Abstract 13821: Induction of Immune Tolerance to Intramyocardial Transplantation of Cardiac Progenitor Cells by Regulatory T Lymphocytes

Abstract

Introduction: The clinical use of human embryonic stem cell (hESCs)-derived cardiac cells is still hampered by rejection which is managed by immunosuppressive drugs and exposes to their side-effects. Hypothesis: We evaluated an alternate strategy based on the induction of immune tolerance by adoptive regulatory T lymphocytes (Treg) transfer. Methods: Human hTreg were isolated from peripheral blood mononuclear cells, expanded for 9 days and phenotyped. Immune-competent mice were then subjected to a myocardial infarction. Three weeks later (baseline), mice with an echocardiographically-measured ejection fraction (EF) ≤50% underwent trans-cutaneous echo-guided peri-infarct injections of 1.4x10 6 hESC-cardiovascular progenitor cells (CPC; n=11) or an equivalent volume of PBS (controls, n=4). Among the CPC-transplanted mice, 6 were intravenously injected with 2x10 6 hTreg at the time of transplantation and 3 days later and 5 only received the vehicle (PBS). Functional and histological end points were assessed 3 weeks after treatments (final) and spleen tissue was processed by flow cytometry for the evaluation of immune cell populations. Results: Three weeks after treatments, all CPC-transplanted hearts had a significantly better preservation of EF [m±SEM], compared with their respective baseline values, than PBS-injected hearts (35.4% ± 5.4% in CPC and 37.5% ± 6.8% in CPC+hTreg vs. -1.3 ± 7.3% in PBS, p=0.004) which was mainly driven by a reduction in LV end-systolic volumes (p=0.004) but only in the hTreg group global longitudinal strain improved by 15.7% ± 13.3% from baseline while it worsened by 36.5% ± 18.8% in their non-hTreg counterparts (p=0.037). Infarct size did not differ among the 3 groups but Treg reduced interstitial fibrosis in remote non infarcted myocardium (0.6% ± 0.1%, p=0.007 vs. CPC-non hTreg and PBS, respectively) and, in spleen tissue, induced significant decreases in CD80+ M1 macrophages (p=0.010) and NKG2D+ NK cells (p=0.013) and an increase in CD206+ M2 macrophages (p=0.004) compared with the other 2 groups. Conclusions: Systemic hTreg administration mitigates adverse heart remodeling by modulating the immune response, potentially facilitating transplantation of hESC-CPC with reduced immunosuppression requirements.