Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance.
The critical roles of TGF-β in the reciprocal differentiation of tolerance-promoting CD4(+)Foxp3(+) regulatory T cells (Tregs) and proinflammatory Th17 effector cells affect alloimmune reactivity and transplant outcome. We reasoned that a strategy to harness TGF-β and block proinflammatory cytokines would inhibit the differentiation of Th17 cells and strengthen the cadre of Tregs to promote tolerance induction and long-term allograft survival. In this study, we report the development of a long-lasting autoactive human mutant TGF-β1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3(+) Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17 cell differentiation. Short-term combined treatment with TGF-β1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donor-specific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3(+) Tregs, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6, and IL-17. Our strategy of combined TGF-β1/Fc and rapamycin to target the IL-6-related Tregs and Th17 signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application.
Zhang
Wensheng
W
Division of Plastic and Reconstructive Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Zhang
Dong
D
Shen
Miaoda
M
Liu
Yun
Y
Tian
Yan
Y
Thomson
Angus W
AW
Lee
W P Andrew
WP
Zheng
Xin Xiao
XX
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D055879:Gene Knock-In Techniques; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D020123:Sirolimus / Q000276:immunology / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D053773:Transforming Growth Factor beta1; D020123:Sirolimus