CBI Transplantation Immunology - Anti-rejection Therapies L3 PDF

Transplantation Immunology Lecture 3 Allograft rejection: Anti-rejection strategies Hershna Patel Acknowledgements: Dr Niall McMullen Aims To promote awareness of anti-rejection therapies. To consider mechanism of action of different anti- r...

Transplantation Immunology Lecture 3 Allograft rejection: Anti-rejection strategies Hershna Patel Acknowledgements: Dr Niall McMullen Aims To promote awareness of anti-rejection therapies. To consider mechanism of action of different anti- rejection drug classes. By the end of this session you should be able to: Show knowledge of the different immunosuppressive drugs used in preventing graft rejection. Show awareness of the effects of classical inhibitors on T cells.  Overview of acute rejection Transplantation of DAMPs released organ creating inflammatory environment… cytokine release, cell Donor DCs migrate activation and to lymph nodes increased HLA expression. Alloreactive T-helper cells recognise donor HLA on allogenic DCs. T cells undergo clonal expansion. Ag-primed CTLs destroy donor cells Alloreactive T-helper Ag-primed B cells expressing HLA class I cells migrate into activated, anti-HLA including endothelial graft, primed and antibodies target cells and parenchymal activated. Cytokine donor cells resulting in cells. release drives ADCC… Prevention of allograft rejection - Introduction (1) All vascularised allografts will initiate an anti-graft immune response. One or two HLA mismatches are sufficient to induce the rejection process. Acute rejection process begins within days of transplant. Transplant patients must take anti-rejection drugs - typically for the rest of their lives to prevent chronic rejection. Prevention of allograft rejection - Anti-rejection drugs Several classes of anti-rejection drugs with different mechanisms of action. Patients will typically be on a combination of 2/3 anti-rejection drugs. Induction therapy - treatment initiated at time of transplant. confers high immunosuppression in early weeks. Maintenance therapy – long-term therapy. Requirement for anti-microbials. Anti-rejection therapy - Rationale Anti-rejection drugs have immunosuppressive actions. Target different aspects of immune cell function. Broad immunosuppression. Selective targeting of signalling pathways involved in T cell activation. Activation of T cells - general T cells require various signals for full activation. Effects mediated through 3 main transcription factors: NFAT, NF-kB and AP-1. Nature of response determined by signal(s). Signal 1. TCR-ligation by MHC:Ag peptide complex. Signal 2. Accessory membrane molecules notably CD28. Signal 3. Cytokine signal – notably Il-2  The Immunological Synapse T Cell Antigen Coreceptor Presenting CD4 or CD8 Cell TCR:CD3 signaling alone activates TCR MHC calcineurin- dependent pathway (NFAT Costimulation activation). CD28 CD80 or CD86 CD28 initiates both PI3K and mTOR pathways (AP-1 and NF-kB activation) IL-2 Cytokines  Anti-inflammatory agents - Corticosteroids Lipophilic, bind to high-affinity cytoplasmic receptors. Receptor-steroid complex binds specific DNA sequences (CREs). Main outcomes: 1. Production of lipomodulin - phospholipase A2 inhibitor  reduced arachidonic acid metabolism…anti-inflammatory action. 2. Inhibit cytokine gene expression… Anti-rejection therapies - Antimetabolites Purine analogues – azathioprine (AZA), derivative of 6- mercaptopurine pro-drug, converted to 6-MP Blocks purine biosynthesis via both de novo and salvage DNA pathways Most effective in primary response to renal grafts. Lowers steroid-dosages (steroid ‘sparing’). Second choice drug. Classical anti-rejection drugs – Antimetabolites Mycophenolate mofetil (MMF) – blocks lymphocyte-specific form of inosine monophosphate dehydrogenase Enzyme required for de novo synthesis of guanines. Most effective in acute rejection – 6 months post- transplantation. Alternative to azathioprine depending on patient drug tolerance. Classical anti-rejection drugs Calcineurin inhibitors (CnIs): Cause inhibition of calcineurin- dependent pathways, most notably in T cells. Downregulate transcription of cytokine genes (notably Il-2) and Il-2R. Reduces IL-2-induced T cell activation and maturation. E.g. Cyclosporin A (CsA), FK 506 (tacrolimus) Classical anti-rejection drugs mTOR inhibitors, E.g. Rapamycin (Sirolimus), Everolimus: Bind to intracellular FKBP12. Rapamycin:FKBP12 complex binds to mTORC1 preventing activation of serine/threonine kinase mTOR. Loss of mTOR kinase activity. Inhibits T cell proliferation. No effect on Il-2 production.  Selective Inhibition of signalling pathways in T cells Cyclosporin A (CsA), FK 506 (tacrolimus) Causes inhibition of calcineurin (phosphatase) Downregulate transcription of cytokine genes (notably Il-2) and Il-2R Rapamycin (Sirolimus) – forms complexes similar to FK506. Inhibits mTOR Blocks T cell proliferation. Often used in conjunction with CsA. Antibody-based (specific) anti- rejection therapies Key components of induction therapy. Antilymphocyte globulin (ALG) and anti-thymocyte globulin (ATG). Reduction in lymphocyte/T cell activity. Anti-CD3 antibodies – depletion of T cells. Anti-CD25 (Il-2Ra subunit) Anti-CD20 – novel approach to transplant rejection and autoimmune disease. Co-stimulation blockade of T cells Belatacept Recent introduction to anti-rejection drugs regimen. Ig-CTLA-4 fusion protein blocks CD28 co-stimulation. Binds to CD80/86 on APCs preventing interaction with CD28. Significant reduction in T cell activity. Note: CTLA-4 (CD152) expressed late on activated T cells, negative regulator of T cells through competition with CD28 for CD80 and CD86 binding. Summary Immunosuppression of alloreactive T cells is essential for most allografts. Cytotoxic drugs have broad effects but high toxicity. Calcineurin inhibitors (CnI) and mTor inhibition more selective (T cells). CnIs and mTOR inhibitors may be used in induction and maintenance therapy. mTOR inhibitors display much lower nephrotoxicity than CnIs. References/Recommended Reading Mukherjee, S., Mukherjee, U. A comprehensive review of immunosuppression used for liver transplantation. J Transplant. (2009). doi: 10.1155/2009/701464. Kervella, D., & Blancho, G. New immunosuppressive agents in transplantation. La Presse Médicale, (2022). https://doi.org/10.1016/j.lpm.2022.104142. Chapter 9 – Transfusion & Chapter 17 – Cellular & Molecular Transplantation Science. Chapter 15 – Janeway’s Immunology (616.079 ABB) (615.39 TRA ) Immunology