Pathways of allorecognition: implications for transplantation tolerance.

Allorecognition occurs when the host immune system detects same-species, non-self antigens and this is the trigger for allograft rejection. Host T cells detect these 'foreign' antigens which are mostly derived from a highly polymorphic region of the genome called the major histocompatibility complex. Allorecognition can occur by two distinct, but not mutually exclusive pathways: direct and indirect. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells--this is the manner in which the immune system normally sees antigen. However, in addition to antigen recognition, T cell activation requires the provision of costimulatory signals, the prerogative of bone marrow-derived, specialised antigen-presenting cells (APC). Once these have been depleted from a transplanted organ, as occurs within weeks of transplantation, the parenchymal cells of the transplant are incapable of driving direct pathway activation of recipient T cells. Alloantigen recognition on these non-professional APCs may have a tolerising effect and indeed, the frequency of T cells reactive to the direct pathway diminishes with time irrespective of whether or not chronic transplant rejection occurs. This implies that while the direct pathway plays a dominant role in acute rejection, it is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection and animal models support a role for the indirect pathway in both acute and chronic rejection. The indirect pathway is likely to be permanently active due to traffic of recipient APCs through the graft. The challenge that this poses in the pursuit of clinical tolerance is how to induce tolerance in T cells with indirect allospecificity. The answer may lie in manipulation of the environment of the interaction between the T cell and APC. Apart from recognition without costimulation, there are other circumstances when recognition without activation can occur although the in vivo relevance is uncertain. The presence of regulatory cytokines or inhibitory surface molecules either from a distinct regulatory cell, or as a negative feedback loop may prevent activation; this could also happen without sufficient stimulatory support: the final outcome is likely to be decided by the overall balance. Furthermore, some peptides may act as antagonists to T cell activation, usually when the agonist peptide is structurally very similar. It is hoped that the careful study of these mechanisms will reveal ways of ensuring allorecognition without activation and thus donor-specific tolerance.