Organ Graft Rejection Flashcards
Describe transplantation.
-transplantation via taking cells, tissues, organs called ‘graft’ from one individual & placing into a diff individual
-individual who provides graft is called donor & receiver is called recipient
-if graft is placed into normal anatomic location = orthotopic transplantation
>diff site = heterotropic transplantation
-transfusion = transfer circ blood cells/plasma from one individual to another
Describe rejection.
-transplantation of cells/tissue from one individual to a non identical individual = rejection bc adaptive immune resp (inflam reaction)
Describe the adaptive immune resp to graft rejections.
-memory & specifics mediated by lymphocytes
-individuals that reject grafts from one donor show faster rejection of another graft from the same donor BUT not from a diff donor = rejection process is immunologically specific
Describe autologous, syngeneic, allogeneic, xenogeneic, grafts.
-autologous = graft transplanted from one individual to the same individual
-syngeneic = graft transplanted between two genetically identical individuals
-allogeneic/allograft = graft transplanted between 2 genetically diff individuals of same species
-xenogeneic/xenograft = graft transplanted between individuals of diff species
*molecules recog as foreign in allografts = ‘alloantigens’ & in xenografts ‘xenoantigens’
Describe MHC in allografts.
-antigens that stim adaptive IR against allografts are proteins encoded by polymorphic genes (MHC proteins)
-all animals of inbred strain = genetically identical
-inbred animals of diff strains & individuals in outbred species differ in genes they inherit
Describe the rules of transplantation immunology.
- Cells/organs transplanted between genetically identical individuals are not rejected
- Cells/organs transplanted between genetically non identical people OR 2 diff inbred strains of a species = always rejected
- Offspring of mating between 2 diff inbred strains wont reject grafts from either parent
- Graft from offspring of mating between 2 diff inbred strains = rejected by either parent
Describe the 2 ways allogeneic MHC molecules of a graft can be presented.
- Unprocessed MHC in graft = direct presentation of alloantigens
- Indirect = recog foreign protein antigen APC -> draining lymph nodes
Describe activation & effector functions of alloreactive T lymphocytes.
-transplanted organs carry with them APCs that express donor MHC
-donor APCs can migrate to LN & present on surface unprocessed allogeneic class I or II MHC to recipient CD4 & CD8 T cells
Describe the activation of alloreactive B cells & production & functions of alloantibodies.
-antibodies against graft antigens = donor specific antibodies contribute to rejection
-high affinity alloantibodies made by helper T cell = dependent activation of alloreactive B cells
-antigens recog by alloantibodies are donor MHC I & II
-alloreactive antibodies made in graft recipients engage same effector mechanism like Fc receptor mediated binding & activation of neutrophils, macrophages, & NK cells
Describe the innate immune resp to allografts.
-interruption of blood supply to tissue/organs from removal to placement = ischemic damage -> expression of DAMPs in graft -> stim innate immune resp by graft & recipient -> graft injury & enhance adaptive immune resp by increase migration of alloreactive circ memory T cells into graft & activating APCs
-host NK cells resp to absence of self MHC on donor graft cell
Describe the mechanisms of allograft rejection.
-CD4, CD8 T cells & alloantibodies = mediate allograft rejection
-hyperacute -> acute -> chronic
Describe hyper acute.
-thrombotic occlusion of graft vasculature
-min/hrs after host blood vessels anastomosed to graft vessels -> mediated by preexisting antibodies in host circ that bind to donor endothelial antigens
Describe acute reaction.
-injury to graft parenchyma & blood vessels mediated by alloreactive T cells (cellular) & antibodies (humoral)
>cellular = both CD4 helper T cells & CD8 CTLs specific for graft alloantigens -> parenchymal & endothelial injury
>humoral = alloantibodies -> complement activation -> Fc neutrophils, NK = destruction
Describe acute antibody mediated (humoral) rejection.
-alloantibodies bind to alloantigens (HLA) on vascular endothelial cells -> endothelial injury & intravascular thrombosis = graft destruction
-binding of alloantibodies to endothelial cell surface = trigger complement activation -> lysis of cells, activate neutrophils, thrombus formation
-Fc receptors on neutrophils & NK cells = kill endothelial cells
Describe chronic rejection.
-kidney & heart -> vascular occlusion & interstitial fibrosis
-lung -> thickened small airways
-liver transplants -> fibrotic/nonfunctional bile ducts
-dominant lesion of rejection in vascularized grafts = arterial occupation bc prolif of sm m cells & graft eventually fail bc ischemic damage
Describe the methods to reduce immunogenicity of allograft.
-min alloantigenic diff between donor & recipient
-avoid hyperacute rejection = ABO blood group antigens of graft donor must be compatible with recipient
-patients that need allografts tested for presence of performed antibodies against donor MHC or other cell surface antigens
Describe immunosuppression to prevent or treat allograft rejection.
- Inhibitors of T cell signaling pathway
- Antimetabolites
- Function-blocking or depleting anti lymphocyte antibodies
- Costim blockade
- Treatment to reduce alloantibodies & alloreactive B cells
- Anti inflammatory drugs
- Xenogeneic transplantation
Describe inhibitors of T cell signaling pathways.
-calcineurin inhibitors: cyclosporine & tacrolimus = inhibit transcription of certain genes in T cells like IL2
-immunosuppressive drugs: rapamycin = inhibits growth of factor mediated T cell prolif
Describe antimetabolites.
-metabolic toxins = kill prolif T cells
-azathioprine = inhibit prolif of lymphocyte precursors during maturation & kill prolif mature T cells stim by alloantigens
Describe function blocking / depleting anti lymphocyte antibodies.
-antibodies that react w T cell surface & deplete/inhibit T cells used to treat acute rejection
Describe costim blockade.
-drugs that block T cell costim pathways to reduce acute allograft rejection
-antibody binds to T cell CD40L & prevents interactions w CD40 on APCs
Describe treatments to reduce alloantibodies & alloreactive B cells.
-plasmapheresis
-bortezomib = kill plasma cells & treat antibody mediated allograft rejection
Describe anti inflammatory drugs.
-corticosteroids = reduce inflam reaction to organ allografts
-block syn & secretion of cytokines like TNF & IL1 -> reduced leukocyte recruitment
-immunosuppressive therapy = increased susceptibility to infection & tumor -> antiviral therapy
-opportunistic infections = fungal & protozoan
Describe xenogeneic transplantation.
-transplantation of organs from other mammals like pig into human recipient
-immunologic barrier bc natural antibodies in human = hyper acute rejection
>prevention = xenografts damaged by form of acute vascular rejection occurs 2-3d after transplantation ‘delayed xenographic rejection’
