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Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy

Zhu, Peng MD; Bailey, Stefanie R. PhD; Lei, Biao MD; Paulos, Chrystal M. PhD; Atkinson, Carl PhD; Tomlinson, Stephen PhD

doi: 10.1097/TP.0000000000001625
Original Basic Science—General

Background Recipients of vascularized composite allografts require aggressive and lifelong immunosuppression, and because the surgery is usually performed in nonlife-threatening situations, the development of strategies to minimize immunosuppression is especially pertinent for this procedure. We investigated how complement affects acute graft injury, alloimmunity, and immunosuppressive therapy.

Methods Vascularized composite allografts were transplanted from Balb/C to C57BL/6 mice that were complement deficient (C3 or double C3a Receptor (R)/C5aR), or treated with a targeted complement inhibitor (CR2-Crry). Allografts were analyzed for acute inflammation and injury, subacute T cell response, and survival in the absence and presence of cyclosporine A (CsA) therapy.

Results Allografts in C3-deficient or CR2-Crry–treated recipients were protected from skin and muscle ischemia-reperfusion injury (IRI). C3aR/C5aR-deficient recipients were more modestly protected. IgM and C3d colocalized within allografts from wild type and C3aR/C5aR-deficient recipients indicating IgM-mediated complement activation, and C3d deposition was almost absent in allografts from C3-deficient and CR2-Crry–treated recipients. Inflammatory cell infiltration and P-selectin expression was also significantly reduced in C3-deficient and CR2-Crry–treated recipients. Acute treatment with CR2-Crry or with 3 mg/kg per day CsA modestly, but significantly increased median allograft survival from 5.8 to 7.4 and 7.2 days, respectively. However, combined acute CR2-Crry treatment and CsA therapy increased mean graft survival to 17.2 days. Protection was associated with significantly reduced T cell infiltration of allografts and Tc1 cells in recipient spleens.

Conclusions Complement-mediated IRI augments graft allogenicity, and appropriate complement inhibition ameliorates IRI, decreases alloimmune priming and allows more immune-sparing CsA dosing.

A report on the impact of immunosuppression on complement mediated injury and immune responses in a vascularized composite allograft mouse model. The authors show that inhibition of posttransplant complement responses together with sub-therapeutic doses of CsA prolongs allograft survival.

1 Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

2 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC.

3 Department of Surgery, Division of Transplantation, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Charleston, SC.

4 South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, Charleston, SC.

5 Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC.

Received 20 July 2016. Revision received 2 November 2016.

Accepted 14 November 2016.

This work was supported by grants from the NIH (R56AI119026 and R01DK102912), Department of Veterans Affairs (Merit Award 1I01RX001141 and 1BX001218) and the Department of Defense (W81XWH-16-1-0783).

S.T. is an inventor on a licensed patent for CR2-targeted complement inhibition.

S.T. and C.A. designed the study and analyzed the data. P.Z. and B.L performed all surgeries, and prepared and analyzed grafts specimens. S.T, C.A. and P.Z. wrote the manuscript. S.R.B. and C.M.P. designed, performed and analyzed flow cytometry experiments.

Correspondence: Stephen Tomlinson, PhD, Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC. ( Carl Atkinson, PhD, Department of Microbiology and Immunology, and Surgery, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC. (

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