Transforming growth factor beta 1 (TGF-β1) and rapamycin synergize to effectively suppress human T cell responses via upregulation of FoxP3+ Tregs

• Published in: Transplant immunology 2010-05, Vol.23 (1), p.28-33
• Main Authors: Kawamoto, Koichi, Pahuja, Anil, Hering, Bernhard J, Bansal-Pakala, Pratima
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Anti-CD3; Cell Differentiation - drug effects; Drug Synergism; Forkhead Transcription Factors - metabolism; Human T cells; Humans; Islet transplantation; Rapamycin (sirolimus); Sirolimus - pharmacology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - drug effects; TGF-β1; Transforming Growth Factor beta1 - pharmacology; Up-Regulation - drug effects
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2010.03.004

Abstract Background The major obstacle faced by patients with type 1 diabetes who undergo islet transplantation is a gradual decline in insulin independence. This decline may reflect alloimmune rejection, autoimmune recurrence and toxicity of drugs such as rapamycin to islet β cells. Thus, there is a pressing need to refine immunosuppressive protocols in order to reduce toxicity to islet grafts and yet prevent rejection. Recent studies demonstrated that TGF-β1 is a critical cytokine for the regulation of immune responses. In naive T cells, TGF-β1 induces FoxP3+ regulatory T cells and thus could promote transplant tolerance. In this study, in vitro experiments were performed to determine whether TGF-β1 could synergize with low-dose rapamycin and inhibit T cell activation and production of inflammatory cytokines, as well as enhance FoxP3 expression for potential application in islet transplantation. Methods Human peripheral blood mononuclear cells were stimulated with either anti-CD3/CD28 or anti-CD3 during TGF-β1 and rapamycin treatment. Results TGF-β1 inhibited T cell proliferation induced with anti-CD3 stimulation, but not with anti-CD3/CD28 stimulation. The combination of these reagents produced a synergistic inhibition of T cell proliferation induced with both anti-CD3/CD28 and anti-CD3 stimulations. Moreover, TGF-β1 and rapamycin significantly suppressed cytokine production and induced regulatory T cells by upregulating FoxP3 expression. Conclusions These results suggest that the combination of TGF-β1 and low-dose rapamycin can potently inhibit T cell responses in vivo and would be beneficial in supporting islet graft survival by limiting toxicity and preventing immune rejection.