Background: The clinical implementation of costimulation blockade (CoB) provides long-term benefit to transplant recipients, with the short-term drawback of increased acute rejection. Cellular therapies are a potential adjuvant that may promote survival and tolerance. Mesenchymal stem cells (MSCs) are being investigated for their impact in autoimmunity and transplantation. However, their mechanism remains unclear and a preclinical model is lacking. Here we characterize the effect of MSCs in vitro as well as in a preclinical nonhuman primate (NHP) renal transplant model.

Methods: NHP MSCs were derived from bone-marrow aspirates and characterized. MSC effects on T cell proliferation and effector function were assessed using mixed lymphocyte reactions (MLRs). ELISA was used to quantify secreted cytokine. Transwells assessed if MSC effects were contact dependent. MHC-mismatched NHPs underwent bilateral nephrectomy and life-sustaining kidney transplantation, treated with either CoB (n=5) or CoB + donor derived MSCs (n=3).

Results: When MSCs were added to stimulated cells in MLRs, responder proliferation significantly decreased; the secreted amount of IFNγ and TNFα also significantly decreased (p=.011, .006). Furthermore, transwell experiments suggest MSCs exert their effects independent of cell contact. NHP transplant survival was significantly prolonged (MST 41 to 257) with the addition of donor derived MSC infusions (p=.032).Conclusions: Here we establish a preclinical model to investigate the impact of MSC therapy in vitro and in vivo, establishing a translational strategy for combination CoB and MSC cellular therapy to promote allograft tolerance. These data suggest MSCs suppress proliferation and effector function of alloreactive T cells independent of cell contact.

CITATION INFORMATION: Kim S, Mathews D, Higginbotham L, Breeden C, Larsen C, Adams A. Mesenchymal Stem Cells Suppress T Cell Proliferation and Improve Allograft Survival in a Nonhuman Primate Transplant Model. Am J Transplant. 2017;17 (suppl 3).

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