Islet allograft rejection in sensitized mice is refractory to control by combination therapy of immune-modulating agents.
Retransplantation is common in allogeneic islet transplantation, and therefore, memory responses in previously sensitized recipients present a distinct obstacle for successful islet transplantation. Given the difficulties in controlling memory responses contributing to allograft rejection, it is worth investigating the effects of new immune-modulating agents against islet allograft rejection in the sensitized recipients. In this study, we investigated immune-modulating agents including 5-azacytidine and IL-2/anti-IL-2 complex to ascertain their suppressive effects on memory responses. In suppression assays, rapamycin effectively suppressed the proliferation of memory T cells, whereas 5-azacytidine, a methylation inhibitor suppressed the survival and proliferation of memory T cells. Combination therapy of anti-CD40L, anti-OX40L, and rapamycin slightly prolonged BALB/c islet allograft survival in sensitized C57BL6 mice, and reduced intragraft infiltration of macrophages, T cells, and B cells. However, the addition of IL-2/anti-IL-2 complex, an inducer of regulatory T cells, did not exhibit additional suppression against rejection in sensitized mice. Although a combination of 5-azacytidine and rapamycin markedly suppressed islet allograft rejection in naïve mice, it failed to achieve long-term graft survival even when combined with anti-CD40L and anti-OX40 in sensitized mice. In short, 5-azacytidine-based or IL-2/anti-IL-2 complex-based regimens can suppress islet allograft rejection in naïve recipients, but fail to control islet allograft rejection in sensitized recipients.
Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
Juho
J
Hong
Hye Jung
HJ
Yeom
Eunwon
E
Lee
Kyu Hyun
KH
Han
Tai Yeon
TY
Koo
Bumrae
B
Cho
Han
H
Ro
Kook Hwan
KH
Oh
Curie
C
Ahn
Jaeseok
J
Yang
D000818:Animals; D023201:CD40 Ligand / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D020123:Sirolimus / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D023201:CD40 Ligand; D020123:Sirolimus