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55 Cards in this Set
- Front
- Back
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what is an autograft |
transplantation of a graft form one part of the body to another; ex. fibula to jaw or skin grafts to treat burns |
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what is a syngeneic (isograft) graft |
transplantation of a graft between 2 genetically identical individuals; example= kidney from identical twin (monozygotic twins) |
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what is an allograft |
transplantation of a graft between 2 genetically different individuals of the same species; example= Mr. Smith to Mr. Jones |
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what is a xenograft |
transplantation of tissue form one species to another; example= pig to human |
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what is going on in rejection of a graft |
failure of the transplant due to an immune response of the recipient against the donor tissue; due to major histocompatibility antigens (MHC) |
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what is the major histocompatibility complex (MHC) |
molecules responsible for almost all strong allogeneic rejection reactions; MHC and T cell interactions describes earlier; MHC present peptides to T cells leading to T cell activation; MHC molecules interact with complementarity determining regions of TCR |
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the immunologic synapse |
MHC-peptide |
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TCR CDRs |
there are complementarity determining regions (CDRs) on TCRs; TCR CDRs engage MHC alpha helices and peptide; self MHC molecules present foreign peptide to T cell selected to recognize self MHC-foreign peptide complexes |
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what is alloimmunity |
a cross reaction; TCRs specific for useful 'self-plus-X' shapes cross react with allo MHC shapes; the self MHC restricted T cell recognizes the allogreneic MHC molecule whose structure resembles the self MHC-foreign peptide complex |
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molecular basis of allogenic recognition |
they recognize that the HLA is incorrect (not self) |
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what does histocompatibility mean |
tissue compatibility |
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what is the human MHC? |
human leukocyte antigen (HLA) |
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what are the HLAs most important for transplantation |
HLA-A, HLA-B, HLA-C, and HLA-DR |
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recognition of transplanted cells as self or foreign is determined by what |
polymorphic genes that are inherited form both parents and are expressed codominantly (MHC) |
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polymorphic antigens |
graft antigens vary from different individuals of the same species; for example MHCa and MHCb; human MHC class I molecules; 506 A alleles, 872 B alleles, and 274 C alleles |
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co-dominance antigens |
if heterozygous, both antigens are expressed; for example offspring express both MHCa/b antigens |
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MHC control of immune responses- an mouse graft example |
if the donor mouse has the MHCa gene and the recipient has the MHCa gene then there won't be graft rejection; if the donor has the MHCb gene and the recipient has the MHCa gene there there will be graft rejection; if the donor is MHCb and the recipient is MHCa/b then there won't be graft rejection; if the donor is MHCa/b and the recipient is MHCa then there will be rejection (rejection due to polymorphic co-dominant expression of molecules) |
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self peptide+ self MHC evokes |
tolerance |
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viral peptide+ self MHC evokes |
response |
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(peptide)+ allo MHC evokes |
response (direct) |
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allo peptide + self MHC evokes |
response (indirect) |
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in allogeneic transplantation allogeneic MHC molecules can be presented for recognition by T cells by what 2 presentation methods |
direct or indirect |
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direct presentation |
an intact MHC (allo) molecule displayed by donor APCs in the graft is presented for recognition (donor APC x with intact donor MHC); allogeneic antigen presenting call in graft with allogeneic MHC binds to alloreactive T cell; class I and II CD8 and CD4 T cells |
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indirect presentation |
donor proteins are processed by recipient APCs and the resulting peptides are presented by host MHCs (host APCs present peptides from donor); uptake and processing of allogeneic MHC molecules by recipient APC and then alloreactive T cell binds to the presented allogeneic peptide (derived from allogeneic MHC molecule); recipient APCs may also process and present graft proteins other than allogeneic MHCs of course; class II CD4 T cells |
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does MHC 'matching' prevent rejection? |
reduces rejection but there are still 'minor histocompatibility antigens' (MiHA); MiHA are due to polymorphic proteins that are presented by MHC class I or II; but we cannot MHC match most grafts because there is too much polymorphism and too little time (ex is human leukocyte antigen (HLA) with 506 A alleles, 872 B alleles, and 274 C alleles); therefore need immunosuppression |
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hyperacute graft rejection kicks in when and what is the cause |
minutes to hrs; caused by pre-existing host serum antibodies specific for antigens of the graft; the antigen-antibody complexes that form activate the complement system resulting in an intense infiltration of neutrophils into the grafted tissue; the ensuing inflammatory reaction causes massive blood clots within the caps preventing vasculatization of the graft; characterized by thrombotic occlusion of graft vasculature; this can be due to ABO blood group antigens present on RBC, epithelial cells, and endothelial cells (rare with tissue typing, can happen with blood transfusion, AMO mismatched transplants are performed successfully in babies); can also be due to MHC mismatch where multiple transplants, pregnancy, or blood transfusion can generate preformed antibodies against MHC molecules |
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acute graft rejection kicks in when and what is the cause |
days to weeks; activation of T cells and antibody production; vascular and parenchymal injury mediated by T cells and antibodies; APCs move to secondary lymphoid tissue; APCs present antigens leading to activation of T and B cells; 'homing' or effector T cells, recruit macrophages (DTH) (produce cytokines that recruit/activate inflammatory cells); destructive events (effector T cell mediated cytotoxicity (CD8 T lymphocytes, CTL), alloantibody plus compartment mediated lysis); rejection or resolution, adaptation, and tolerance; CD4 (class II, direct/indirect) differentiate into cytokine-producing effector cells that damage graft by DTH; CD8 (donor class I, direct) CTL activity kill nucleated cells in graft; requires co-stimulation; also B cell activation to produce alloantibodies |
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chronic graft rejection kicks in when and what is the cause |
months to yrs; antibodies, immune complexes, slow cellular reaction, recurrence of disease; usually means slow late rejection process; combines features of T cell mediated or antibody mediated rejection with evidence of organ deterioration (atrophy, scarring); characterized by fibrosis and thickening of vessel walls; decreased blood supply and ischemia with loss of graft function over a prolonged period; NOT clearly distinct from mechanisms of acute rejection; alloantibodies recruit inflammatory cells to the blood vessel walls of the transplanted organ --> increased damage enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage leading to smooth muscle cell proliferation and vessel occlusion |
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what are the hurdles to immune response in blood transfusion |
ABO antigens= preexisting antibodies can activate hyperacute rejection (antibody binding activation of complement and lysis), clotting and bleeding, overload kidneys, life threatening; Rh antigen= no natural preexisting antibodies, if Rh- can respond after second Rh+ transfusion, Rh- mother can be exposed to fetal Rh+ red blood cells at childbirth leading to antibody production and risk to second Rh+ child |
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prevention of allograft rejection= |
decreased immunogenicity to allografts, histocompatibility testing, immunosuppressive drugs |
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decreased immunogenicity to allografts |
to improve change of allograft success decrease the immunogenicity; ABO blood group antigens are matchedl test for preformed antibodies; tissue typing= MHC (HLA) matching (HLA-A, -B, -C, and -DR most important); test for activation of T cells with the mixed lymphocyte reaction (MLR) test |
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how do you do HLA typing |
aka tissue typing; serological using known antibodies against donor and recipient cells |
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how do you screen for preformed anti-HLA antibodies |
serological using recipient's serum (antibodies) against cells with known HLA types |
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HLA antigen typing |
PCR to detect specific sequences of HLA genes in donor or recipient DNA; kits available against HLA class I (A, B, C) and class II (DRB, DQB, or DQ) |
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the mixed lymphocyte reaction (MLR) |
predictive test for T cell mediated graft rejection (direct recognition in vitro); an in vitro model for acute graft rejection; stimulators are donor leukocytes (APCs) which you irradiate to prevent response; responders are recipient T cells (CD4 (donor class II) proliferate and differentiate into cytokine producing effector T cells), CD8 (donor class I) proliferate and differentiate into CTL to kill target cells); will the donor antigen presenting cells activate the recipient T cells? look to see if recipient T cell proliferate and differentiate and it there is killing of cells and production of cytokines |
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what are immunosuppressive drugs |
corticosteroids (anti inflammatory), cytotoxic drugs, T cell inhibitors, antibodies, and co-stimulation blockade |
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corticosteroids: examples, what do they do, are they enough, what are the side effects, when are they used |
hydrocortisone (cortisol) pr prednisone (synthetic pro drug); anti inflammatory, decrease inflammation by decreasing inflammatory cytokines, NO, and prostaglandins; inhibit all WBCs including macrophages, APCs, and lymphocytes; insufficient to prevent graft rejection without addition of other drugs; have many adverse side effects (fluid retention, weight gain, DM, bone mineral loss, thinning of skin); used sparsely pre transplant or acutely during rejection episode |
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cytotoxic drugs: examples, what do they do |
in general they are DNA replication inhibitors that prevent cell division in all tissues including lymphocytes and healthy tissue; azathioprine, mycophenolate mofetil (MMF), methotrexate= inhibit production of nucleotide needed for DNA synthesis); cyclophosphamide= alkylates and cross links DNA which prevents cell division |
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what are the 3 signals for T cell responses |
antigen, co-stimulation, and cytokines; all of these lead to expression of effector activity |
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T cell inhibitors: what do they do, examples |
calcineurin inhibitors like cyclosporine and tacrolimus (FK-506) which prevent T cell activation, proliferation, and differentiation, and inhibit B cells and granulocytes but they do not inhibit proliferation so there are fewer side effects; rapamyacin (sirolimus) target of rapamycin (mTOR) inhibitor, prevents signal transduction from IL-2 receptor (mitotic/differentiation inhibitor); FTY720 (Fingolimod) is a lymphocyte recirculation inhibitor |
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immunosuppressive drugs that deplete antibodies: how do they do it, examples |
lymphocyte destruction by antibody binding, complement fixation, and phagocytosis; polyclonal anti-T cell antibodies= antithymocyte globulin (ATG) or antilymphocyte globulin (ALG); lymphocyte, monocyte, and macrophage depletion= anti-CD52; T cell depletion= anti-CD3; B cell depletion= anti-CD20 |
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immunosuppressive drugs= non deleting antibodies |
daclizumab (anti-CD25) targets activated T cells and blocks IL-2 binding |
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immunosuppressive drugs= co-stimulation blockade |
CTLA4Ig fusion protein (blocks co-stimulation); anti-CD40 ligand (blocks co-stimulation) |
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what are the perils of immunosuppression |
not specific so suppression of the whole immune system; infection with common organisms (bac/viruses) can occur (e.g. pneumocytosis); increase in cancers (3x nontransplant recipient) e.g. carcinomas of skin/genital tract, lymphoma, Kaposi's sarcoma; direct toxic effects like kidney damage; now safer; life long treatment |
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tolerance induction can prevent what |
can prevent rejection of graft by making host tolerant to alloantigens of the graft; tolerance leads to depletion, anergy, or suppression by regulatory lymphocytes; unresponsiveness to an antigen does not injure graft despite withdrawal or immunosuppresion |
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ways to induce tolerance |
mixed chimerism (hematopoietic cells in blood transfusion or bone marrow transplant)= organ transplantation with mini bone marrow transplant, wean off immunosuppressive drugs, leads to tolerance due to regulatory T cells, has been maintained for up to 10 yrs); block co-stimulation (CTLA-4); induce regulatory T cells |
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immunoprivileged sites |
brain, eye, liver, testis |
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immune privileged sites: eye |
corneal transplantation has a 90% success in absence of HLA matching or immunosuppressive therapy; cornea and anterior chamber of eye are immune privileged= environment suppresses inflammation, cornea lacks blood vessels, anterior chamber is immunosuppressive inhibits activation of T cells, macrophages, neutrophils, and complement, results in tolerance |
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xenotransplantation- why do we do it, what do we use, why is it bad |
it could provide an unlimited supply of transplantable tissue; optimal source is pigs; graft rejection= hyperacute rejection (natural antibodies present against alphagal from bacteria), delayed xenograft rejection (also called accelerated acute rejection or acute vascular rejection) occurs within 2-3 days but it's not well understood, acute/chronic rejection (similar to allograft rejection), genetically modified pigs with human genes (hDAF) could decrease immunogenicity; zoonosis (endogenous pig retroviruses) |
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bone marrow transplantation: what is it, when do we do it, where do we take the marrow from |
transplantation of pluripotent hematopoietic stem cells; can replace defects in hematopoietic system or immune system; treatment for leukemia or after chemotherapy; source= bone marrow from iliac crest of HLA matched donor or autologous bone marrow transplant, mobilized hematopoietic stem cells in peripheral blood, umbilical cord blood |
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myeloblatic therapy |
chemotherapy/radiation deplete pts bone marrow (memory cells and long lived plasma cells); to prevent rejection of grafted cells and make room for grafted cells; results in immunodeficiency; susceptible to viral and bacterial infections |
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graft-versus-host disease (GVHD) |
grafted mature T cells react with alloantigens of the host and attack skin, intestine, and liver; sensitive to HLA difference; also minor histocompatibility antigens; can remove mature T cells to decrease GVHD but leads to increase in graft failure and disease relapse (cancer pts) |
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acute GVHD |
epithelial cell necrosis in the skin, liver, and GI tract; skin rash, jaundice, diarrhea, and GI hemorrhage, in severe cases the skin or lining of the gut may slough off; may be fatal |
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chronic GVHD |
fibrosis and atrophy of the skin, liver, and/or GI tract; may involve lungs; severe cases lead to complete dysfunction of the affected organ; may be fatal |
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clinical outcome |
greater the HLA match decreases risk of GVHD and increases survival probability |
