What intrinsic mechanism is primarily responsible for chronic transplant rejection?

Chronic transplant rejection is predominantly driven by the T-cell mediated response. Over time, even after the initial acute rejection episodes are managed, the immune system continues to recognize the transplanted organ as foreign, primarily due to the ongoing activity of T-cells. These T-cells contribute to the gradual destruction of the transplanted tissue through direct cytotoxicity and by activating other immune cells.

While factors such as HLA mismatch can play a significant role in the initial acceptance or rejection of a transplant, chronic rejection is more often linked to the sustained immune response rather than a direct consequence of mismatched HLA alone. In chronic rejection, the process is gradual and may lead to fibrosis and the eventual failure of the transplant.

Antibody-mediated damage and neurovascular events can also be involved in specific contexts, but these are more relevant to acute rejection or other complications rather than the intrinsic mechanisms guiding chronic rejection, which fundamentally rely on cellular immunity.