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02 - January 15, 2013.docx

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MISSING FIRST TEN-ISH MINUTES… Cyclosporine – mainstay of immunosuppressive regimen – both inhibiting calcineurine, important because activated downsream of T cell receptor lead to dephosphorylation of NFAT, what cyclosporine and ___ do is inhibit alcineurin Downstream of IL2 transcription – working to inhibit IL2 synthesis Nephrotoxic – very high levels will damage kidneys Sirolimus – Tacrolimus acting on calciuneurin; mTOR affected by sirolimus mTOR important for multiple parts of body – downstream of mTOR Signalling antibody therapy immunosuppressive agents called induction agents – used immeidatley post-transplant – direct activation pathway – vigorous anti-graft response – hammer the patient with lots of things to suppress with – also use for people having lots of injections further out – thymoglobulin – polyclonal rabbit antibody against human thymocytes – injecting human cells from rabbits, collecting serum, which is injected in early stages of transplant anti-CD3 antibody – CD3 is T cell receptor – effective but activates T cells – results in fevers, shaking – phased out medication IL2 receptor antibodies – basiliximab – binds to IL2 receptor – T cells require IL2 to proliferate – so inhibiting the T cells from proliferating Treatment immunosuppression – where some acgents acting in cell Sirolimus – everolimus work the same way Costimulation – some agents used Standard immunosuppression – designed to give people lots of immunosuppression – typically use this thymoglobulin, rabbit anti-human T cell antibody. Over first few days, get sevral doses of this medication, buys time, prevents terrible rejection. Some side-effects – have infection, have cancers later Takes a while for calcineurin inhibitors to start working. While giving this, either giving cyclosporine or tacrolimus – reach therapeutic levels Use anti-metabolite Prednisone, mmf, tacrolimus – tpical first year regimen How much immunosuppression – balance – if too little, problem with rejection, allograft; can also over suppress, infections, cancer, medication side effects (ex. Cyclosporine and tacrolimus are necrotoxic, leading to needing dialysis) Biopsies – one way to tell if rejecting – check drug levels – heart function with echocardiogram (ultrasound) Heart biopsy – into the jugular vein, put in – into right atrium, right ventricle Pretty safe – can puncture heart, can be fatal Types of rejection Four types Hyperacute – rare – due to having pre-formed antibodies against graft – acute is cel mediated and antibody mediated, Chronic Hyperacute rejection Having preformed antibodies against donor heart – rare because check for these antibodies Virtual cross match where beads with different HLA antigens – mix patient serum with these beads, tell us patients if the patient have any antibodies against any antigens – may be due to prior transfusions Histocompatibility report Specificity – antigen against HLA 1, 11, 23, 24, 25, 26, etc. Just make sure patient doesn’t have any of these antibodies that would cross-react with the donor Know donor HLA – know what the patient HLA, which antibodies they have – virtual thing – make sure patient doesn’t have antibodies against donor antigen – In some areas, like kidney transplantion, match HLAs so donor and recipient would have most similar HLA and least amount of rejection – in heart transplantation, heart given to sickest patient as long as do not have antibodies against donor – survive by dialysis, but heart transplant patients needed heart for survival Complement activation – cross-matching due to looking for antibodies – can avoid all this Acute cellular rejection – first six months have highest risk of rejection – mostly related to direct donor antigen presentation from donor antigen presenting cells – Acute cellular rejection – left side, pink heart cells; blue cells are infiltrating cells, bad; No rejection; worst terrible rejection Types of infiltrating cells Types of infiltrating cells Regulatory T cells and transplantation – potentially, these cells useful to decide amount of immunosuppression; now is crude, based on the pink and blue stain Acute cellular rejection Mild rejection – Severe – given antibodies and steroids Antibody mediated rejection Antibodies against graft – anti-HAL antibodies tested before and after transplant, to make sure not developing antibodies More specialized stains to look for antibodies – look for complement deposition – called C4D rejection If people’s cells look bad – treat with – therapies that target antibodies and B cells – like plasma exchange to try to remove antibodies in plasma – IVIG is human Ig useful for inhibiting antibody responses – rituximab is anti-CD20 marker – plasma cells – this medication is not great for that – is bad outcome – Chronic rejection – months to years, usually years – chracterisized by fibrosis and stiffening of the heart Cardiac allograft vasculopathy Mechanisms Un clear Immune and non-immune effects causing chronic rejection Chroic rejection may be due to heart sitting in a case before transplant Or due to attack by CD4+ t cells and macrophages and maybe antibodies as well Problems with immunosuppression causing – leads to patient dying and in the end Shows smooth muscle proliferation and blood vessel shrinks Similar to atherosclerosis – where there are lesions – put stents on – chronic rejection and chronic CAV – infecting the whole vascular tree – Diffuse luminal narrowing – cannot put stents through vascularature entire Transplant tolerance – acehieve tolerance, recipient would not attack graft No immunosuppression – Tolerance can develop ocassionally – in lier patients, for instance Central tolerance – thymus is important – donor cells that can popular thymus and serve as antigen presenting cells – target graft – Peripheral tolerance – regulatory T cells in blocking the alloreactive cells Co-stiulation – signal one and two for lymphocyte activation – signal one was T cell being activated – need signal two as
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