Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Differentiation / immunology
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Cell Separation
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Flow Cytometry
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / immunology
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Gene Knock-In Techniques
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Humans
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / immunology
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Immunohistochemistry
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Immunosuppressive Agents / immunology
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Immunosuppressive Agents / therapeutic use*
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Interleukin-17 / biosynthesis
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Interleukin-17 / immunology
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Interleukin-6 / biosynthesis
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Interleukin-6 / immunology
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Islets of Langerhans Transplantation / immunology*
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Male
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Mice
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Mice, Inbred C57BL
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Mutation
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / therapeutic use*
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Sirolimus / immunology
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Sirolimus / therapeutic use*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / immunology*
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Transplantation Tolerance / immunology*
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Transplantation, Homologous
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Immunoglobulin Fc Fragments
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Immunosuppressive Agents
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Interleukin-17
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Interleukin-6
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Recombinant Fusion Proteins
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Transforming Growth Factor beta1
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Sirolimus