Abstract 19631: The Immunoregulatory Protein FGL2 Extends Graft Survival in a Fully-Mismatched Cardiac Transplantation Model
Transplantation is the only treatment for end-stage organ failure. One of the main aspirations of transplant research is to induce graft-specific immunological tolerance in the recipient to avoid the toxic side-effects of immunosuppressant drugs and to prevent chronic rejection of the graft. Fibrinogen-like protein 2 (FGL2) is an effector molecule expressed by several subsets of regulatory T cells (Treg), including CD4+CD25+Foxp3+ Treg. FGL2 binds to the inhibitory FcγRIIB receptor expressed on APC thereby inhibiting DC maturation and T cell activation, as well as, inducing B cell apoptosis. Further evidence from studies of fgl2KO mice shows increased immune reactivity as seen by impaired suppressive activity of Treg, increased effector T cell activity, increased numbers of antibody-producing B cells and DC activation. We hypothesize that the immunoregulatory activity of FGL2 as an effector of Treg is important in regulating immune responses to alloantigens. To test this hypothesis, we generated an FGL2 over-expressing mouse (fgl2Tg) using a conditional, double reporter cre/lox expression system. These mice express 1000-fold higher levels of FGL2 in the plasma compared to wildtype mice. The high levels of FGL2 do not appear to adversely affect development. Treg isolated from the fgl2Tg mice have increased suppressive function and CD4+ T cells are hyporesponsive when stimulated with alloantigens. In a fully mismatched model of cardiac allotransplantation, the treatment of C57BL/6 recipients with recombinant FGL2 prolonged graft survival with a mean survival time of 30 days (p<0.05 by Logrank test). However, cardiac grafts were rejected following treatment withdrawl. When fgl2Tg mice were used as recipients, there was indefinite survival of the cardiac grafts in 50% of transplant recipients in the absence of immunosuppression. Characterization of graft infiltrates in accepted hearts showed an increase in the frequency of Foxp3+ Treg cells as a proportion of CD3+ T cell infiltrates, suggesting that the mechanism of graft acceptance involves Foxp3+ Treg activity. These data demonstrate that FGL2 is an important effector immunosuppressive molecule of Treg which has therapeutic implications for cardiac transplantation.
- © 2010 by American Heart Association, Inc.