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

Koichi Kawamoto, Anil Pahuja, Bernhard J. Hering, Pratima Bansal-Pakala

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)28-33
Number of pages6
JournalTransplant Immunology
Volume23
Issue number1-2
DOIs
StatePublished - May 1 2010

Keywords

  • Anti-CD3
  • Human T cells
  • Islet transplantation
  • Rapamycin (sirolimus)
  • TGF-β1

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