Abstract 10901: CD3 Antibodies are a Promising Tool for Modulating the Immune Response to Embryonic Stem Cells and Their Cardiac Derivatives
Background: Transplantation of embryonic stem cells (ESCs) and their differentiated derivatives in an allogeneic host triggers an immune response that represents a significant barrier to clinical applications. We assessed the kinetics of this immune response and tested whether immune tolerance could be induced using CD3 antibodies.
Methods: We implanted mouse ESC -derived embryoid bodies (EBs) or cardiac progenitors under the kidney capsule in 39 fully mismatched recipient mice. A short CD3 antibody treatment was administered on day 0 or day 7 following cell implantation. The host immune response and graft survival (i.e. occurrence of a teratoma) were monitored for up to 9 weeks post transplantation using bioluminescence, histological analysis and q-PCR. The specific immune response against grafted cells and the characterization of the infiltrate were evaluated by IFNγ Elispot and flow cytometry, respectively.
Results: Allogeneic EBs and cardiac progenitors were consistently rejected in untreated immunocompetent mice (n=9). A major cellular infiltration including CD3+T cells, mostly CD8+, was observed within and around the graft. Grafted mice treated with CD3 antibody on day 7 after EB (n=15) or cardiac progenitor (n=15) implantation showed long term graft survival (11 weeks). Five weeks after implantation, cells infiltrating the grafts mostly included CD4+ T cells in mice grafted with cardiac progenitors, while CD8+ T cells predominated in EB-transplanted mice. CD3 antibody-treated mice showed an upregulated expression of tolerogenic cytokines (TGFβ and IL10) and inhibitory costimulation molecules (PD-1 and CTLA-4) in the grafts while, in contrast to control mice, they did not exhibit molecules involved in cell death like Granzyme B, Perforin, Fas and FasL. Nine weeks after implantation, CD3 antibody-treated mice showed a reduced graft infiltrate which consisted mostly of regulatory FoxP3+ T cells.
Conclusions: These results suggest that the CD3 antibody treatment promotes survival of allogeneically transplanted cells by upregulating tolerogenic mechanisms and could therefore represent a promising tool for modulating the immune response to ESC-derived cardiac progenitor cells.
- © 2013 by American Heart Association, Inc.