TREATMENT WITH AN HLA-PEPTIDE AND CYCLOSPORINE-A PROLONGS RAT SMALL-BOWEL ALLOGRAFT SURVIVAL

a Background: The ultimate treatment for severe short bowel syndrome i s small bowel transplantation (SET). Current immunosuppression for SET is relatively ineffective and toxic. Peptides derived from residues 7 5-84 of the HLA-B7 molecule are immunomodulatory in vitro, and in rode nts, when combined with subtherapeutic doses of cyclosporine (CsA), pr olong cardiac and skin allograft survival without altering the recipie nt's rejection kinetics to third party allografts. We investigated the effects of HLA-B7 peptide fragment in a rat model of SET. Methods: He terotopic allogeneic SET was performed in Dagouti (RT1(a)) to Lewis (R T1(l)) high-responder rat strain combination. E7.75-84 (40 mg/kg/d) an d subtherapeutic CsA (10 mg/kg/d) were administered alone, or in combi nation, by gavage to allograft recipients on days 0 to 4 after SET. Re cipient pretreatment with E7.75-84 on days -14, -12, -10, and -7 follo wed by subtherapeutic CsA on days 0 to 4 after SET was also carried ou t. Graft rejection was determined by the presence of a palpable abdomi nal mass on daily examination or by loss of more than 10% initial body weight. Results: Without immunosuppression allografts rejected at a m edian time of 6 days (range, 5 to 7; n = 7). This was not significantl y altered with either CsA therapy alone (median 6 days; range, 6 to 7; n = 6) or E7.75-84 alone (median, 5 days; range, 5 to 6; n = 6). Reci pient combination therapy with E7.75-84 and CsA after allografting sig nificantly prolonged allograft survival (median, 11 days; range, 9 to 13; n = 9), as did recipient E7.75-84 pretransplant therapy (median, 1 0 days; range, 9 to 12; n = 6), when administered over a a-week period before allografting. Conclusion: Post-SET recipient treatment with E7 .75-84 produced statistically significant improvement in allograft sur vival only after combination with subtherapeutic CsA. Recipient pre-SE T treatment with E7.75-84 alone however, resulted in statistically sig nificant improvement in allograft survival in combination with post-SE T subtherapeutic CsA. These synergistic effects may be valuable in ach ieving improved SET survival clinically and warrant further exploratio n. Copyright (C) 1997 by W.B. Saunders Company.