Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease

Abstract

Mesenchymal stromal cells (MSCs) are being tested as a cell therapy in clinical trials for dozens of inflammatory disorders, with varying levels of efficacy reported. Suitable and robust preclinical animal models for testing the safety and efficacy of different types of MSC products before use in clinical trials are rare. We here introduce two highly robust animal models of immune pathology: 1) acute radiation syndrome (ARS) and 2) graft versus host disease (GvHD), in conjunction with studying the immunomodulatory effect of well-characterized Interferon gamma (IFNγ) primed bone marrow derived MSCs. The animal model of ARS is based on clinical grade dosimetry precision and bioluminescence imaging. We found that allogeneic MSCs exhibit lower persistence in naïve compared to irradiated animals, and that intraperitoneal infusion of IFNγ prelicensed allogeneic MSCs protected animals from radiation induced lethality by day 30. In direct comparison, we also investigated the effect of IFNγ prelicensed allogeneic MSCs in modulating acute GvHD in an animal model of MHC major mismatched bone marrow transplantation. Infusion of IFNγ prelicensed allogeneic MSCs failed to mitigate acute GvHD. Altogether our results demonstrate that infused IFNγ prelicensed allogeneic MSCs protect against lethality from ARS, but not GvHD, thus providing important insights on the dichotomy of IFNγ prelicensed allogenic MSCs in well characterized and robust animal models of acute tissue injury.

Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion

“…Third, prelicensed MSCs have shown inconsistent efficacy in specific disease models in vivo. In mouse models, allogeneic IFNg prelicensed murine MSCs protected against lethality from ARDS but failed to alleviate acute GvHD [138]. However, in another study, human IFNg-primed MSCs improved survival rates in a GvHD model in SCID mice in an IDO-dependent manner [139].…”

Impact of Cryopreservation and Freeze-Thawing on Therapeutic Properties of Mesenchymal Stromal/Stem Cells and Other Common Cellular Therapeutics

“…We reported on the dichotomic potency of IFN-γ pre-licensed allogeneic MSCs in two different animal models of acute radiation syndrome (ARS) and GvHD [ 22 ]. While the application of IFN-γ pre-licensed MSCs protected animals from ARS and radiation-induced lethality by day 30, we did not find a protective effect of IFN-γ pre-licensed MSCs in modulating acute GvHD in a model of major histocompatibility complex (MHC)-mismatched HSCT.…”

“…The terminology and characteristics of these processes, which may differentially impact on therapeutic cell function and mechanism of action (MoA), are explained in more detail in the “ Key Terminology in “Cryopreservation” and “Freeze- Thawing” of Cell Products ” section (Fig. 2 and Table 1 ) [ 2 , 9 •, 10 – 13 , 14 •, 15 , 16 , 17 ••, 18 – 22 ].…”

Current perspectives on mesenchymal stromal cell therapy for graft versus host disease

“…However, the response to MSC infusion may be disease-specific. For example, infused IFNγ-prelicensed MSCs effectively protected mice against lethal acute radiation syndrome but failed to protect mice with GvHD [ 83 ]. In vitro, in coculture experiments with remestemcel-L, the FDA accepted MSC expression of tumor necrosis factor receptor type I (TNFR1) at a threshold level and inhibition of mononuclear cell expression of interleukin 2 (IL2) receptor α (CD25) as markers of potency and activity.…”