Immunosuppression - Professor Richard Kirk 2023

Professor Richard Kirk
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Immunosuppression is required for life to  prevent rejection. Combinations of drugs are used to target more than  one pathway. Many of the complications of transplant are due to immunosuppression. If it is too little, rejection occurs, if too much,  infections and medication side-effects are more pronounced e.g. renal  impairment. Unfortunately we do not have a reliable test to assess the  level of activation of the immune system, so adjusting medications  relies on "walking the tightrope" between too much and too little, based  on the patient's condition.

The  strategy to prevent early graft rejection usually includes  intraoperative steroids followed either by T cell depletion  (thymoglobulin) or preventing Signal 2 of the T cell activation pathway  with Basiliximab. Long term the mainstay is a combination of calcineurin  inhibition (preventing intracellular cytokine signaling from reaching  the nucleus) and cell cycle inhibition - either directly using azathioprine or mycophenolate mofetil (MMF) or  through mTOR inhibitors.   

  • Steroids  principally act by inhibiting gene expression of IL2. They are also  powerful anti-inflammatory agents suppressing macrophage function,  inhibit lymphocyte migration through vessel walls and induce lymphocyte  apoptosis. The also reduce the expression of HLA proteins.
  • Calcineurin  inhibitors (CNI): Ciclosporin and Tacrolimus are calcineurin  inhibitors. After T cells receptors are activated a signal pathway is  enhanced to produce interleukins (amongst other molecules). This pathway  requires calcineurin (a calcium calmodulin dependent phosphatase).  Inactivation of this pathway reduces IL2 production.
  • Cell  cycle inhibitors: Azathioprine is a purine analogue whilst MMF blocks  purine synthesis by enzyme inhibition. Both impair DNA synthesis and  they thus act as antiproliferation agents.
  • Target of Rapamycin Inhibitors (mTOR)  are also known as Protein Kinase Inhibitors  (PKIs): Sirolimus &  Everolimus are in clinical usage. TOR is a cytoplasmic enzyme that is  involved in the signaling pathway from T cell surface to nucleus  required for cell proliferation.
  • Polyclonal antibodies (thymoglobulin) target T cells resulting in apoptosis and therefore lymphocyte depletion.
  • Monoclonal  antibodies are more specific as they target specific CD proteins on the  lymphocytes and hence reduce only certain populations of lymphocytes.  eg Basiliximab targets CD25 proteins found on T cells, Rituximab targets  CD20 proteins found on B cells and Alemtuzumab targets CD52 found on T, B and APCs.
Drug interactions are common so whenever a new medication is proposed it is advisable to check its interaction with immunosuppressants
Figure 1. Adapted from Philip Halloran. N Engl J Med 2004;351:2715-29
Figure 1 includes drugs that are potential targets for transplant immunosuppression:

  • Belatacept is a selective T-cell co-stimulation blocker. It comprises a recombinant extracellular domain of human cytotoxic T lymphocyte  antigen-4 (CTLA-4) and a fragment of a modified Fc portion of human  IgG1. The drug binds to CD 80/86 ligands of antigen-stimulating cells and thereby inhibits the CD-28-mediated T-cell costimulation.
  • Toralizumab blocks the CD40-CD154 interactions. These molecules belong to the tumor necrosis factor (TNF)  superfamily and are expressed on a wide range of tissues and cell  types, with CD40 constitutively expressed on antigen-presenting cells  (APC), including B cells, macrophages and dendritic cells (DC), and CD154 inducibly expressed mainly on CD4+ T cells and endothelial cells following activation.
  • Tofacitinib is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3), and interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription
  • FK778 is a malononitrilamide and the active metabolite of leflunomide. Its main  mechanism of action is the inhibition of pyrimidine synthesis and thus inhibits T- and B-cell proliferation.
  • Fingolimod down regulates Sphingosine1-Phosphate (S1P) receptors which are involved in multiple biological processes, including preventing lymphocyte egress from lymphoid tissues.
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