Transplant rejections: The MHC (major histocompatibility complex) plays a major role in transplant rejection because it varies greatly among individuals. Graft rejection is an adaptive immune response. HLA matching is essential, but it isn’t the only determinant of transplant rejection.
Molecules called minor histocompatibility antigens present polymorphic self peptides to T cells. They can cause transplant rejection, usually less severe than rejection caused by major MHC polymorphisms. Some minor histocompatibility antigens are encoded on the Y chromosome and are called H-Y antigens.
In direct allorecognition, donor APCs in the allograft present foreign MHC antigens to host T cells. These host T cells are activated and destroy graft cells bearing the foreign MHC (i.e., the graft). In indirect allorecognition, host APCs present alloantigens to host T cells, which are activated and destroy the grafted tissue.
Pre-existing antibodies to blood group antigens and polymorphic MHC antigens can cause complement-mediated rapid transplant rejection within minutes of transplantation. Memory T cells can also accelerate allograft rejection.
Following are the types of transplant rejections:
i) Hyperacute rejection: It is caused by preformed anti-donor antibodies in the recipient (host). These antibodies activate complement and stimulate endothelial cells to secrete Von Willebrand procoagulant factor, resulting in platelet adhesion and aggregation. It occurs within minutes and causes widespread intravascular thrombosis and graft damage. It can be prevented by cross matching between donor graft cells and host sera for ABO and HLA compatibility.
ii) Acute rejection: It occurs between a week and a few months after transplantation. It has both T cell- and B cell-mediated effects.
Effector T cells can cause cytokine- or chemokine-mediated cell lysis and can also act through activation of CD8 T cells. B cells act as APCs and produce antibodies and cytokines that lead to graft rejection.
Microscopy shows the presence of neutrophils and macrophages in peritubular capillaries and tissues, along with fibrinoid necrosis, thrombosis, and tissue damage. Immunoglobulins and complement are present in the tissues.
iii) Chronic rejection: It is the most common cause of transplant rejection and occurs months to years following transplantation. Microscopy shows increased thickness of the vessel intima, arteriosclerosis, interstitial fibrosis, and tubular atrophy. CD4 T cells and macrophages accumulate in the graft.
Both T cells and antibodies play a role in chronic rejection. Antibody-induced complement cell lysis, endothelial proliferation, and NK cell activation cause chronic damage. Adverse effects of immunosuppressive drugs like calcineurin may contribute to tissue damage.
Graft versus host disease or GVHD: It is seen most commonly in bone marrow transplants. Blood transfusions and solid organ transplants like liver, kidney, and heart are also associated with GVHD.
GVHD is caused by donor T cells (in the bone marrow transplant) reacting against host cells. It may be acute or chronic. Acute GVHD is seen within a few weeks after transplantation. Chronic GVHD may be seen up to a few years after stem cell transplant.
Apart from the deleterious effects of GVHD, it also attacks and kills leukemic cells in the host and is associated with a lower rate of relapse.
The presence of alloreactive T cells can be demonstrated by the mixed lymphocyte reaction (MLR). In this test, lymphocytes from a potential donor are mixed with irradiated or mitomycin C-treated lymphocytes from the potential recipient (the treated recipient cells cannot replicate). If alloreactive T cells are present in the donor sample, they will be stimulated to multiply and become effector T cells.
Differences in MHC II alleles cause CD4 T cells to proliferate, which can be measured by a thymidine incorporation assay. This assay uses radioactive thymidine, which is incorporated into newly synthesized DNA. Higher cell proliferation leads to higher measured radioactivity.
Differences in MHC II alleles can also generate activated, cytotoxic CD8 T cells, which can be measured by chromium-labelled cell lysis using a chromium release assay. In this assay, chromium-labelled RBCs are lysed by cytotoxic T cells, causing release of chromium from the cells. Greater CD8 activity leads to more chromium released.
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