The synergistic effect of Tautomycetin on Cyclosporine A-mediated immunosuppression in a rodent islet allograft model.
Most immunosuppressive drugs that support successful allograft survival act by inhibiting or depleting T lymphocytes. Tautomycetin (TMC) is a specific inhibitor of protein phosphatase 1, which has a role in cell-cycle control and T-cell activation and promotes T-cell-specific apoptosis. In this study, we investigated the effect on rat islet transplantation of TMC alone and in combination with cyclosporine A (CsA). TMC treatment inhibited splenocyte proliferation in mixed lymphocyte reactions (MLR) without affecting cell viability. When used alone in islet allograft recipients, TMC did not significantly increase the survival of grafted islets. However, cotreatment of TMC and subtherapeutic doses of CsA significantly prolonged islet graft survival from 5.1 d to more than 100 d (P<0.05). At 100 d, there was no evidence of specific organ toxicity, and histological analyses of grafted liver tissue revealed the presence of viable islets. CD4+ and CD8+ T-cell infiltration and interleukin (IL)-2 mRNA levels were decreased in TMC/CsA-cotreated rats, whereas IL-10 levels were increased. In addition, the number of FoxP3-expressing cells and FoxP3 mRNA levels were also increased. We suggest that CsA and TMC act synergistically to reduce the function of T-effector cells and enhance regulatory cell function in this islet allotransplantation model.
Wee
Yu-Mee
YM
Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea.
Choi
Monica Young
MY
Kang
Choong-Hoon
CH
Kim
Yang-Hee
YH
Kim
Jin-Hee
JH
Lee
Sang-Kyou
SK
Yu
Seung-Young
SY
Kim
Song-Cheol
SC
Han
Duck-Jong
DJ
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006084:Graft Rejection; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods*; D008055:Lipids / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes; D008297:Male; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous
D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D005663:Furans; D007166:Immunosuppressive Agents; D008055:Lipids; C058744:tautomycetin; D016753:Interleukin-10; D016572:Cyclosporine