You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation Immunology of Transplant RejectionArticle Last Updated: Jun 14, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 8
  Author: Randy P Prescilla, MD, Instructor in Anesthesia, Harvard Medical School; Assistant in Perioperative Anesthesia, Children's Hospital Boston Editors: Richard G Ohye, MD, Director, Pediatric Cardiac Transplantation, Fellowship Program Director, Pediatric Cardiac Surgery, Assistant Professor, Department of Surgery, Section of Cardiac Surgery, University of Michigan Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steve Dunn, MD, Chief, Solid Organ Transplantation, Department of Surgery, Alfred I DuPont Hospital for Children at Wilmington; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Mary C Mancini, MD, PhD, Director of Cardiothoracic Transplantation, Professor, Department of Surgery, Louisiana State University Health Sciences Center Author and Editor Disclosure Synonyms and related keywords: immunology of transplant rejection, transplantation immunology, transplantation, transplant immunology OVERVIEWSection 2 of 8
  Transplantation immunology refers to an extensive sequence of events that occurs after an allograft or a xenograft is removed from a donor and then transplanted into a recipient. Tissue is damaged at both the graft and the transplantation sites. An inflammatory reaction follows immediately, and innate immune responses are initiated. In one model, cellular components of the immune system are believed to produce mediators that perpetuate the inflammation and promote maturation of adaptive immune responses. In another model, innate immunity is triggered when highly conserved molecules on the surface of injured cells engage receptors expressed by cells of the innate immune system. Eventually, damage is controlled through tissue repair and reinforcement; if damage is nonpathologic, the graft survives. TISSUE DAMAGE AND INFLAMMATIONSection 3 of 8
Antigen-independent causes of tissue damage (ie, ischemia, hypothermia, reperfusion injury) are the result of mechanical trauma as well as disruption of the blood supply as the graft is harvested. In contrast, antigen-dependent causes of tissue damage involve immune-mediated damage. Macrophages release cytokines (eg, tumor necrosis factor, interleukin-1 [IL-1]), which heighten the intensity of inflammation by stimulating inflammatory endothelial responses; these endothelial changes help recruit large numbers of T cells to the transplantation site. Cytokines also promote T-cell survival. These include IL-2, IL-4, IL-7 and IL-15. The role of T cells in immune response has recently been reviewed (Jiang, 2006). The possible role of natural killer (NK) cells in solid organ rejection and tolerance has also been reviewed (Kitchens, 2006). ACTIVATION OF BIOCHEMICAL CASCADESSection 4 of 8
Damaged tissues release proinflammatory mediators (eg, Hageman factor [factor XII]) that trigger several biochemical cascades. The clotting cascade induces fibrin and several related fibrinopeptides, which promote local vascular permeability and attract neutrophils and macrophages. The kinin cascade principally produces bradykinin, which promotes vasodilation, smooth muscle contraction, and increased vascular permeability. The formation of an antibody-antigen complex (ie, immune complex) activates the classic pathway of the complement system. C1q triggers the activation process when it docks onto antibodies within the immune complexes. Activated complement causes damage through the deposition of the membrane attack complex (eg, C5b, C6, C7, C8, C9) and cell-bound ligands, such as C4b and C3b, which activate leukocytes bearing complement receptors. In addition, production of bioactive anaphylatoxins C5a and C3a causes the influx and activation of inflammatory cells. These chemoattractants also initiate mast cell degranulation, which releases several mediators. Histamine and 5-hydroxytryptamine increase vascular permeability. Prostaglandin E2 promotes vasodilation and vascular permeability. Leukotrienes B4 and D2 promote leukocyte accumulation and vascular permeability. Another means by which complement is activated is through tissue ischemia and reperfusion, which exposes phospholipids and mitochondrial proteins. These by-products activate complement directly through binding C1q or mannose-binding lectin; they activate complement indirectly by binding natural antibodies or C-reactive protein, which can activate the classic complement pathway by binding C1q. ROLE OF HUMAN LEUKOCYTE ANTIGEN SYSTEMSection 5 of 8
Following transplantation, T cells are activated by the presence of allogeneic human leukocyte antigen (HLA) molecules. The HLA system is the human version of the major histocompatibility complex (MHC). It is located on chromosome 6 and contains over 200 genes. At least 40 genes encode leukocyte antigens. The HLA genes involved in the immune response have been classified into class I and II; both class I and II molecules act to present antigens to T cells, a process that initiates the adaptive immune response. Allogeneic MHC antigens provoke the strongest immunologic responses. These reactions can cause rapid elimination of donor cells and graft rejection, thus representing the major hurdle to successful allograft engraftment. For optimal graft outcome, compatibility at 3 HLA loci (ie, HLA-A, HLA-B, HLA-DR) is most desirable. T cells recognize the allogeneic HLA molecules either directly or indirectly. In direct presentation, T cells recognize the determinant peptides on the intact HLA molecules displayed on the surface of the transplanted cells. The mechanism of indirect presentation has been elucidated more recently. Donor HLA molecules are processed and presented as peptides by the recipient's antigen-presenting cells (APCs). APCs, which include dendritic cells, macrophages, B cells, and endothelial cells, possess co-stimulatory adhesion molecules that serve as ligands for counterreceptors on T cells. APCs also provide essential co-stimulatory signals that promote T-cell proliferation and differentiation into either helper or effector lymphocytes. TISSUE REPAIR AND REINFORCEMENTSection 6 of 8
If damage is minimal or the immunologic response has been contained, macrophages begin repair and structural reinforcement of damaged tissues. This process also involves endothelial cells, smooth muscles cells, fibroblasts, and the extracellular matrix. REJECTIONSection 7 of 8
Rejection is the consequence of the recipient's alloimmune response to the nonself antigens expressed by donor tissues. In hyperacute rejection, transplant patients are serologically presensitized to alloantigens (ie, graft antigens are recognized as nonself). Histologically, numerous polymorphonuclear leukocytes (PMNs) exist within the graft vasculature and are associated with widespread microthrombi formation and platelet accumulation. Little or no leukocyte infiltration occurs. Hyperacute rejection manifests within minutes to hours of graft implantation. Hyperacute rejection has become relatively rare since the introduction of routine pretransplantation screening of graft recipients for antidonor antibodies. In acute rejection, graft antigens are recognized by T cells; the resulting cytokine release eventually leads to tissue distortion, vascular insufficiency, and cell destruction. Histologically, leukocytes are present, dominated by equivalent numbers of macrophages and T cells within the interstitium. These processes can occur within 24 hours of transplantation and occur over a period of days to weeks. In chronic rejection, pathologic tissue remodeling results from peritransplant and posttransplant trauma. Cytokines and tissue growth factor induce smooth muscle cells to proliferate, to migrate, and to produce new matrix material. Interstitial fibroblasts are also induced to produce collagen. Histologically, progressive neointimal formation occurs within large and medium arteries and, to a lesser extent, within veins of the graft. Leukocyte infiltration usually is mild or even absent. All these result in reduced blood flow, with subsequent regional tissue ischemia, fibrosis, and cell death. The primary aim of immunosuppression has been to control acute rejection by allowing tissue repair to develop. Most combination therapies block T-cell activation by providing intense immunosuppression during the immediate posttransplantation period (induction phase). Later, multiple-drug cocktails (maintenance immunosuppressive phase) are administered to maintain a state of low- or nonresponsiveness to the allograft. Currently, no accepted therapeutic strategy exists for chronic rejection. CD40 and CD28 pathways have been proposed as important in initiating T-cell responses and lowering T-cell activation threshold, respectively. Blocking T-cell costimulation has been proposed to improve long-term outcomes. REFERENCESSection 8 of 8
Immunology of Transplant Rejection excerpt Article Last Updated: Jun 14, 2006 |
