Our studies show that activated autoreactive inflammatory T cells specific and autoantibodies to collagen (V) and cardiac myosin are consistently detected after lung and heart transplantation, respectively. Clonal expansion of these T cells occurs only after an alloresponse, but once activated they can induce on their own rejection of allogeneic and even syngeneic transplants. Indirect rather than indirect alloresponse triggers autoimmunity after transplantation presumably via antigen mimicry between autoantigen peptides and donor MHC peptides. Also, it is plausible that inflammation and tissue damage associated with initial alloresponse to donor MHC antigens causes the release of formerly sequestered autoantigens. This may result in the presentation of some cryptic self-determinants thereby triggering an autoimmune process at the site of the graft. Finally, tolerance induction to cardiac myosin and collagen (V) results in long-term survival and reduced pathogenesis of heart and lung allografts, respectively. This suggests that, after transplantation, the inflammatory alloresponse to donor MHC triggers a cascade of events including autoimmunity to tissue antigens, a phenomenon that is essential to the actual rejection.