Virus-specific MHC-restricted T lymphocytes may initiate allograft rejection

Abstract

The principal function of the immune system is to protect the host from infection. Thus, therapeutic manipulations of the immune system in the treatment of non-infectious diseases are associated with significant changes in the ability to deal with infection. This is clearly illustrated by allograft recipients who require substantial immunosuppression to prevent allograft rejection and in whom infection is a major source of mortality and morbidity. In addition, a further relationship between infection and immune responses has long been commented on in these patients, namely an association between episodes of infection and aUograft rejection 1-3. Although early reports documenting such an association mentioned various infections (e.g., influenza 2, upper respiratory tract infectionsa), subsequently most attention has centred on the possible role ofcytomegalovirus (CMV) infection in the initiation of rejection 4-7. Clearly infection in an immunosuppressed allograft recipient is a complex situation leading to many non-specific immunological changes each of which might be postulated to lead to rejection4'6; however, we are led by recent experimental evidence to suggest that the initiation of rejection may be directly linked to the specific immune response mounted against a particular infectious agent. Thus, we propose that allograft rejection is initiated by effector T lymphocytes whose primary specificity is for foreign antigens (those of the infecting agent) which they see in the context of self major histocompatibility complex (MHC) antigens [' self + X']: such effectors can mediate rejection because of their crossreactive recognition of allogenic MHC antigens ['non-self]. Thus, the effector T cells generated by an allograft recipient in response to a given infection may initiate graft rejection when the particular alloantigens which they also recognize are present on the allograft. Alloreactivity and immune responses to other antigens can be mediated by the same lymphocytes For twenty years, immunologists have puzzled over the ability of alloantigens to elicit powerful immune responses given the apparent biological irrelevance of such responses. Experiments