Involvement of graft-derived interleukin-15 in islet allograft rejection in mice.
The possibility that islets play a role in graft rejection during islet transplantation for type-1 diabetes patients holds promise for ex vivo islet manipulation and for specific anti-rejection therapy. Interleukin (IL)-15 is a T cell growth factor and chemoattractant that is expressed by non-T cells. Intragraft expression of IL-15 is elevated during acute rejection in patients and in mice, and systemic blockade of IL-15 in mice prolongs allograft survival. However, the source of IL-15 in these conditions is undetermined. Since epithelial cell-derived IL-15 promotes lymphocyte proliferation in culture, we sought to determine whether islet-derived IL-15 promotes rejection in mice. We designed antisense oligodeoxyribonucleotide molecules that target mouse IL-15. Uptake of FITC-labeled antisense molecules and efficacy of IL-15 inhibition in IFNgamma-stimulated islets were evaluated. Islets exhibited typical cytoplasmatic distribution of antisense molecules and produced IL-15 levels that were comparable to non-stimulated cells. Antisense-treated islet allografts, that were transplanted across multiple minor-histocompatibility-antigen mismatched strains of mice, were accepted at a higher rate than control-antisense treated islets or untreated islets (88.9% vs. 37.5% and 20%, respectively). Our results suggest that islet-derived IL-15 may be involved in acute islet allograft rejection.
Lewis
Eli C
EC
Department of Nephrology, Soroka University Medical Center and Ben-Gurion University of the Negev, Faculty of Health Sciences, P.O. Box 151, Beer-Sheva 84101, Israel. Eli.Lewis@UCHSC.edu
Weiler
Michal
M
Tejman-Yarden
Noa
N
Ziv
Nadav
N
Mazar
Julia
J
Chaimovitz
Cidio
C
Douvdevani
Amos
A
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D004847:Epithelial Cells / Q000166:cytology; D006084:Graft Rejection; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism
D019409:Interleukin-15; D016376:Oligonucleotides, Antisense