In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

被引:43
作者
Fisher, James D. [1 ,2 ]
Zhang, Wensheng [3 ]
Balmert, Stephen C. [1 ,4 ]
Aral, Ali M. [1 ,5 ]
Acharya, Abhinav P. [6 ]
Kulahci, Yalcin [6 ]
Li, Jingjing [3 ]
Turnquist, Heth R. [5 ,7 ,8 ,9 ]
Thomson, Angus W. [5 ,7 ,8 ]
Solari, Mario G. [3 ,9 ]
Gorantla, Vijay S. [10 ]
Little, Steven R. [1 ,6 ,8 ,9 ,11 ,12 ]
机构
[1] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Med Scientist Training Program, Pittsburgh, PA USA
[3] Univ Pittsburgh, Dept Plast Surg, Pittsburgh, PA USA
[4] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15260 USA
[5] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA
[6] Univ Pittsburgh, Dept Chem Engn, Pittsburgh, PA 15261 USA
[7] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA
[8] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15260 USA
[9] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA
[10] Wake Forest Sch Med, Dept Surg, Winston Salem, NC 27101 USA
[11] Univ Pittsburgh, Dept Ophthalmol, Pittsburgh, PA 15260 USA
[12] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA
关键词
INDUCTION; REJECTION; CCL22; THERAPY; MURINE; INFLAMMATION; PREVENTION; CCR4; TH17;
D O I
10.1126/sciadv.aax8429
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (T-reg) to suppress inflammation. Specifically, a microparticle-based system engineered to release the T-reg-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These "Recruitment-MP" prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched T-reg populations in allograft skin and draining lymph nodes and enhanced T-reg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human T reg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive T-reg.
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页数:11
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