Normal IgG protects against acute graft-versus-host disease by targeting CD4(+)CD134(+) donor alloreactive T cells

Intravenous immunoglobulin (IVIg) was shown to decrease the severity of acu te graft-versus-host disease (aGVHD) in recipients of allogeneic bone marro w transplants. To investigate the mechanisms involved in the protective eff ect of IVIg, we have used the parent-into-F1 model in which parental lympho cytes are transferred into semi-syngeneic non-irradiated F1 rats. Here we r eport that IVIg, as well as F(ab')(2) fragments of IVIg, protected (Lewis x Brown-Norway) F1 rats against aGVHD induced by a single injection of Lewis lymphocytes. IVIg was given as five consecutive daily injections, starting on the day preceding that of the transfer of Lewis cells. Protection was a ssociated with a decreased ability of lymphocytes to spontaneously prolifer ate and to produce NO and IFN-gamma, in the absence of an increased product ion of IL-10. We further demonstrate that protection was associated with a decrease in CD4(+) T cells bearing the activation marker CD134 in vivo, and with an enhanced apoptosis of activated CD4(+) T cells by IVIg, in vitro. Our observations suggest that the prevention of aGVHD by IVIg in this model is mediated by the induction of apoptosis of activated alloreactive CD4(+) CD134(+) donor T cells. The results further emphasize the role of normal im munoglobulin in modulating alloantigen immune responsiveness.