Synergistic effects of CTLA-4Ig and sirolimus on orthotopic lung-allograft survival and histology.
OBJECTIVE
The combination of CTLA-4Ig with sirolimus can promote indefinite survival in allograft models for which CTLA-4Ig monotherapy is ineffective. We sought to determine whether a limited course of CTLA-4Ig and sirolimus would alter survival of rat orthotopic single-lung transplantations.


METHODS
Left lungs of Brown Norway rats were transplanted into four groups of Lewis recipients (n=6 per group): group 1, no treatment; group 2, mCTLA-4Ig (250 microg/day for 4 days); group 3, sirolimus (3 mg/kg per day for 14 days); group 4, combined therapy with sirolimus and mCTLA-4Ig. Graft survival was determined by daily radiologic examination. Histologic grading of rejection and immunohistochemical staining for T and B lymphocytes were carried out at the time of radiologic graft loss.


RESULTS
Rejection of lung allografts in group 1 occurred at a median of 6.5 days. Neither sirolimus nor mCTLA-4Ig monotherapy resulted in significant prolongation of graft survival (median 9.5 and 8.0 days, respectively). Graft survival in group 4 was significantly prolonged compared with all other groups (median 29.5 days), and a significant reduction in histologic grade of rejection was observed following combination therapy compared with all other groups. Infiltration by CD8+ve T cells at the time of rejection was proportionately greater than CD4+ve T-cell infiltration for groups 1, 2, and 3 but not for the combined-therapy group.


CONCLUSIONS
A brief course of combined mCTLA-4Ig and sirolimus prolongs graft survival, reduces severity of rejection, and attenuates CD8+ve T-cell infiltration of fully major histocompatibility complex mismatched lung allografts.
Ugurlu
Mustafa M
MM
Department of Surgery, Mayo Clinic and Foundation, Rochester, MN, USA.
Griffin
Matthew D
MD
Tazelaar
Henry D
HD
McGregor
Christopher G A
CG
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D060908:CTLA-4 Antigen; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D007166:Immunosuppressive Agents; D020123:Sirolimus