IFN-γ and PPARδ influence the efficacy and retention of multipotent adult progenitor cells in graft vs host disease.

Cell-based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry-sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell-based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)-γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFN-γ-licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX-2 expression in human MAPC was significantly decreased in IFN-γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX-2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell-based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy.

Multipotent Adult Progenitor Cells Suppress T Cell Activation in In Vivo Models of Homeostatic Proliferation in a Prostaglandin E2-Dependent Manner.

Lymphodepletion strategies are used in the setting of transplantation (including bone marrow, hematopoietic cell, and solid organ) to create space or to prevent allograft rejection and graft versus host disease. Following lymphodepletion, there is an excess of IL-7 available, and T cells that escape depletion respond to this cytokine undergoing accelerated proliferation. Moreover, this environment promotes the skew of T cells to a Th1 pro-inflammatory phenotype. Existing immunosuppressive regimens fail to control this homeostatic proliferative (HP) response, and thus the development of strategies to successfully control HP while sparing T cell reconstitution (providing a functioning immune system) represents a significant unmet need in patients requiring lymphodepletion. Multipotent adult progenitor cells (MAPC®) have the capacity to control T cell proliferation and Th1 cytokine production. Herein, this study shows that MAPC cells suppressed anti-thymocyte globulin-induced cytokine production but spared T cell reconstitution in a pre-clinical model of lymphodepletion. Importantly, MAPC cells administered intraperitoneally were efficacious in suppressing interferon-γ production and in promoting the expansion of regulatory T cells in the lymph nodes. MAPC cells administered intraperitoneally accumulated in the omentum but were not present in the spleen suggesting a role for soluble factors. MAPC cells suppressed lymphopenia-induced cytokine production in a prostaglandin E2-dependent manner. This study suggests that MAPC cell therapy may be useful as a novel strategy to target lymphopenia-induced pathogenic T cell responses in lymphodepleted patients.