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

Abstract

Background Recipients of vascularized composite allografts require aggressive and life-long immunosuppression, and since 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 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/day cyclosporine A (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.

Emphysema-associated Autoreactive Antibodies Exacerbate Post–Lung Transplant Ischemia–Reperfusion Injury

“…Given these data, the use of short-term complement inhibition may provide relief from autoantibody-driven injury (8,43). With the current availability of U.S. Food and Drug Administration-approved complement therapeutics and ongoing research to develop a number of different complement-inhibitory compounds (44,45), this may represent a significant step forward in the care of this patient population.…”

Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling

“…Eculizumab (Soliris, Alexion Pharmaceuticals) is also in phase II clinical trials to determine its efficacy in preventing posttransplant DGF (NCT01403389, NCT01919346). CR2/FH (TT30) is a fusion complement inhibitor that targets only the alternative pathway (61), and it efficiently ameliorates experimental C3 glomerulopathy (62) and attenuates IRI in the liver, brain, intestine, lung, and vascularized composite allografts (63)(64)(65)(66). Recently, an engineered mini-FH also showed a protective role for C3 glomerulopathy (67).…”

Botulinum toxin A increases allograft tolerance in an experimental transplantation model: a preliminary study

“…In the present study, 5 days prior to skin transplantation, the recipients were treated with BoTA (10 IU) considering that the maximal effects of BoTA on tissues are known to occur approximately 2 weeks after injection. Previous studies used multiple injections of immune modulators with regular intervals [ 11 ]. Compared with other protocols, our is very cost-effective and causes minimal discomfort when applied to clinical practice.…”