Prolonged cardiac allograft survival in presensitized rats after a high activity Yunnan-cobra venom factor therapy

Complement-dependent antibody-mediated acute humoral rejection is the major obstacle of clinical transplantation across ABO incompatibility and human leukocyte antigen presensitization. We previously demonstrated that Yunnan-cobra venom factor (Y-CVF) could almost completely abrogate complement activity and successfully prevent hyperacute rejection in some xenotransplant models without any obvious toxicity. In this study we investigated whether depletion of complement by Y-CVF prevented acute humoral allograft rejection in presensitized rats thereby prolonging graft survival.

Presensitization was achieved in Lewis rats by sequential grafting of three full-thickness skin pieces from Brown Norway rats. Serum cytotoxic alloantibody titers were determined by a modified in vitro complement-dependent microcytotoxicity assay. After presensitization, each Lewis rat received a heterotopic Brown Norway cardiac allograft. Fifteen recipients were divided into two groups: (1) no treatment control (n = 7); (2) Y-CVF therapy group (86 u/kg, IV, day -1) (n = 8). After cessation of the heart beat, allograft rejection was confirmed by pathologic as well as IgG and C3 immunohistochemical examinations.

The mean graft survival time was significantly prolonged to 99.50 +/- 38.72 hours among rats that received Y-CVF vs 12.71 +/- 13.94 hours in nontreated controls (P < .001). Upon pathological and immunohistochemical examination, acute humoral rejection was mainly exhibited in the control group, whereas acute cellular rejection was mainly displayed in the Y-CVF therapy group.

Our study demonstrated that complement depletion by Y-CVF significantly inhibited acute humoral allograft rejection in presensitized rats. As a therapeutic immunointervention tool for complement, Y-CVF has shown potential efficacy across ABO incompatible and positive cross-match barriers.