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.
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.