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.
Highlights
High immunological risk cornea transplant recipients have a much higher rate of rejection and lower long-term graft survival than conventional cornea transplant recipients [1]
It was concluded that the inoculation of recipients with corneal donor strain splenocytes 14 days prior to transplantation provided a robust, high immunological risk model in which to investigate the effects of third-party allo-mesenchymal stromal cell (MSC) administration
Using the same injection strategy (Figure 2A), it was observed that the rejection rate of corneal transplants in pre-sensitized recipients was strongly reduced by intravenous injections of third-party allo-MSC at day−7 and day−1 (Figure 2B)
Summary
High immunological risk cornea transplant recipients have a much higher rate of rejection and lower long-term graft survival than conventional cornea transplant recipients [1]. Factors that place patients at high-risk of rejection include corneal ulcers, bullous keratopathy or a failed previous graft [1, 2] These conditions frequently lead to increased blood and lymphatic vessel infiltration to the recipient graft bed and/or some pre-existing donor-specific cellular immune response [3]. Preclinical high-risk cornea transplantation models have mainly involved the formation of a pre-vascularised graft bed, either by placing sutures into the recipient cornea 7–14 days prior to transplantation [4,5,6] or causing a chemical injury to the cornea prior to transplantation [7] These models result in ingress of blood and lymphatic vessels to the recipient graft bed which removes the immune privileged nature of the anterior chamber of the eye. A preexisting immunity to a single antigen mismatch has been shown to significantly accelerate graft rejection in a mouse model [8]
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