Immunopharmacology

• Immunosuppressive drugs


  Used for three main applications: 1) Suppression of rejection of transplanted organs and tissues, 2) Suppression of 'Graft-Versus-Host' disease, 3) Auto-immune diseases

  
• Transplantation


  • Antigens may be recognized as 'non-self' and elicit an immune response that attacks the donor organ
  • Immunocompetent cells in the donor graft can mount an immune response against the host

  
• There is a lot of overlap between cancer chemotherapeutic drugs and immunosuppressants
• Specific immunological response


  Focuses on the induction phase (recognition, presentation, activation, proliferation) and the effector phase (cell-mediated, antibody-mediated)

  
• Immune response


  • Key phases are the induction phase and the effector phase
  • Most drug effects influence the induction phase

  
• Immunosuppressant drug targets


  • Inhibition of IL-2 production/action
  • Inhibition of cytokine gene expression
  • Cytotoxicity (killing immune cells or preventing their maturation/expansion)
  • Inhibition of nucleic acid synthesis
  • Blockage of various T-cell surface receptors to prevent immune activation
• Calcineurin inhibitors


  Suppress the calcineurin-NFAT pathway, which is required for T-cell activation and proliferation
• Calcineurin inhibitor mechanism of action

  1. Activation of T-cell receptor generates Ca2+ signal

  2. Calcineurin (phosphatase) is activated

  3. Dephosphorylated NFAT migrates to nucleus

  4. NFAT induces IL-2 gene transcription

  5. Drug-bound targets (cyclophilin, FKBP) suppress calcineurin, preventing NFAT-mediated gene transcription
• Proliferation signal inhibitors


  Inhibit signaling pathways that regulate cell proliferation
• NFAT


  Dephosphorylated NFAT migrates to the nucleus, leading to expression of IL-2 that is required for activation and proliferation of T-cells
• Cyclosporine and tacrolimus mechanism of action

  1. Bind to their targets (cyclophilin, FKBP, respectively)

  2. Suppress calcineurin

  3. Suppress the pathway that leads to IL-2 gene transcription

  
• Cyclosporine mechanism of action

  • Inhibition of calcineurin by the cyclophilin:cylcosporin complex
  • Prevents NFAT-mediated gene transcription, leading to inhibition of T-cell maturation and proliferation (IL-2 is a major signal)
• Tacrolimus mechanism of action

  • Inhibition of calcineurin by the FKBP:tacrolimus complex
  • Prevents NFAT-mediated gene transcription, especially important is the suppression of IL-2
• Immunosuppressant drug classes


  • Proliferation Signal Inhibitors (e.g. rapamycin, AKA sirolimus)
  • Cytotoxic agents (e.g. cyclophosphamide, azathioprine)
• Rapamycin/sirolimus mechanism of action

  • Inhibition of mTOR by the FKBP:sirolimus complex
  • Suppresses cellular responses to IL-2 receptor activation
• FKBP


  • FK506-binding protein
  • Family of proteins that are 'peptidyl-proline cis-trans isomerases' (role in protein maturation)
  • Also have a variety of endogenous binding partners
  • Part of the 'immunophilin' protein family, all are proline isomerases
  • Other targets include the ryanodine receptor and IP3 receptor (Ca2+ release channels)
• Cyclophosphamide


  • Alkylating agent
  • Leads to cross-linking of neighboring bases, interfering with DNA replication
  • Most effective in rapidly dividing cells, so useful in cancer treatment and for suppression of rapidly dividing immune cells

  
• Azathioprine


  • Metabolized to 6-mercaptopurine, a 'fraudulent' nucleotide
  • Inhibits synthesis of nucleotides and interferes with cell division (effective against rapidly dividing cells during clonal expansion)

  
• • Antibody structure: 2 Heavy chains, 2 Light chains
  • The Fab region determines antigen specificity
  • The Fc region determines the antibody 'class' (IgA, IgG, IgM, etc.)
  • Different classes of Fc regions are recognized by receptors on different immune cell types, leading to different immune responses

  
• Monoclonal antibodies


  Antibodies can be raised to recognize specific antigens that may be selectively expressed in 'troublesome' cells (e.g. tumor cells, or hyperactived immune cells causing an autoimmune disease)

  
• Humanization/chimerization of monoclonal antibodies

  • Replacement of conserved regions of the mouse monoclonal antibody with corresponding sequence from human antibodies
  • Reduces antigenicity and increases lifetime in the body
• Antibody-based therapies


  • Alemtuzumab (humanized IgG1 that recognizes CD52, leads to cell death by lysis or phagocytosis)
  • Basiliximab (chimeric mouse-human IgG1 that binds to CD25, part of the the IL-2 receptor, blocks IL-2 binding)