Transplant rejections | Immunology

Transplant rejections: The MHC or major histocompatibility complex plays a major role in transplant rejection as it is very heterogeneous amongst individuals. Graft rejection is an adaptive immune response. HLA matching is essential but not the only determinant of transplant rejections. Molecules of the “minor histocompatibility antigens” present polymorphic self peptides to T cells. They may cause transplant rejections which are less severe than those caused by major MHC polymorphisms. Some minor MHC antigens are present on the Y chromosome and are called H-Y antigens.

Donor APCs in the allograft present foreign MHC antigens to host T cells which are activated and destroy graft cells bearing the foreign MHC i.e. the entire graft. This is called direct allorecognition. In indirect allorecognition, host APCs present alloantigens to the 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 rejections within minutes of transplantation. Memory T cells can 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), that 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 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 by 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 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 accomplished 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.

Acute versus chronic GVHD

Acute GVHD

Involves skin, GIT and liver
Fever, erythroderma and skin desquamation, enteritis, diarrhea, hepatitis, jaundice, elevated liver enzymes

Chronic GVHD

Involves skin, GIT, liver, lungs, eyes and mouth
Dermal thickening and contractures, jaundice, pruritus, cirrhosis, photophobia, hemorrhagic conjunctivitis, corneal erosions, bronchiolitis obliterans, wheezing, dry mouth

The presence of alloreactive T cells can be demonstrated by the mixed lymphocyte reaction or MLR, in which lymphocytes from a potential donor are mixed with irradiated or mitomycin C treated lymphocytes from the potential recipient (the treated cells in the recipient cannot replicate). If alloreactive T cells are present in the donor, then they will be stimulated to multiply and become effector T cells. Differences in MHC II alleles will cause CD4 T cells to proliferate which can be measured by thymidine incorporation assay. It uses radioactive thymidine which will be incorporated by new DNA which means that higher the cell proliferation, higher will be the measured radioactivity. Differences in MHC II alleles will generate activated, cytotoxic CD8 T cells which can be measured by chromium labelled cell lysis on chromium release assay. In this assay, chromium labelled RBCs are lysed by cytotoxic T cells causing release of chromium from cells. More is the CD8 activity, higher will be the chromium released.