Immunosuppressant Drugs

Immune System

• Designed to protect the host from harmful foreign molecules, but can result in serious problems
• Two main arms: cell-mediated immunity and humoral (antibody-mediated) immunity

Cell-Mediated Immunity

• Involves ingestion and digestion of antigens by antigen-presenting cells
• Activated TH cells secrete IL-2, which stimulates TH1 and TH2 cells
• TH1 cells produce TNF-β and IFN-γ, which activate:
  • NK cells (kill tumor and virus-infected cells)
  • Cytotoxic T cells (kill tumor and virus-infected cells)
  • Macrophages (kill bacteria)

Humoral Immunity

• B-lymphocytes bind to antigens and are induced by IL-4 and IL-5 produced by TH2 cells
• Results in B-cell proliferation and differentiation into:
  • Memory cells
  • Antibody-secreting plasma cells

Mutual Regulation of T Helper Lymphocytes

• TH1 cells produce interferon-γ, which inhibits TH2 cell proliferation
• TH2 cells produce IL-10, which inhibits TH1 cytokine production

Cytokines

• Soluble, antigen-nonspecific signaling proteins that bind to cell surface receptors
• Include:
  • Interleukins (IL-1, IL-2, etc.)
  • Interferons (IFN-α, IFN-β, etc.)
  • Tumor Necrosis Factors (TNF-α, etc.)
  • Transforming Growth Factors (TGF-α, etc.)
  • Colony-stimulating factors (CSFs)

Immunosuppressant Drugs

• Inhibitors of cytokine production or action:
  • Calcineurin inhibitors (cyclosporine, tacrolimus)
  • Sirolimus (rapamycin)
• Inhibitors of cytokine gene expression:
  • Corticosteroids
• Cytotoxic drugs:
  • Inhibitors of purine or pyrimidine synthesis (antimetabolites: mycophenolate mofetil, azathioprine, etc.)
  • Alkylating agents (cyclophosphamide)
• Immunosuppressive antibodies:
  • Antilymphocyte globulins (ALG)
  • Antithymocyte globulins (ATG)
  • Monoclonal antibodies (muromonab-CD3, basiliximab, daclizumab)

Cyclosporine

• Fungal polypeptide composed of 11 amino acids
• Mechanism of action: inhibits interleukin-2 production, decreases T cell proliferation and differentiation
• Pharmacokinetics: oral or i.v. administration, variable absorption, peak levels in 1-4 hours
• Uses: organ transplantation, autoimmune disorders, graft-versus-host disease

Adverse Effects of Cyclosporine

• Nephrotoxicity
• Hypertension
• Liver dysfunction
• Hyperglycemia
• Viral infections
• Lymphoma
• Hirsutism
• Neurotoxicity
• Gum hyperplasia

Tacrolimus (FK506)

• Macrolide antibiotic produced by bacteria
• Mechanism of action: inhibits calcineurin, decreasing T cell proliferation and differentiation
• Pharmacokinetics: oral or i.v. administration, variable absorption, peak levels in 9-12 hours
• Uses: organ transplantation, atopic dermatitis, psoriasis

Adverse Effects of Tacrolimus

• Nephrotoxicity
• Neurotoxicity
• Hyperglycemia
• GIT disturbances
• Hypertension
• Anaphylaxis

Sirolimus (Rapamycin)

• Macrolide antibiotic
• Mechanism of action: inhibits response to IL-2, blocking T cell and B cell proliferation
• Pharmacokinetics: oral administration, reduced by fat meal, extensively bound to plasma proteins
• Uses: solid organ allografts, hematopoietic stem cell transplantation

Adverse Effects of Sirolimus

• Hyperlipidemia
• Thrombocytopenia
• Leukopenia
• Hepatotoxicity
• Hypertension
• GIT dysfunction

Corticosteroids

• Mechanism of action: anti-inflammatory and immunosuppressant effects
• Kinetics: oral, parenteral, topical, or inhalational administration
• Uses: solid organ allografts, autoimmune disorders, acute or chronic rejection

Adverse Effects of Corticosteroids

• Adrenal suppression
• Osteoporosis
• Hypercholesterolemia
• Hyperglycemia
• Hypertension
• Cataract
• Infection

Azathioprine

• Antimetabolite immunosuppressant
• Mechanism of action: inhibits de novo synthesis of purines
• Pharmacokinetics: oral or i.v. administration, metabolized in the liver
• Uses: autoimmune disorders, acute glomerulonephritis, Crohn's disease

Adverse Effects of Azathioprine

• Bone marrow depression
• Gastrointestinal toxicity
• Hepatic dysfunction
• Increased risk of infections
• Leukopenia
• Thrombocytopenia

Mycophenolate Mofetil

• Antimetabolite immunosuppressant
• Mechanism of action: inhibits de novo synthesis of purines
• Pharmacokinetics: oral or i.v. administration, metabolized in the liver
• Uses: solid organ transplantation, autoimmune disorders

Adverse Effects of Mycophenolate Mofetil

• GIT toxicity
• Leukopenia
• Lymphoma

Leflunomide

• Antimetabolite immunosuppressant
• Mechanism of action: inhibits pyrimidine synthesis
• Pharmacokinetics: oral administration, active metabolite undergoes enterohepatic circulation
• Uses: rheumatoid arthritis

Adverse Effects of Leflunomide

• Elevation of liver enzymes
• Renal impairment
• Teratogenicity
• Cardiovascular effects

Methotrexate

• Antimetabolite immunosuppressant
• Mechanism of action: inhibits dihydrofolate reductase
• Pharmacokinetics: oral or parenteral administration
• Uses: autoimmune disorders, cancer

Adverse Effects of Methotrexate

• Pulmonary fibrosis
• Nausea, vomiting, diarrhea
• Alopecia
• Bone marrow depression
• Teratogenicity

Cyclophosphamide

• Alkylating agent
• Mechanism of action: destroys proliferating lymphoid cells
• Pharmacokinetics: oral or i.v. administration
• Uses: autoimmune disorders, cancer

Adverse Effects of Cyclophosphamide

• Alopecia
• Hemorrhagic cystitis
• Bone marrow suppression
• GIT disorders
• Sterility

Antibodies

• Polyclonal antibodies: anti-lymphocyte globulins (ALG), anti-thymocyte globulins (ATG)
• Monoclonal antibodies: muromonab-CD3, basiliximab, daclizumab

Muromonab-CD3

• Mechanism of action: binds to CD3 proteins on T lymphocytes, disrupting T-lymphocyte function
• Uses: treatment of acute renal allograft rejection, steroid-resistant acute allograft rejection

Adverse Effects of Muromonab-CD3

• Anaphylactic reactions
• Fever
• CNS effects
• Infection
• Cytokine release syndrome

Basiliximab and Daclizumab

• Mechanism of action: bind to CD25 (α-subunit chain of IL-2 receptor on activated lymphocytes), blocking IL-2-stimulated T cell replication
• Uses: prophylaxis of acute organ rejection in renal transplantation

Adverse Effects of Basiliximab and Daclizumab

• Well tolerated, only GIT disorders reported

Learn about immunosuppressant drugs, the immune system, and its two main arms - cell-mediated immunity and humoral immunity. Understand how the immune system works and its response to allograft introduction.