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. Shortterm combined treatment with TGF-β1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donorspecific 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.
Original language | English (US) |
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Pages (from-to) | 4750-4759 |
Number of pages | 10 |
Journal | Journal of Immunology |
Volume | 185 |
Issue number | 8 |
DOIs | |
State | Published - Oct 15 2010 |
Externally published | Yes |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology