IN-VIVO IGM DEPLETION BY ANTI-MU MONOCLONAL, ANTIBODY THERAPY - THE ROLE OF IGM IN HYPERACTIVE VASCULAR REJECTION OF DISCORDANT XENOGRAFTS

Xenoreactive natural antibodies (XNA) and complement activation are th ought to be the 2 main factors responsible for the hyperacute vascular rejection (HVR) of discordant xenografts. The aim of this work was to study the role of IgM XNA in the HVR of guinea pig to rat cardiac xen ografts, a discordant model. Adult LOU/C rats were depleted of circula ting IgM and therefore of IgM XNA using an anti-mu mAb (mouse anti-rat IgM mAb 7 [MARM-7]). Rats were injected with 10 mg and 5 mg of MARM-7 at days -3 and -1, respectively, and guinea pig cardiac xenografts we re performed on day 0. Control animals were injected on the same days with 10 mg and 5 mg of anti-alpha mAb (MARA-1) or equivalent volumes o f PBS. Xenografts were performed on day 0. Guinea pig cardiac xenograf t survival time was significantly prolonged in IgM-depleted animals (6 2 min, P<0.01) compared with controls using PBS (18 min) or MARA-1 mAb (12 min). This prolongation was not due to a decrease in the compleme nt activity in IgM-depleted rats, since no significant variation of th e C-1q, C-4, C-3, and C-5 complement hemolytic activity was observed b etween control and treated animals before HVR. Prolongation of the xen ograft survival time in the MARM-7-treated group was correlated with a n undetectable serum level of IgM and IgM XNA and a lack of IgM XNA de posits on the rejected xenograft vascular endothelium. Contrarily, bot h IgM-depleted and control animals showed C-3 deposits on the rejected xenograft vascular endothelium and myocardium, as well as diffuse dep osits of IgG2a XNA, Although HVR was not abrogated by the depletion of IgM XNA, our data indicate that IgM is implicated in the HVR and that the anti-mu approach is a potential therapeutic treatment for discord ant xenografts. Finally, we suggest that other factors such as IgM-ind ependent activation of complement might be one of the mechanisms respo nsible for the pathogenesis of HVR in the guinea pig to rat xenograft model.