Treatment with an HLA-peptide and cyclosporine A prolongs rat small bowel allograft survival.
BACKGROUND
The ultimate treatment for severe short bowel syndrome is small bowel transplantation (SBT). Current immunosuppression for SBT is relatively ineffective and toxic. Peptides derived from residues 75-84 of the HLA-B7 molecule are immunomodulatory in vitro, and in rodents, when combined with subtherapeutic doses of cyclosporine (CsA), prolong cardiac and skin allograft survival without altering the recipient's rejection kinetics to third party allografts. We investigated the effects of HLA-B7 peptide fragment in a rat model of SBT.


METHODS
Heterotopic allogeneic SBT was performed in Dagouti (RT1a) to Lewis (RT1l) high-responder rat strain combination. B7.75-84 (40 mg/kg/d) and subtherapeutic CsA (10 mg/kg/d) were administered alone, or in combination, by gavage to allograft recipients on days 0 to 4 after SBT. Recipient pretreatment with B7.75-84 on days -14, -12, -10, and -7 followed by subtherapeutic CsA on days 0 to 4 after SBT was also carried out. Graft rejection was determined by the presence of a palpable abdominal mass on daily examination or by loss of more than 10% initial body weight.


RESULTS
Without immunosuppression allografts rejected at a median time of 6 days (range, 5 to 7; n = 7). This was not significantly altered with either CsA therapy alone (median 6 days; range, 6 to 7; n = 6) or B7.75-84 alone (median, 5 days; range, 5 to 6; n = 6). Recipient combination therapy with B7.75-84 and CsA after allografting significantly prolonged allograft survival (median, 11 days; range, 9 to 13; n = 9), as did recipient B7.75-84 pretransplant therapy (median, 10 days; range, 9 to 12; n = 6), when administered over a 2-week period before allografting.


CONCLUSIONS
Post-SBT recipient treatment with B7.75-84 produced statistically significant improvement in allograft survival only after combination with subtherapeutic CsA. Recipient pre-SBT treatment with B7.75-84 alone however, resulted in statistically significant improvement in allograft survival in combination with post-SBT subtherapeutic CsA. These synergistic effects may be valuable in achieving improved SBT survival clinically and warrant further exploration.
Willetts
I E
IE
Nuffield Department of Surgery, University of Oxford, England.
Tam
P K
PK
Morris
P J
PJ
Dallman
M J
MJ
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects*; D015235:HLA-B Antigens / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007421:Intestine, Small / Q000637:transplantation*; D008297:Male; D011292:Premedication; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D012778:Short Bowel Syndrome / Q000601:surgery*; D018709:Statistics, Nonparametric
D015235:HLA-B Antigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine