Transplant Immunology Session 29 PDF

Immunology Session 29 Transplant Immunology Jeremy Ellermeier 360J Dobbelaere Hall 623-572-3687 Learning Objectives ▪ Define the different graft types: autograft, isograft, allograft, xenograft ▪ Describe an alloantigen and how it can be recognized by both alloreactive T and B lymphocytes to m...

Immunology Session 29 Transplant Immunology Jeremy Ellermeier 360J Dobbelaere Hall 623-572-3687 Learning Objectives ▪ Define the different graft types: autograft, isograft, allograft, xenograft ▪ Describe an alloantigen and how it can be recognized by both alloreactive T and B lymphocytes to mediate graft rejection Compare/contrast direct vs indirect alloantigen presentation ▪ Compare/contrast the types of graft rejection with respect to the timing, effector cells/substances, and mechanism of graft destruction Host vs Graft: hyperacute, acute, and chronic Graft vs Host Disease (GvHD): can be acute and/or chronic ▪ Understand the significance of ABO typing, crossmatching, and HLA typing in minimizing or preventing graft rejection ▪ Explain the difference between general immunosuppressive therapy and specific suppression of T cells, and know the examples discussed in class Focus on the mechanisms of action 2 Transplantation ▪ The process of taking cells, tissues, organs (graft) from one individual (donor) and placing them into another individual (recipient) ▪ Individual differences in the molecular structures of cells and tissues occur due to genetic variation inherent in humans Grafts are likely antigenically different and may stimulate an immune response that can result in graft rejection Graft rejection is mediated by the adaptive immune system Terminology ▪ Autologous graft = autograft Transplant from one individual to the same individual ▪ Syngeneic graft = isograft Transplant between two genetically identical individuals ▪ Allogeneic graft = allograft Transplant between two genetically individuals in the same species ▪ Xenogeneic graft = xenograft Transplanted between individuals of different species ▪ The degree of the immune response varies with the type of graft Autograft  Isograft < Allograft < Xenograft Transplantation ▪ Both HSC & solid organ/tissue transplants ▪ Most transplants done today are allografts Foreign antigens on the surface of the transplanted cells/tissue = alloantigens Most of these are protein antigens encoded by polymorphic genes that differ among individuals The lymphocytes and antibodies that react against the alloantigens are alloreactive: Alloreactive T cells These are also called alloantigen-specific Alloreactive B cells Alloreactive immunoglobulins ▪ The major limitation to transplantations is the presence of alloreactive T and B cells Histocompatibility Antigens ▪ Major histocompatibility antigens = MHC molecules These elicit strong immune responses Mismatches in MHC are responsible for strong allograft rejection reactions ▪ Minor histocompatibility antigens: various molecules (not pictured) Induce weaker or slower rejection reactions Histocompatibility: MHC ▪ Histocompatibility type = each person’s set of MHC glycoproteins Haplotype = set of MHC alleles on each chromosome; each individual has two haplotypes Identical twins are haploidentical = 100% HLA-matched MHC molecules are required for T cell activation – why they are responsible for strong, rapid rejection events – Focus on MHC molecules as alloantigens Inheritance pattern of the HLA-A, HLA-B, & HLA-DR alleles, which are the 6 most important alleles to match for many (but not all) solid organ transplants There is a 25% chance two siblings with same parents are haploidentical; parents are only 50% HLA-matched with their children (assuming the parents are heterozygous and different from each other) Recognition of Allogeneic MHC ▪ Allogeneic MHC molecules of a graft are recognized by recipient’s T cells: Direct recognition: cDCs from the donor (graft) present various peptides in MHCs to Activate T cells CTL killing of graft ▪ Indirect recognition: Recipient cDCs phagocytose graft cells; present peptides derived from donor MHC molecules in Class II MHC Activate Th cells Antibody-mediated injury and inflammation Direct Recognition of Allogeneic MHC ▪ An allogeneic MHC molecule (on the donor’s cells) with a self peptide can mimic the shape of a self MHC molecule (on the recipient’s cells) containing a foreign peptide. Fig. A: Normal presentation of foreign peptide to T cells Fig. B: Presentation of self peptide in allogeneic MHC – Allogeneic MHC itself mimics the “shape” in Figure A Fig. C: Presentation of self peptide in allogeneic MHC – combination of allogeneic MHC + self-peptide mimics the “shape” in Figure A ▪ Allografts can elicit strong immune responses Direct Recognition of Allogeneic MHC ▪ Transport of alloantigens to secondary lymphatic tissues; activation of alloantigen-specific T cells, which migrate back into the graft and destroy graft cells Alloantibodies also can be produced and participate in rejection events (not shown in this figure) Summary: Immune Mechanisms Involved in Graft Rejection ▪ Alloreactive Th cells play a big role in chronic rejection (hypersensitive reaction) ▪ Alloreactive CTLs play a big role in acute rejection (directly kill nucleated cells in the graft) Cytokine help ▪ Alloantibodies are involved in MAC-mediated lysis and ADCC Host vs Graft Rejection ▪ Hyperacute rejection Begins within minutes to hours after blood vessels are anastomosed to graft vessels. Mediated by preexisting antibodies in the recipient against alloantigens on endothelial cells of the graft Commonly alloantigens are ABO blood group antigens or MHC molecules Antibodies arise as a result previous exposure to alloantigens Eg., blood transfusions or previous transplantations Host vs Graft Rejection ▪ Hyperacute rejection Complement activation attracts PMNs PMNs release lytic enzymes that damage the endothelium, activating clotting mechanisms Thrombi formation No blood flow to graft ▪ Hyperacute rejections are prevented by performing ABO blood Hyperacute rejection of a kidney allograft typing and cross- matching tests Host vs Graft Rejection ▪ Acute rejection Can occur as early as 7-10 days post- transplantation, but typically will be within the first 2 months (if it occurs) T cells play a major role = acute cellular rejection T cells respond to alloantigens on endothelial and parenchymal cells – CD4 T cell-mediated inflammation – CD8 T cell lysis of graft cells Host vs Graft Rejection ▪ Acute rejection Alloantibodies can also participate in rejection = acute antibody-mediated rejection Alloantibodies cause acute rejection by binding to alloantigens on vascular endothelial cells – Complement activation – Endothelial cell injury & intravascular Acute antibody-mediated rejection thrombosis of a kidney allograft; inflammatory Complement deposition in capillaries cells in peritubular capillaries in acute antibody-mediated rejection Preventing Acute Rejection ▪ In order to minimize acute rejection events, HLA typing (tissue typing) and crossmatching tests are performed Generally, the fewer the number of HLA mismatches, the greater the chance for graft survival Patients will be on life-long immunosuppressive therapy Host vs Graft Rejection ▪ Chronic rejection Loss of graft function during a prolonged period of months to years post- transplantation Increased fibrosis due to chronic inflammation – TH1 cell cytokines stimulate increased matrix synthesis Smooth muscle cell proliferation in the vascular intima – Activated T cells in the graft induce Both inflammation macrophages to secrete cytokines & and proliferation smooth muscle growth factors result in reduced blood flow, with subsequent regional tissue ischemia, fibrosis, and cell death Graft vs Host Disease (GvHD) https://emedicine.medscape.com/ ▪ T cells from the graft become activated against the recipient’s article/429037-overview tissues Complication in HSC transplants; may also occur in other transplanted tissue containing a large number of T cells Donor T cells (from graft) recognize various alloantigens on the recipient’s (host) cells and attack host tissues Can be acute or chronic: often attacking the skin, liver and GI tract http://www.cancernetwork.com/hematologic-malignancies/graft-versus- https://www.aboutkidshealth.ca/Article?contentid=1569&language=English host-disease-complex-long-term-side-effect-hematopoietic-stem-cell Immunosuppressive Therapy ▪ Immunosuppressive drugs are classified as induction therapies and maintenance therapies Induction therapies: intense, early post-operative immune suppression Maintenance therapies: live-long therapies to prevent rejection events Details in these two tables are FYI General Immunosuppressive Therapy ▪ Some general immunosuppressive agents: Corticosteroids: inhibit inflammation, decrease IL-1 & IL-2 production, and reduce MHC expression on APCs Mitotic inhibitors: inhibit the biosynthesis of nucleic acids Azathioprine (Aza) Mycophenolate mofetil (MMF) T Cell Specific Immunosuppressive Therapy ▪ Some specific T cell immunosuppressive agents: Tacrolimus Inhibition of IL-2 synthesis Basiliximab anti-CD25 that blocks IL-2 binding to IL-2R Sirolimus inhibition of IL-2R signaling (mTOR inhibitor) Summary Graft Type Definition Examples Potential Immune Response Autograft Self to self Skin grafts No Isograft Between identical Any tissues Yes, but often twins minimal Allograft Human to human Any tissues Yes (not identical) Xenograft Between species Baboon to human Yes, more than heart transplant allografts ▪ MHC alleles elicit strong graft rejection; minor histocompatibility antigens can also play a role Direct presentation = Donor APCs can present donor antigens to recipient T cells Indirect presentation = Recipient APCs can present donor antigen (peptides of donor MHC) to recipient T cells Summary Rejection Mechanism (see slide 11) Time Frame Prevention Therapy Hyperacute Pre-existing antibodies Minutes to Type blood, None activate complement + ADCC hours post- screen for pre- transplant existing Igs Acute B/T cell activation: Earliest: 7-10 Above, plus type General and specific T cells: CTL killing + Th1 cell- days post- and match MHCs immunotherapy (see mediated inflammation transplant; as best as notes for specific B cells: antibodies activate generally possible (degree ones covered & complement + ADCC within 2-3 mo. of matching varies summary table on among tissues) next slide): induction and maintenance phases Chronic Th1-mediated inflammation; Months to Match MHCs as Preventing acute growth factors to increase years post- best as possible may slow proliferation of vascular transplant development of smooth muscle chronic. GvHD Same as for both acute and Varies – Match MHCs + Same as for acute chronic; donor immune similar to partial T cell system attacking host acute and depletion of graft chronic Summary Note: we did not cover all the ones in these figures/tables; you are only responsible for the ones covered in class Summary: Immunosuppressive Therapies  See slides 19-21 for additional Note: we did information not cover all the ones in these figures/tables; you are only responsible for the ones covered in class 24  Midwestern Wellness Support Professional school can be difficult, we have resources Other Mental Health Resources Student Counselors If you or someone you know are feeling suicidal: Brandy Strom, Psy.D., MS, LPC Krista Sheldon, MSW, LCSW  EMPACT Mobile Crisis Intervention/Suicide Melody McGee-Hillard, MA, Ed.S, LPC, NCC Prevention Center – 24/7 Emergency Mental Health Aaron “Baab” Aster, MA, LPC, NCC Crises, including Suicidal ideation/Suicide 480-736-4952 Please email to request an appointment:  Call or text 988 – 24/7 Confidential Lifeline network crisis center [email protected] Teletherapy (ALL MWU students can access the following free services) Academic Support Academic, Communication, and Language Support Academic Live Care: Amy Woodbeck, M.Ed., M.S.Psy– Learning https://midwestern.myahpcare.com/telehealth to register. 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