Immunopharmacology Notes

Main Applications of Immunosuppressive Drugs

  • Used for three primary purposes:
    • Suppression of organ/tissue rejection:
      • E.g., bone marrow transplants
    • Suppression of Graft-vs-Host Disease (GVHD):
      • A reaction of donor immune cells against host tissue
    • Autoimmune diseases:
      • Conditions like lupus, rheumatoid arthritis, psoriasis, ulcerative colitis.

Introduction to the Immune Response

  • The immune system consists of:
    • Innate immunity
    • Adaptive immunity (focus of immunosuppressants)
  • Key phases of the adaptive immune response:
    • Induction Phase:
      • Recognition and presentation of antigens by Antigen Presenting Cells (APCs).
      • Activation and proliferation of naïve T helper cells into Th1 and Th2 cells.
    • Effector Phase:
      • Cell-mediated responses from Th1 cells (T-cells) and antibody-mediated responses from B cells (Th2 derived).
      • Result in destruction of infected or foreign cells.

Key Drug Targets in Immune Response

  • Drugs target several critical pathways:
    • Inhibition of IL-2 production/action
    • Inhibition of cytokine gene expression (e.g., glucocorticoids)
    • Cytotoxic effects on immune cells
    • Inhibition of nucleic acid synthesis
    • Blockade of T cell surface receptors preventing activation

Immunosuppressant Drug Classes

  • Calcineurin Inhibitors:
    • Example: Cyclosporine and Tacrolimus
    • Mechanism:
    • Bind to specific proteins/enzymes (cyclophilin for cyclosporine, FKBP for tacrolimus) inhibiting calcineurin and halting IL-2 gene transcription.
    • Consequence: Inhibition of T-cell activation and proliferation.
  • Proliferation Signal Inhibitors:
    • Example: Rapamycin (sirolimus)
    • Mechanism: Binds FKBP but inhibits mTOR instead of calcineurin.
    • Function: Regulates cell growth and proliferation.
  • Cytotoxic Agents:
    • Example: Cyclophosphamide and Azathioprine
    • Mechanism:
    • Azathioprine metabolized to 6-mercaptopurine, which inhibits nucleotide synthesis and affects rapidly dividing cells.
    • Cyclophosphamide interferes with DNA replication by cross-linking DNA bases.

Monoclonal Antibodies

  • Structure: Y-shaped proteins from B cells, consisting of four polypeptide chains (2 light, 2 heavy).
  • Fab region: Determines specificity for antigens.
  • Fc region: Determines antibody class (e.g. IgA, IgG) and mediates immune response.

Antibody-based Therapies

  • Challenges:
    • Antibodies raised in animals (like mice) are recognized by human immune systems, leading to rapid degradation.
  • Solutions:
    • Use of chimeric or humanized antibodies to reduce antigenicity (e.g., alemtuzumab, basiliximab).
    • Chimeric antibodies (imab) contain mouse and human components; humanized antibodies (umab) are mostly human.

Examples of Antibody-based Therapies

  • Alemtuzumab:
    • Humanized IgG1 targeting CD52 on T and B cells leading to immune-mediated cell destruction.
  • Basiliximab:
    • Chimeric IgG1 binding CD25 on activated T-cells; acts as an IL-2 antagonist, blocking IL-2 signaling.

Conclusion

  • Immunosuppressive drugs play a crucial role in managing transplant rejection, autoimmune diseases, and involve diverse mechanisms targeting key immune pathways.