Chronic Rejection in the Aorta Transplantation Model

Since the first successful heart transplantation in man in 1967, cardiac transplantation has become an accepted form of therapy for certain types of end-stage heart diseases.! After transplantation of a cadaveric heart graft, the immune system of the recipient will come in contact with donor cells. As clinical heart transplantation is an allogeneic type of grafting (genetically non-identical members of the same species), an immune response, which may result in graft rejection, will be inevitable. Of the foreign antigens that may be recognized by the immune system of the recipient, the major histocompatibility complex (MHC), in man the human leucocyte antigen (HLA) system, is the most important.2 - 4 In short, the HLA system consists of a group of closely linked genes, located on the short arm of chromosome-6 and divided in three regions, which encode class I and class II cell surface glycoproteins and several components of the complement system respectively. Class I is expressed on the surfaces of all nucleated cells. Class II is mainly expressed on antigen presenting cells (e.g, macrophages, dendritic cells, and B cells). After transplantation, T cell receptors of recipient CD4+ cells are able to recognize HLA class II, resulting in activation of type I and type 2 helper (THI and TH2) cells.' The activated THI cell start to preferentially synthesize and release interleukin-2 (IL-2) and interferon-gamma (IFN-y). IL-2 stimulates CD8+ T cells to develop into mature cytotoxic effector cells. Binding of these cells to donor HLA class I may result in graft cell lysis. IFN-y is responsible for the activation of macrophages, which are believed to be cytotoxic to graft cells. TH2 cells preferentially secrete IL-4, IL-6 and IL-IO. These interleukins are growth and differentiation factors for B cells. Activation of B cells may result in maturation into plasma cells with a11ospecific antibody production. Clinically, the two most important types of rejection that may occur after transplantation are acute and chronic rejection.