Alloantibodies reactivity with allogenic human cardiac stem/progenitors cells destined for cardiac repair

Introduction Allogenic human cardiac-derived stem/progenitor cells (hCPC) are promising therapeutics for repairing and regenerating injured inflamed myocardium. Beside their capacity to regenerate cardiac cell these cells act through paracrine effects. Immunologically, allogenic hCPC have HLA and PD-L1-dependent “tolerogenic/immunomodulatory” behavior that could contribute to their repairing/regenerating capacity. Although “safe” in the context of cellular allogenic immune response resolving their reactivity with determinants of grafts rejection or persistence, Donor-Specific Antibodies (DSA) in particular those against HLA (DSA-HLA) is mandatory for their clinical application. Methods We investigated the reactivity of hCPC with sera from transplantation patients screened for anti HLA (class I, class II) antibodies with clinical conventional procedures. Using tailored crossmatch and experimental allogenic cellular assays we determined the susceptibility of hCPC ( n = 9) to CDC (complement dependent cytotoxicity) and to ADCC (antibody dependent cellular cytotoxicity) upon their recognition by anti-HLA-I and HLA-II specific for their haplotype. Results The reactivity of hCPC with alloantibodies was dependent on their HLA expression level. Sera containing anti HLA-I, but not anti HLA-II, specific antibodies induced considerable CDC and ADCC in hCPC, indicating that the presence of DSA-HLA I but not DSA-HLA II, antibodies could be deleterious. Anti-HLA can also induce signals via HLA I or HLA II molecules, modulating the activity and fate of hCPC. Our preliminary data demonstrate that engagement of HLA-I but more importantly HLA-II with specific antibodies induces rapid phosphorylation of MAPK/Erk, major pathway of cells proliferation and/or survival suggesting a potential beneficial effect of DSA-HLA. Conclusions Allogenic hCPC are low-risk therapeutics in regard of cellular response but precaution should be taken in regard of humoral response, in particular, for patients possessing DSA-HLA I. Although warranted further investigation, signaling via HLA might counterbalance eventual deleterious effects, which calls upon proper evaluation through well-established immune testing platforms to maximize the benefit while minimizing the risk of allogenic hCPC therapeutics.