Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

Abstract

High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (p = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45+CD11b+ B220+ monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4+ FoxP3+ regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In in vitro experiments, third-party allo-MSC polarized primary lung-derived CD11b/c+ myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E2 and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.

Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review

“…These results indicate that xenogeneic MSCs seem to be equally efficacious as autologous and allogeneic MSCs in the [147]. In this model, freshly cultured allogeneic rat MSCs showed equal efficacy as the same cells after cryopreservation [148].…”

“…That said, in other models this may not be the case, as has been shown in a rat corneal transplantation model where human MSCs in contrast to rat MSCs failed to prolong allograft survival . In this model, freshly cultured allogeneic rat MSCs showed equal efficacy as the same cells after cryopreservation .…”

TNF‐α/IL‐1β—licensed mesenchymal stromal cells promote corneal allograft survivalviamyeloid cell‐mediated induction of Foxp3+regulatory T cells in the lung

“…Although the mechanism of MSC-mediated immunomodulation following intravenous administration remains to be fully elucidated, it is evident that the lungs (where the majority of MSCs become trapped and are subsequently cleared within 24 h) play an important role (15)(16)(17)(18). Our group and others have reported that MSCs enrich innate immuneregulatory cells in the lungs following intravenous administration (9,15,16,(19)(20)(21).…”

Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory and Foxp3+ T regs induction capacity

“…[34][35][36][37][38][39][40] Furthermore, ex-vivo expanded MSCs display potent immunomodulatory effects in a wide array of animal disease models and have been validated in clinical trials to represent safe, feasible, and potentially effective immunotherapies for human immune-related disorders including graft-versus-host disease (GVHD) as well as autoimmune diseases. [41][42][43][44] A large number of these animal model studies [45][46][47][48][49][50] and clinical trials [51][52][53][54][55][56][57][58] have also documented changes in T reg number and function after systemic or localized administration of either autologous or allogeneic MSCs.…”