title: Targeted Complement Inhibition Protects Vascularized Composite Allografts From Acute Graft Injury and Prolongs Graft Survival When Combined With Subtherapeutic Cyclosporine A Therapy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Complement-mediated IRI augments graft allogenicity, and appropriate complement inhibition ameliorates IRI, decreases alloimmune priming and allows more immune-sparing CsA dosing.
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhu
authors.forename: Stefanie R
authors.initials: SR
authors.lastname: Bailey
authors.forename: Biao
authors.initials: B
authors.lastname: Lei
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D064595:Composite Tissue Allografts / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D016572:Cyclosporine / Q000494:pharmacology*; D005838:Genotype; D006085:Graft Survival / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010641:Phenotype; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects
chemical_list: C545610:C3 protein, mouse; C000609604:C3a-derived anaphylatoxin receptor, mouse; C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D051056:Complement Inactivating Agents; D007166:Immunosuppressive Agents; D044087:Receptor, Anaphylatoxin C5a; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D016572:Cyclosporine