 Immune System Overview

 Current Treatment Techniques

◦ Immunosuppressants

◦ Immunostimulants

◦ Immunization

Immune System Overview

 Two types of Immune Response

 Non-specific

 Barriers

 Inflammation

 Phagocytes

 Specific (Adaptive) Response

 Lymphocytes

 B Lymphocytes (B Cells)

 Produced in bone marrow

 Humoral Response

 T Lymphocytes (T Cells)

 Start in bone marrow, but mature in Thymus

 Cell Mediated Response

 Helper T Cells

 Cytotoxic T Cells

 Once activated, T Cells and B Cells differentiate and divide

 Causes cytokine and lymphokine release

Three-signal model of T-cell Activation

T- Lymphocyte Activation

 Three signals involved in T-cell activation

 Signal 1: antigen specific; signal 2: costimulatory signal

 Signal 1 and 2  activate three signal transduction pathways:

- Calcium-calcineurin pathway

- RAS – MAP kinase pathway

- PKC – NF-kB pathway

 Induces cytokine genes and T-cell activation genes

 IL-2 activates TOR (signal 3) and promotes T-cell proliferation

 Purines synthesis is necessary for B and T cell proliferation

 Proliferation and differentiation  effector T cells >>

Immunological Diseases

Autoimmune Diseases

 Loss of self-tolerance leads to production of antibodies or T cells that react against one’s own
antigens.

 Immune system response to self antigens causes damage to organs.

 Three types of autoimmune disorders:

 Cytotoxic (Type II reactions)

 Immune complex (Type III reactions)

 Cell-mediated (Type IV reactions)

Treatment Strategies

 Immunosuppression – involves downregulating immune system activity

 Immunostimulation – involves upregulating immune system activity

 Immunization – active or passive

Drugs Affecting the Immunological System

 Immunosuppressants

 Antirejection, anticancer, corticosteroid drugs

 Immunomodulating agents

 Serums

 Vaccines

What is Immunosuppresive Drugs ?

 Any of a variety of substances used to prevent production of antibodies.

 They are commonly used to prevent rejection by a recipient's body of an organ transplanted
from a donor.

 Immunosuppressive drug has one meaning: a drug that lowers the body's normal immune
response.

Effects of Immunosuppressive drugs:

- therapeutic effect (suppressing rejection),

- undesired consequences of immunodeficiency

- nonimmune toxicity to other tissues.

Side-Effects of Immunosuppressants

1) General Side Effect: Immunosuppression

• Reactivation of latent viral infections (e.g. herpes, varicella, CMV, PML)

• Bacterial and fungal infections

• Bone marrow suppression

• Increased risk of cancer

• Specific Side Effects:

• Nephrotoxicity of the calcineurin inhibitors

• Metabolic changes with steroids

• “cytokine release syndrome”

Classification of immunosuppressive drugs: Small-molecule drugs

 Immunophilin-binding drugs

- Calcineurin inhibitors:

- Cyclophilin-binding drugs: cyclosporine, ISA(TX)247

- FKBP12-binding drugs: tacrolimus, modified release tacrolimus

- TORIs: sirolimus, everolimus

 Inhibitors of nucleotide synthesis

- Purine synthesis (IMPDH) inhibitors:

- Mycophenolate mofetil

- Enteric-coated mycophenolic acid

- Pyrimidine synthesis (DHODH) inhibitors

- Leflunomide

- FK778

 Antimetabolites: azathioprine

 Sphingosine-1-phosphate–receptor antagonists: FTY720

Classification of immunosuppressive drugs: Protein drugs

Depleting antibodies (against T cells, B cells, or both)

 Polyclonal ab: horse or rabbit antithymocyte globulin

 Mouse monoclonal anti-CD3 ab (muromonab-CD3)

 Humanized monoclonal anti-CD52 ab (alemtuzumab)

 B-cell–depleting monoclonal anti-CD20 ab (rituximab)

Nondepleting antibodies and fusion proteins

 Humanized or chimeric monoclonal anti-CD25 ab (daclizumab, basiliximab)

 Fusion protein with natural binding properties: CTLA-4–Ig (LEA29Y)

Intravenous immune globulin

Other Classification

Chemical Immunosuppression

Purine synthesis inhibitor:

- Azathioprine

Mycophenolate mofetil

Calcineurin inhibitor

- Cyclosporine

- Tacrolimus

Target of rapamycin inhibitor

- Sirolimus

Corticosteroids

Biological Immunosuppression

Polyclonal antibodies

- Thymoglobulin

- Atgam

Monoclonal antibodies

- Blocks Il-2 receptor

Daclizumab

Basiliximab

OKT3 (anti-CD3)

Cyclosporine

 cyclic 11 amino acid polypeptide (very lipophilic, rally absorbed)

 very effective against T cell dependent responses, less effective against B cells
Therapeutic uses:

• kidney, liver, heart and other organ transplantation

• severe cases of RA

• severe disabling psoriasis where other therapies have failed

Pharmacokinetics:

• Administered i.v. or orally

• oral availability 20-50%

• plasma peak between 1.5 to 2 h; t1/2 5-18 hours

• extensively metabolized through CYP3A4; excreted through bile

 Plasma drug levels must be monitored, drug interactions avoided and doses adjusted for hepatic
insufficiency

Cyclosporine

Doses:

Adults, children, P.O:

 Initial:

14-18 mg/kg/day, beginning 4-12 hr prior to organ transplantation.

 Maintenance:

5-10 mg/kg/day divided every 12-24 hrs; maintenance dose is usually tapered to 3-10 mg/kg/day.

Adverse effect:

 Nephrotoxicity is the most common and important adverse effect of cyclosporine.

 Infections in patient taking Cyclosporine are common and may be life-threatening.

 Viral infections due to herpes group.

 Lymphoma may occur, presumable due to immunosuppression.

 Other toxicities include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance, and
gum hyperplasia.
Drug Interactions with Cyclosporine

 any drug that is metabolized through CYP3A4 affects CsA metabolism

 CYP3A4 blockers (ketoconazole, fluconazole, verapamil, idinavir, grape fruit juice) increase CsA
plasma levels

 CYP3A4 inducers (phenobarbital, phenytoin) reduce CsA plasma levels

Cyclosporine Side Effects

1. Nephrotoxicity: occurs in nearly all patients  cessation or modification of therapy

2. Hypertension: occurs in ~50% of kidney and 100% of heart transplant patients

3. Hyperlipidemia

4. Tremor

5. Hirsutism and hypertrichosis

6. Diabetogenic in combination with glucocorticoids

Monitoring Parameters:

 Cyclosporine trough levels.

 Serum electrolytes.

 Renal function.

 Hepatic function.

 Blood pressure.

 serum cholesterol.

Tacrolimus (FK506)

 macrolide antibiotic produced by Streptomyces tsukunaensis

 available for oral and i.v. administration (PROGRAF)

 t1/2 ~12 hours, PK variable. Metabolized through CYP3A4 (same interactions like CsA)

Therapeutic Uses:
 • Similar to CsA

• “Rescue Therapy” in patients who show rejection despite therapeutic CsA

plasma levels

Side Effects:

• Same as CsA, nephrotoxicity is limiting

Doses:

 Cardiac transplant rejection; Prophylaxis: initial, 0.075 mg/kg/day PO in 2 divided doses (given
every 12 h).

 Liver transplant rejection; Prophylaxis: initial,

0.1 to 0.15 mg/kg/day PO in 2 divided doses (given every 12 h).

 Renal transplant rejection; Prophylaxis: initial, 0.2 mg/kg/day PO in 2 divided daily doses (given
every 12 h).

Monitoring parameters:

 Blood pressure.

 Echocardiography.

 Hepatic and renal function.

 Electrolyte (especially magnesium and potassium).

 Fasting glucose.

 CBC.

 signs and symptoms of rejection, serum tacrolimus levels.