o oMAJOR CONCEPTS IN TRANSPLANT IMMUNOLOGY oHow does the immune system deal with a transplant, i.e.

What are the mechanisms of rejection? oWhat are the current clinical strategies to block rejection? oWhat are the new and future strategies to promote specific immune tolerance? oWhat is the role of xenotransplantation? oWhat is graft versus host disease? oContent oMechanisms oRejection types nHyperacute nAcute nChronic o oLaboratory tests oManagement of rejection oBone marrow transplantation, GvHD and GvL effect oIn vivo imaging cool images for those who are patient oANTIGEN INDEPENDENT MECHANISMS oPERITRANSPLANT ISCHEMIA

oMECHANICAL TRAUMA

oREPERFUSION INJURY oPeritransplant injury induces chemokines that increase inflammation and immunity o oEarly inflammatory injury to graft promotes continued chemokine expression that persists and contributes to and chronic rejection oTransplants and the immune system oDiscrimination between self/nonself oThis is not good for transplants oAt first the only possible transplants were blood transfusions oOtherwise the grafts were disastrous

Why are blood transfusions tolerated?

oImmune mechanisms oSkin is transplanted to genetically different organisms oGraft oCellular and Molecular Understandings oHyperacute Rejection oAcute Rejection oSeen in recipient that has not been previously sensitized to the transplant oMediated by T cells and is a result of their direct recognition of alloantigens expressed by the donor oVery common in mismatched tissue or insufficient immunosuppressive treatment oReduced by immunosuppressive therapy o

o oAllograft 1.Exam of rejection site reveals lymphocyte and monocytic cellular infiltration reminiscent of the delayed type hypersensitivity reaction 2.Animals that lack T lymphocytes do not reject allograft or engrafts 3.Rejection doesnt occur at all in immunosuppressed individuals oChronic rejection oCaused by both antibody and cell-mediated immunity oMay occur months to years down the road in allograft transplants after normal function has been assumed oImportant to point out rate, extent, and underlying mechanisms of rejection that vary depending on tissue and site oThe recipients circulation, lymphatic drainage, expression of MHC antigens and other factors determine the rejection rate oInflammation, smooth muscle proliferation, fibrosis oTissue ischemia o oHistology of graft rejection oRole of MHC molecules oWhen T cells are exposed to foreign cells expressing non-self MHC, many clones are tricked into activation - their TCRs bind to foreign MHC-peptide complexs presented o T cells are reacting directly with the donor APCs expressing allogeneic MHC in combination with peptide. These donor APCs also have costimulatory activity to generate the second signal for the second reaction to occur oMinor H antigens are encoded by genes outside the MHC oT Cells and Cytokines oCD4+ and CD8+ oDTH o oIndirect donor APC shed MHC that activate immune system that then reacts to transplanted organ oLaboratory Tests oABO Blood typing oTissue typing (HLA Matching) o(Lymphocytotoxicity test) o(Mixed leukocyte reaction) oScreening for Presence of Preformed Antibodies to allogeneic HLA oCrossmatching oProlonging Allograft Survival oAnti-inflammatory Agents oCytotoxic Drugs oAgents that interfere with Cytokine production and signaling oImmunosuppressive Therapies oNew Immunosuppressive strategies oProlonging Allograft Survival oCyclosporine and Tacrolimus (FK-506) oAzathioprine oMycophenolate Mofetil oRapamycine oCorticosteroids oAnti-CD3, Anti-CD52, Anti-IL-2, AntiCD25 oProlonging Allograft Survival oProlonging Allograft Survival oSITES OF ACTION OF MAJOR IMMUNOSUPPRESSIVE DRUGS oANTIGEN SPECIFIC TOLERANCE

(VS GENERAL IMMUNOSUPPRESSION) oDecreases risk of infections and secondary cancers oEnhance allospecific T regulatory cell stimulation oMonoclonal antibodies or protein blockers for costimulatory molecules oMyeloablation followed by reconstitution with chimeric marrow - as T cells mature in the thymus, the immune system is recreated oDecrease graft immunogenicity oTransplant to privileged sites oInject thymus with alloantigen to induce clonal deletion with tolerance for donor antigens o o oHow to manipulate T reg activity to induce transplant tolerance? oBone Marrow oAttempts to use these cells have been around for at least 60 years oExplored intensely since world war II oUsed for treating blood diseases, severe combined immunodiffency and leukemia oThis type of transplant is also called a form of gene therapy oTypes of Transplants oAutologous Transplant nPatients own stem cells o oAllogeneic Transplant nStem cells from someone else=donor stem cells n oEarly Allogeneic Transplants oToxicity noted in early allogeneic studies: n2 disease of diarrhea, liver necrosis & skin nTermed Graft Versus Host Disease (GVHD) nNow well recognized toxicity of alloBMT o oGVHD pts had less leukemic relapse nin 1968, of 14 AlloBMT patients n10/20 died of GVHD w/o evidence of leukemia n4/20 had no GVHD, died of recurrent leukemia nSame donor cells causing toxicity were anti-leukemic nTermed the Graft Vs Leukemic Effect (GVL)

oGVL & GVHD is Immune Mediated oDonor Immune cells recognize Recipient cells as non-self oT-cell & NK cell response nAttack host cells: malignant and normal host cells oBalance of this immune response: oMinimize GVHD + Maximize GVL n1) Immunosuppressive Therapy with BMT n2) HLA-Match Donor & Recipient oMatch major antigens to decrease GVHD oMismatch of minor antigens results in GVL n oSource of stem cells for Transplants o Bone Marrow graft o Peripheral Blood Stem Cells (PBSCT) o Umbilical cord

n oSource of stem cells for Transplants o Peripheral Blood Stem Cells (PBSCT) oStem cells collected peripherally using apheresis (cell separator machine) oLess invasive; less discomfort; less morbidity than BM oOutpatient procedure oPBSCT results in more rapid hematopoietic recovery than BM oNo difference in treatment outcome oQuickly replacing traditional BM o nUsing cytokine stimulation (G-CSF injections) n BM releases large number CD34 stem cells into circulation nStem cells harvested via peripheral line

n oComplications oInfections nEarly: oPotentially life threatening oMain complication in first 30 days oCMV infections have high mortality (so prophylaxis and early intervention important) nLate: oImmune function takes 1 year (autologous) to 2 years (allogeneic) to fully recover oLater opportunistic infections common, including pneumocystis carinii (PCP) and herpes zoster oProphylaxis required for 6-12 months oComplications (Cond) oGVHD oAllogeneic complication oDonor T cell response against recipient tissue cells oProphylaxis against GVHD begins day +1 with immunosuppressive agents nCyclosporine, methotrexate, mycophenelate oAcute GVHD first 3-6 months: n Skin, GI (especially diarrhea) or obstructive Liver dysfunction n>60% develop oChronic GVHD develops 12-18 months post transplant: nAutoimmune manifestations of Skin especially, as well as GI, Liver and Lung n30-40% develop oComplications (Cond) oVeno-Occlusive Disease (VOD) oObstructive liver disease due to microthrombi in liver venules oPatients with previous liver disease at greater risk oNo good treatments oGraft Rejection oRare in present day (<1%) o o o o oXenogenic Transplantation o>50,000 people that need organs die while waiting for a donor oStudies are underway involving nonhuman organs

oAttention has been focused on the pig but the problem is the existence of natural or preformed antibodies to carbohydrate moieties expressed in the grafts endothelial cells oAs a consequence activation of the compliment cascade occurs rapidly and hyperacute rejection ensues oConcern has given to debate about the safe use of xenografts and animal tissues that the tissues might harbor germs o