Cutting Edge: NK Cells Mediate IgG1-Dependent Hyperacute Rejection of Xenografts

Abstract

Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-α1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcγR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcγR, and NK cells.

Hyperacute Rejection by Anti-Gal IgG1, IgG2a, and IgG2b Is Dependent on Complement and Fc-γ Receptors

“…The efficacy of NK cell depletion by the two reagents is likely to be the explanation for the slight differences in outcomes. Consistent with our previous report (33), both anti-NK1.1 and antiasialo GM1 completely protected xenografts against anti-Gal IgG1-induced HAR. Neither anti-NK1.1 nor anti-asialo GM1 treatment protected xenografts from anti-Gal IgG3-mediated HAR.…”

“…We previously described the ability of IgG1 and IgG3 mAbs to induce HAR in vivo in Gal Ϫ/Ϫ Rag Ϫ/Ϫ recipients (33). The current experimental model involves the use of immunocompetent Gal Ϫ/Ϫ mice as recipients of Gal ϩ/ϩ rat cardiac xenografts, thus permitting the possible contribution of T and B cells to HAR.…”

“…We had previously reported that anti-Gal IgG3 (GT4-31) and IgG1 (GT6-27) mediated the HAR of xenografts by different mechanisms (33). In those studies Rag Ϫ/Ϫ mice were used as recipients, raising the possibility that a role of T and B cells may have been overlooked.…”

“…Our previous study (33) revealed that the blocking 2.4G2 specific for Fc␥RII/III, effectively inhibited anti-Gal IgG1-mediated but not IgG3-mediated HAR in Gal Ϫ/Ϫ Rag Ϫ/Ϫ recipients. We confirm in immunocompetent Gal Ϫ/Ϫ recipients that the 2.4G2 mAb did not inhibit IgG3-mediated HAR (Fig.…”

Complement and Fc Function Are Required for Optimal Antibody Prophylaxis againstPneumocystis cariniiPneumonia

“…However, under conditions of high epitope density, mouse IgG1 exhibits enhanced ability to fix complement (20). In addition, IgG1 mediates rejection of xenografts (30). This effect of IgG1 was only demonstrable in the presence of complement, NK cells, and functional Fc receptor activity on the NK cells.…”