Abstract 13221: Costimulatory Molecule Blockade Permits Transplanted Cardiac Allograft Survival
Introduction: Traditional immunosuppressive approaches (i.e., Tacrolimus, Sirolimus) to prevent heart transplant rejection are problematic because they require chronic administration and cause significant toxicity. The ideal therapy should involve only a brief period of immunosuppression, but induce a specific long-lasting tolerance to the donor graft. With this goal in mind, we tested whether or not a brief course of treatment with leukoctye costimulatory receptor blocking agents _ CTLA4-Ig, anti-CD40-ligand (anti-CD40L), and anti-LFA-1 _ could induce long-term cardiac allograft survival.
Methods/Results: Hearts of FVB (H-2kq) green fluorescent protein-firefly luciferase transgenic mice were heterotopically transplanted into fully allogeneic BALB/c (H-2kd) or syngeneic FVB recipients. Quantitative bioluminescent imaging (BLI) and qualitative graft beating scores (0 to 4) were used to longitudinally monitor graft survival for 100 days. BALB/c mice (n=5–10/group) were randomized to receive either no immunosuppression or a short course of combined immunosuppression with anti-LFA1, CTLA4-Ig, and anti-CD40L on days 0, 2, 4 and 6 post transplantation. In the absence of immunosuppression, cardiac allografts were acutely rejected by day 14 after transplantation (beating score = 0 in no treatment group vs. 2.8±0.45 in control syngeneic group; P<0.01). In contrast, combined treatment with anti-LFA, CTLA4-Ig and anti-CD40L induced long-term indefinite allograft survival out to at least 100 days and was comparable to syngeneic survival (P<0.001; see Figure 1).
Conclusions: A short immunosuppressive course of costimulatory molecule blockade treatment is sufficient to induce long-term cardiac allograft survival. This approach is advantageous because it bypasses the chronic administration and systemic toxicity associated with traditional immunosuppressive regimens.
- © 2010 by American Heart Association, Inc.