Transplantation
Our group has shown that membrane and secreted FGL2 play important roles in the immune responses to both xeno- and allografts. Our initial studies demonstrated that pig-to-baboon kidney xenografts, and rat to mouse xenografts undergoing AVR were associated with the induction of membrane associated pFGL2 expression on graft vascular endothelial cells (EC). We developed gene-targeted fgl2 -deficient (fgl2-/-) mice that allowed our group to examine the contribution of m- and sFGL2 to the pathogenesis of acute xenograft vascular rejection (AVR). Hearts that were heterotopically transplanted from fgl2+/+ and fgl2+/- mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of mFGL2 in graft vascular ECs. In contrast, xenografts from fgl2-/- mice were devoid of thrombosis due to the loss of membrane associated FGL2, but these grafts developed accelerated cellular rejection due to the loss of immune suppression that would normally be mediated by sFGL2 (Published in Ghanekar et al., J. Immunol., 2004 and Mendicino et al., Circulation, 2005). More recently, we have published novel data showing that recombinant FGL2 infused into FcγRIIB+/+ (C57BL/6J, H2b) mice but not FcγRIIB-/- mice inhibited the rejection of fully mismatched BALB/cJ (H2d) skin allografts (Liu et al., Eur. J. Immunol., 2008). To further examine the immunoregulatory function of FGL2, we used a murine fully mismatched heterotopic cardiac model of transplantation. In this model, we transplanted BALB/c hearts into wild-type recipients and treated the recipients with recombinant FGL2. Wild-type recipients that did not receive FGL2 treatment rejected their grafts at day 8. However, mice that received the treatment following transplant had prolonged graft survival, with most of the grafts surviving as long as FGL2 was given. The protective effect was lost within 10 days following cessation of treatment (Unpublished data- will be provided upon request ). Furthermore, we showed that fgl2 -Tg recipient mice that over-express FGL2 ubiquitously were able to accept heart grafts indefinitely in 50% of cases in the absence of immunosuppression. Wild-type and fgl2-/- recipients rejected hearts between days 7 and 10. We performed reciprocal transplants (fgl2-Tg hearts into BALB/c mice) and found that FGL2 expression was critical in the host for graft acceptance. Increased proportion of Foxp3+ Treg cells was found in the accepted grafts of fgl2 -Tg recipient mice (Unpublished data- will be provided upon request).