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Graft rejection occurs when the recipient's immune system recognizes donor tissue as foreign. Hyperacute rejection (minutes to hours) is antibody-mediated against ABO or HLA; acute rejection (days to months) involves T cell and B cell responses against donor MHC; chronic rejection (months to years) involves slow fibrosis and vasculopathy. HLA matching and immunosuppression reduce but do not eliminate risk.
Examine the molecular basis of direct and indirect allorecognition. Study how immunosuppressive drugs (calcineurin inhibitors, mTOR inhibitors) prevent each rejection type.
Hyperacute rejection can be predicted by pretransplant crossmatching and prevented by ABO matching. Chronic rejection involves immune-independent mechanisms (recurrence of original disease); immunosuppression may slow but not stop it.
From your study of transplant immunology and MHC molecules, you understand that every individual expresses a unique set of HLA proteins on their cell surfaces, and that the immune system is trained to recognize "self" MHC as friendly. When tissue from a genetically different donor is transplanted into a recipient, the donor's HLA molecules look foreign — they are alloantigens, and the recipient's immune system mounts a response against them. Graft rejection is this immune attack on transplanted tissue, and it manifests in three distinct forms defined by their timing and mechanism.
Hyperacute rejection is the fastest and most dramatic form, occurring within minutes to hours after transplantation. It happens when the recipient already has preformed antibodies against donor antigens — typically anti-ABO blood group antibodies or anti-HLA antibodies from prior transfusions, pregnancies, or transplants. These circulating antibodies bind immediately to the donor endothelium (the blood vessel lining of the graft), activate the complement cascade, and trigger massive thrombosis within the graft vasculature. The organ turns dark and necrotic, and there is no treatment — it must be removed. The good news is that hyperacute rejection is almost entirely preventable today through ABO blood type matching and crossmatch testing, where recipient serum is mixed with donor cells before surgery to check for preformed antibodies.
Acute rejection develops over days to weeks (sometimes months) and involves the full force of the adaptive immune response. The recipient's T cells recognize donor MHC molecules through two pathways: direct allorecognition, where recipient T cells bind directly to intact donor MHC molecules on donor antigen-presenting cells (which look like self-MHC loaded with foreign peptide), and indirect allorecognition, where recipient APCs process shed donor MHC molecules and present donor-derived peptides on self-MHC. Both CD4+ helper T cells and CD8+ cytotoxic T cells participate — cytotoxic T cells directly kill graft cells, while helper T cells drive inflammation and activate B cells to produce anti-donor antibodies. Acute rejection is the most common form encountered clinically and is the primary target of immunosuppressive drugs like cyclosporine and tacrolimus (calcineurin inhibitors that block T cell activation) and mycophenolate (which inhibits lymphocyte proliferation).
Chronic rejection is the slowest and most insidious form, developing over months to years and currently the leading cause of long-term graft loss. It involves progressive fibrosis and thickening of graft blood vessel walls (transplant vasculopathy), gradually strangling the organ's blood supply. The mechanisms are incompletely understood but involve both immune factors (ongoing low-grade T cell and antibody responses against donor antigens) and non-immune factors (ischemia-reperfusion injury, drug toxicity, and recurrence of the original disease). Unlike acute rejection, chronic rejection responds poorly to increased immunosuppression — there is no reliable treatment once it is established. This is why HLA matching remains so important: better matching reduces the alloimmune stimulus driving both acute and chronic rejection, improving long-term graft survival.