Decreased anti‐donor major histocompatibility complex class I and increased class II alloantibody response in allograft tolerance in adult rats

Abstract

Permanent tolerance to allografts can be induced in adult rats by donor‐specific transfusions (DST) prior to transplantation. We have previously reported, in a model of heart allograft, the presence of a heavy leukocyte infiltrate, in the allograft which displayed a strong allospecific cytotoxicity when tested in vitro against donor cells, and a strong accumulation of mRNA for granzyme A and perforin in vivo. In contrast, there was a major decrease in the accumulation of mRNA for interleukin‐2 and interferon‐γ. These results suggested that the DST‐induced tolerance was associated with a decrease in type‐1 T helper (Th1) cell function. The major role of preformed antibodies in xeno and allorejection is clearly established. Nevertheless, the consequences of alloantibody production in acute rejection and tolerance induction remains to be elucidated. We here analyze the alloantibody response in rejecting and DST‐treated recipients. We show that, after transplantation, tolerant recipients, in contrast to rejecting ones, mount a low IgM alloresponse that switches to low IgG production. Detailed analysis of IgG alloantibodies in DST‐treated recipients revealed that their production decrease was not equally distributed. Whereas rejecting animals mounted a strong anti‐class I and II IgG alloantibody response, DST‐treated recipients produced anti‐class II and low titers of anti‐class I IgG alloantibodies. Furthermore, among IgG subclasses, tolerant recipients predominantly produced IgG2a, a profile which, in the rat, is compatible with a Th2‐controlled response. Finally, the passive transfer of immune serum from rejecting animals to DST‐treated recipients could abrogate the tolerance. We suggest that the absence of anti‐class I alloantibodies combined with preserved and/or increased anti‐class II production plays a major role in graft tolerance in this model. These results reinforced the role of alloantibodies in rejection and in induction of tolerance.