TRANSPLANT IMMUNOLOGY Shiv Pillai Ragon Institute of MGH, MIT and Harvard
Outline MHC / HLA Direct vs indirect allorecognition Alloreactive cells: where do they come from? Rejection and Immunosuppression Tolerance
DEFINITIONS Syngeneic: Refers to transplants betweeen genetically identical animals (I.e. identical twins, inbred strains of animals). Accept transplants from one-another without immunosuppression. Allogeneic: Transplants between animals mismatched for MHC or other histocompatibility genes, within the same species. Xenogeneic: Transplants between species.
People living with a functioning graft at year end 1999-2007
Genetics of solid organ transplantation
Inheritance and Expression of HLA genes HLA haplotype A2, B5, DR3 A1, B7, DR9 HLA haplotype A1, B24, DR14 A24, B27, DR2 HLA haplotype A2, B5, DR3 A1, B24, DR14 HLA genes are inherited as a haplotype and co-dominantly expressed
Why such a high precursor frequency of Alloreactive T cells? Frequency of T cells that recognize an alloantigen: Approx. 1/20 Frequency of T cells that recognize a given peptide antigen: Approx. 1/100,000-1/1,000,000
The TCR is generated with a bias towards MHC recognition 11
All DP TCRs see MHC like Shapes BEFORE selection 12
Thymic T cell development Downloaded from: StudentConsult (on 26 April 2013 09:12 PM) 2005 Elsevier
Strong anti-self Weak anti-self Strong anti-allo
Two Types of Allorecognition
Two Types of Allorecognition
Minor antigens I have the same MHC! Minor antigens are polymorphic variants of peptides that bind the same MHC
Hyperacute Rejection
Preventing Hyperacute Rejection The Crossmatch Sera from potential recipients Donor cell + vital dye positive crossmatch + negative crossmatch
Acute Rejection
Acute Graft Rejection Induction Therapy T cell depleting: Thymoglobulin rabbit anti-thymocyte globulin CAMPATH-1H anti-cd52 Concept: 1. Many antigen-specific cells will be deleted, enabling more effective immunosuppression. 2. Possibly, the antigen-specific reconstituting cells will be educated to be regulatory T cells by the presence of the graft in a non-inflammatory environment.
Acute Graft Rejection Induction Therapy MHC CTLA4Ig B7 APC TCR CD28 T Cell Activation Inhibit T cell activation/block costimulation: Belatacept (modified CTLA4Ig) Concept: 1. Antigen-specific cells will be selectively rendered anergic/apoptotic because CD28 costimulation is blocked.
Acute Graft Rejection Induction Therapy TCR MHC Anti-CD25 APC B7 CD28 Y Growth and Survival IL-2R T Cell Targets activated T cells: Anti-CD25 mabs (basiliximab, daclizumab) Concept: 1. Blocks a key cytokine needed for cell proliferation/survival
Acute Graft Rejection Maintenance Therapy CD8 APC cytokines CD4 T cell expansion more cytokine production activated T lymphocytes (CTLs, DTH effectors) macrophage activation B cell maturation, antibody production
Acute Graft Rejection Maintenance Therapy CD8 Azathioprine Mycophenolate APC T cell expansion Belatacept Rapamycin cytokines CD4 Cyclosporine Tacrolimus activated T lymphocytes (CTLs, DTH effectors) Steroids more cytokine production macrophage activation B cell maturation, antibody production
Acute Rejection is not that common: Incidence of first acute rejection among adult patients receiving a kidney transplant in 2005 2009
Chronic Rejection Both T cell memory and long-lived anti-hla antibodies are a problem
Chronic Rejection remains a problem
Mechanism: cyclosporin A and FK-506
Early Signaling Events in T cell Activation (1) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Saunders, an imprint of Elsevier Inc.
Early Signaling Events in T cell Activation (2) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by Saunders, an imprint an imprint of of Elsevier Inc. Inc.
T cell Signaling Downstream of PLCg1 (1) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Saunders, an imprint of Elsevier Inc.
T cell Signaling Downstream of PLCg1 (2) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Saunders, an imprint of Elsevier Inc.
T cell Signaling Downstream of PLCg1 (3) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 Copyright by Saunders, 2011 by Saunders, an an imprint of of Elsevier Inc. Inc.
Activation of Transcription Factors in T Cells Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Saunders, Copyright 2011 an by Saunders, imprint an imprint of Elsevier of Inc.
Tolerance is an obvious solution Transplantation tolerance - durable and functional persistence of a tissue, in the absence of a deleterious immune response without ongoing therapeutic intervention. MIXED CHIMERISM HAS BEEN OCCASSIONALLY SUCCESSFUL
Allogeneic bone-marrow transplantation to create tolerance David Sachs, Tatsuo Kawai and Ben Cosimi, MGH One-haplotype HLA mismatched living donors Kidney Transplant Donor Bone Marrow Transplant Thymic Irradiation 7 Gy Cyclophosphamide steroids CsA or Tacrolimus -7-5 4-2 1 0 1 day 9-12 months Rituximab (anti-b cell) Anti-CD2 mab
Renal allograft tolerance through mixed chimerism T=0 T=2yr T=4yr T=6yr T=8yr T=0 T=2yr T=4yr Cr 1.9 mg/dl Cr 1.8 mg/dl Cr 1.6 mg/dl Cr 1.2 mg/dl Transplant IS free Post-transplant follow-up Tapering Graft loss Post-study observation All patients developed transient multi-lineage mixed chimerism, which was lost in 7 14 days Engraftment syndrome developed ~ day 10 with fever, and self limited renal dysfunction. Previously described in BMT but renal dysfunction more severe in transplanted kidneys
Other bone marrow/chimerism approaches Anti-thymocyte globulin, cyclophosphamide, fludaribine, low dose total body irradiation (Johns Hopkins). Similar to above plus a proprietary product called a facilitating cell (Northwestern). Anti-thymocyte globulin, hi dose total lymphoid irradiation (Stanford). Thanks to Jon Maltzman and Larry Turka
Cyclosporin Blues.. 44