Anti-galactose-α(1,3) galactose antibody production in α1,3-galactosyltransferase gene knockout mice after xeno and allo transplantation

Antibodies (Abs) that mediate the hyperacute rejection and acute vascular rejection/delayed xenograft rejection of pig organs in humans and Old World primates are predominantly directed at a single carbohydrate epitope, galactose-alpha 1,3-galactose (alpha 1,3Gal). The T-cell dependence of elicited anti-alpha 1,3Gal Ab responses in humans and Old World primates is controversial. In this study we have characterized anti-alpha 1,3Gal Ab production in mice with disrupted alpha 1:3-galactosyltransferase genes (GT-Ko mice) and determined the T-cell dependence of anti-alpha 1,3Gal Ab responses, following xenograft and allograft transplantation. GT-Ko mice produce natural anti-alpha 1,3Gal IgM and IgG in an age-dependent manner, however, these Abs could not elicit hyperacute rejection nor affect the rate of cardiac xenograft (3-5 days) or allograft rejection (7-9 days). Transplantation of xenogeneic Lewis rats hearts elicited modest anti-alpha 1,3Gal Ab, but vigorous xenoAb responses. The anti-alpha 1,3Gal Ab response was restricted to the IgM, and IgG3 subclass while the xenoAb response comprised IgM and all four IgG subclasses. Transplantation of allogeneic C3H hearts elicited weak anti-alpha 1,3Gal Ab responses that were primarily IgM, but vigorous alloAb responses. Despite the restriction of elicited anti-alpha 1,3Gal Ab responses to the IgM and IgG3 isotypes, these responses are T-cell dependent. The ability of allografts to elicit weak anti-alpha 1,3Gal but strong allo-Ab responses, can be explained by the dependence of alpha 1,3Gal-specific B cells on cognate help from T cells. (C) 2000 Elsevier Science S.A. All rights reserved.