Strategies in Current Practice

The direction of development in immunosuppression is toward the long-term use of non-lymphocyte–

Table 2: Potential Immunosuppressive Drug Protocols

TREATMENT OF ACUTE REJECTION

Optimizing Immunosuppressive Regimens

Antibody Induction Therapy

Table 3. Immunosuppressive Agents for Treating Acute Graft Rejections

T-cell-Mediated Rejection Steroids

Antibody-Mediated Rejection Steroids

Therapy of the acute rejection is tailored toward the type of rejection.

Strategies to Refine Immunosuppressive Therapy

Calcineurin Inhibitor-Sparing Regimens

Remaining Issues and Unmet Needs in Immunosuppression in

Toxicities of Immunosuppressive Therapy

AGENT TOXICITIES MONITORING CONSIDERATIONS1

II. Small Molecule Drugs

1. Inhibitors of nucleotide syntheses

cyclophosphamide Leukopenia, thrombocytopenia, alopecia, skin rashes, nausea, vomiting,

severe bone marrow depression.7

a. Calcineurin Inhibitors As a class, CNIs exhibit dose-dependent nephrotoxicity31

antithymocyte Cytokine-release syndrome (fever, chills, hypotension),

alemtuzumab Mild cytokine-release syndrome, neutropenia, anemia, idiosyncratic

rituximab Infusion reactions, uncommon hypersensitivity reactions1,67

basiliximab, GI disturbances, uncommon hypersensitivity reactions1,18,19 No monitoring required1

Calcineurin Inhibitor (CNI) Nephrotoxicity

Immunosuppressive Strategies for Specific Patient Populations

High Immunologic Risk

Based on clinical observations, immunosuppressive protocols for African-American recipients, recipients

Table 5. Immunosuppressive Strategies for Specific Patient Populations

RISK FACTOR CONSIDERATIONS OR ALTERATIONS

African Americans Standard triple immunosuppressive therapy, including CNI,

High Panel-Reactive Antibodies Standard triple immunosuppressive therapy, including CNI,

High Medical Risk

Diabetes Avoid steroids, CNIs, or sirolimus

Hyperlipidemia Avoid steroids, CNIs, or sirolimus

Vascular Disease Steroid withdrawal or avoidance

Older Donor CNI withdrawal or avoidance

High Medical Risk

Issues of Chronic Rejection

Table 6: Modification of Immunosuppressive Therapies

Deteriorating Graft Blood pressure control, ACE-I, ARB, Non-CNI

Investigational Immunosuppressive Agents in Clinical Trials in Renal

Table 7: Investigational Agents in Clinical Trials in Transplantation

LEA29Y Bristol-Myers Squibb

Efalizumab Genentech Anti-CD11, a monoclonal antibody,

Non-Biologics / Small Molecules