Indirect recognition of T-cell epitopes derived from the alpha 3 and transmembrane domain of HLA-A2

Indirect allorecognition has been implicated in the mechanism of chronic rejection and alloantibody formation but precise definition of the epitopes involved has been limited. We have undertaken a detailed assessment of the antigenic properties of peptides derived from HLA-A2. Candidate epitopes were identified in vitro by assessment of MHC class II binding. The immune response to these epitopes was determined in patients awaiting a renal transplant by the assessment of PBMC activation using gamma-interferon ELISPOT. Twenty-two of fifty-five patients responded to peptides from HLA-A2 and this was associated with but not confined to those who had made antibody to HLA-A2 (14/18). Nineteen of twenty-two patients responded to peptides derived from the hypervariable alpha1 and alpha2 domains and 18/22 responded to peptides from the alpha 3 and transmembrane domain, the sequences of which show little polymorphism. In six patients, the sequence of these peptides was identical to self, that is, the response was autoimmune. The finding of indirect epitopes derived from regions of MHC class I that exhibit little polymorphism provides a novel perspective on the immune response to alloantigen and has potential implications for the development of specific therapies.