Prolongation of cardiac allograft survival by rapamycin and the invariant natural killer T cell glycolipid agonist OCH.
BACKGROUND
Invariant natural killer T (iNKT) cells are glycolipid-responsive cells with potent immunomodulatory properties. Although iNKT cells have been implicated in cardiac allograft tolerance, whether in vivo triggering of iNKT cells with Th2-promoting glycolipids offers a therapeutic benefit in heart transplantation remains unexplored.


METHODS
C3H (H-2k) hearts were transplanted into C57BL/6 (H-2b) mice. The recipients were left untreated or received the Th2-promoting iNKT cell agonist OCH, the antirejection agent rapamycin, or both. Allografts were recovered on postoperative day 8 or at endpoint, stained with hematoxylin-eosin, and analyzed for intragraft transcript levels of effector cytokines and iNKT cells' invariant T-cell receptor segment Valpha14-Jalpha18. The presence of circulating alloantibodies was assessed in recipients' sera at similar time points. A second fully mismatched cardiac allograft model (BALB/c-to-C57BL/6) was used to further validate the efficacy of our treatment regimens.


RESULTS
Combination immunotherapy with OCH and rapamycin significantly enhanced C3H allograft survival and led to nearly normal graft histology with minimal vascular changes and mononuclear cell infiltration, and an almost normal IgG1:IgG2a ratio in recipients' sera. These were accompanied by elevated intragraft mRNA levels of interleukin (IL)-4, and to a lesser extent IL-10 and IL-13, and high transcript levels of Valpha14-Jalpha18 T-cell receptor gene segment. Furthermore, when used alone or together with rapamycin, OCH delayed allograft rejection in our BALB/c-to-C57BL/6 model.


CONCLUSIONS
In vivo administration of OCH may deviate alloimmune responses towards a Th2 phenotype and prolong allograft survival. Select iNKT cell glycolipid agonists can therefore be used in monotherapy or combination immunotherapy of transplant rejection.
Haeryfar
S M Mansour
SM
Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada. mansour.haeryfar@schulich.uwo.ca
Lan
Zhu
Z
Leon-Ponte
Matilde
M
Duffy
Kathleen Rose Langley
KR
Ge
Wei
W
Liu
Weihua
W
Mele
Tina
T
Garcia
Bertha
B
Wang
Hao
H
D000818:Animals; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004359:Drug Therapy, Combination; D019673:Genes, T-Cell Receptor alpha; D006017:Glycolipids / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000097:blood; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000097:blood; D020123:Sirolimus / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous
D016207:Cytokines; D006017:Glycolipids; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D012333:RNA, Messenger; C501055:tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide; D020123:Sirolimus