Abstract 14887: Short-Term Costimulatory Molecule Blockade Promotes Long-Term Engraftment of Transplanted Human Embryonic Stem Derivatives and Improves Cardiac Recovery
Introduction: Transplantation of human embryonic stem cells (hESC) and their derivatives offers great promise in preventing cardiac failure following acute myocardial infarction. However, transplantation requires effective long-term immunosuppression which is problematic due to toxicity of traditional drugs, e.g. Cyclosporine A (CsA). Here, we test the hypothesis that briefly blocking costimulatory molecule signaling with two agents (CTLA4-Ig and anti-LFA-1) promotes cell survival and improves functional outcome of transplanted hESC-derived endothelial cells (hESC-ECs) after myocardial infarction.
Methods/Results: Human ESC-ECs were stably transduced with GFP-Fluc for fluorescence and bioluminescence imaging (BLI). 2×106 cells were injected into the left ventricle of immunocompetent (FVB) and immunodeficient (SCID) mice following LAD ligation. Animals were randomized to receive either no immunosuppression, a standard approach (CsA and prednisone), or a short course of costimulatory blocking agents. In the absence of immunosuppression or after standard therapy, transplanted cells were rejected by day 14 after transplantation. In contrast, combined treatment with CTLA4-Ig and anti-LFA-1 enhanced cell engraftment and was associated with improved myocardial function assessed by MRI and echo. In a Matrigel plug assay, the same survival patterns were observed. Histological analyses revealed minimal immune cell infiltration and significantly more angiogenesis in the group receiving costimulatory agents. Flow cytometric analysis showed equivalent levels of circulating T cells in all groups, but CD4+ helper T cell infiltration into the Matrigel plugs of animals receiving costimulatory blockade was lower than in those treated with CsA + prednisone.
Conclusion: A short immunosuppressive course of costimulatory blockade is sufficient to induce engraftment of transplanted hESC-ECs associated with attenuated cardiac remodelling. This approach is beneficial, because it circumvents the chronic administration and systemic toxicity associated with traditional immunosuppressive drugs.
- © 2012 by American Heart Association, Inc.