Transplantation Immunology

Introduction Transplantation: The process of taking cells, tissues, or organs from one individual and placing them into a different individual or different site of the same individual Graft: Transplanted cells, tissues, or organs Donor: The individual who provides the graft Recipient: The individual who Receives the Graft, also called the host

Allograft Rejection Displays Specificity and Memory. Autograft Isograft ( Syngenic Graft ) Allograft Xenograft The most formidable barrier is the Immune System Allograft Rejection Displays Specificity and Memory.

Genetic Basis of Transplant Rejection Inbred mouse strains - all genes are identical Transplantation of skin between strains showed that rejection or acceptance was dependent upon the genetics of each strain Skin from an inbred mouse grafted onto the same strain of mouse ACCEPTED Skin from an inbred mouse grafted onto a different strain of mouse REJECTED

Immunological basis of graft rejection Primary rejection of strain skin e.g. 10 days Lyc Transfer lymphocytes from primed mouse 6 months Naïve mouse Secondary rejection of strain skin e.g. 3 days Primary rejection of strain skin e.g. 10 days Transplant rejection is due to an antigen specific immune response with immunological memory

Transplantation Antigens Major Histocompatibility Complex (MHC) Molecules ABO Blood Group Antigens and Tissue Specific Antigens

Mechanisms of Allograft Rejection The Immune Responses in Allogeneic Transplantation: T cell mediated rejection of allograft Antibody mediated rejection of allograft

T cell mediated rejection of allograft 1) Recognition of alloantigens 2) Activation of T cells and rejection of allograft

Recognition of alloantigens

① Direct recognition of alloantigens Recognition of an intact MHC molecule displayed by donor APC in the graft An allogeneic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus peptide

Fast and strong reaction in acute rejection

Direct recognition is a cross-reaction of a normal TCR ( which was selected to recognize self MHC molecules plus foreign peptides) with an allogeneic MHC molecule (plus peptide) As many as 2% of an individual’s T cells are capable of directly recognizing and responding to a single foreign MHC molecule.

Direct Recognition of Allogeneic MHC Molecules by TCR T cell from recipient CD8+T CD8+T APC from donor CD4+T

Direct Recognition of Allogeneic MHC Molecules by TCR CTL T cells from Recipient CTL Donor Tissue cells

② Indirect Recognition of Alloantigens Donor MHC molecules may be Processed and Presented by Recipient APCs that enter Grafts, and the Processed MHC Molecules are Recognized by T cells like Conventional Foreign Antigens

Indirect Recognition of Allogeneic MHC Molecules by TCR Host T cell CD8+T Host APC CD8+T CD4+T self APC uptakes Graft processing Presentation by self APC

Antibody Mediated Rejection of Allograft Complement activated by antibody involved in transplantation rejection

Classification of Allograft Rejection Hyper-Acute Acute Chronic

Hyper-Acute Rejection Within Minutes to 1-2 days after host blood vessels are anastomosed to graft vessels Characterized by thrombotic occlusion of the graft vasculature Mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens Results in Complement Activation, Endothelial Damage, Inflammation and thrombosis Immune suppression is not effective

Acute tubulointerstitial rejection: Mononuclear interstitial infiltrate.

Chronic Rejection Develops Months or years after Transplantation Characterized by fibrosis and vascular abnormalities with Loss of Graft Function The mechanisms of chronic rejection include both humoral and cell-mediated responses

Chronic Vascular Rejection - Concentric Fibrous Intimal Thickening and Lymphocytic Infiltration

Prevention and Treatment of Allograft Rejection ① Reducing the Immunogenicity of Allografts（Tissue Typing) ② Immuno-suppression

① Reducing the Immunogenicity of Allografts Donors and Recipients are Typed for ABO and MHC Antigens Blood Group Antigen Matching, Cross Match MHC Matching HLA-A, B and HLA-DR is important for Predicting outcome.

② Immunosuppression Immunosuppressive drugs that inhibit or kill T cells Cyclosporine(CsA), FK506 Anti-inflammatory agents are also routinely used Corticosteroids to block the synthesis and secretion of cytokines

Xenotransplantation lack of organs for Transplantation Hyper acute Rejection Lack of Inhibitory Mechanisms of Complement Transgenic Pigs

GVHD