Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination

The efficacy of two synthetic major histocompatibility complex (MHC)-derive d DA (RT1.A(a)) 25-mer peptides (residues 56-80 and 96-120) to modulate all oreactivity was tested in Lewis (RT1.A(1)) responder animals. The DA peptid e 56-80, but not peptide 96-120, induced delayed-type hypersensitivity (DTH ), DTH was significantly reduced by oral feeding of peptide 56-80, P = 0.00 9. In addition, oral feeding of this peptide in combination with a short co urse of cyclosporin A (CsA) prolonged graft survival of 60% of heterotope t ransplanted DA cardiac allografts in Lewis recipient rats. Long-term surviv ors developed low levels of allo-antibodies against donor tissue as compare d to rejecting animals and increased levels of interleukin-4 (IL-4) within the allograft, Similarly, IL-4-secreting splenocytes were identified by flo w cytometry in these animals, indicating a Th2-type cytokine pattern, Howev er, graft survival was particularly limited to cardiac allografts because d onor-type skin grafts were acutely rejected in tolerant animals. It is inte resting that residue alignment of peptide 56-80 to the motif of the RT1.A(1 ) molecule showed a preferred class I motif within this sequence, suggestin g indirect presentation of this peptide to recipient T cells, Thus, peptide 56-80 appears to represent a dominant epitope that can be exploited for es tablishing tolerance in this transplantation strain combination.