How does the immune system recognize a transplanted organ as foreign tissue?

The immune system recognizes a transplanted organ as foreign through the detection of specific cell-surface molecules known as transplantation antigens or histocompatibility antigens.12

In humans, these primary markers are called the major histocompatibility complex (MHC), also referred to as human leukocyte antigens (HLA). These proteins are encoded by a cluster of genes on chromosome 6 and are present on the surface of nearly all cells. Because these genes have a vast number of variations, it is extremely rare for two individuals—unless they are identical twins—to share the same set of antigens.132

When a transplant occurs, the recipient’s immune system identifies these donor MHC molecules as "nonself" antigens. This recognition triggers lymphocytes—specifically T cells—to initiate a cell-mediated immune response, leading to the infiltration and destruction of the graft tissue. Additionally, B cells may produce antibodies that attack the foreign tissue, a process that is particularly rapid if the recipient has been previously sensitized to the donor's antigens.42