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Oliver Treacy, Lisa O'Flynn, Aideen Ryan, Mourice Morcos, Paul Lohan, Sabine Schu, Mieszko Wilk, Matthew Griffin, Mikhail Nosov, Thomas Ritter; Donor- and third party-derived, but not recipient-derived mesenchymal stromal cells, promote corneal allograft survival in rats. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3211.
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Mesenchymal stromal cells (MSCs) have potent immunomodulatory potential and are being investigated clinically to promote allograft survival. Here, we investigated the ability of MSCs to promote allograft survival in a rat corneal transplant model.
Recipient-derived (syngeneic-syn), donor-derived (allogeneic-allo) or 3rd party MSCs were isolated from bone marrow of Lewis (LEW), Dark Agouti (DA) or Wistar-Furth rats, respectively. A fully allogeneic rat cornea transplant model (DA to LEW) was used for in vivo studies. Recipient (LEW) rats received one dose of 1x106 MSCs (syn, allo or 3rd party) intravenously on day -7 and a second dose on the day of transplantation (day 0). Graft survival and neovascularization was monitored. Flow cytometry was used to analyze graft-infiltrating cells and cellular distribution in the draining lymph nodes and spleens of MSC-treated transplanted rats and also to analyze allo-antigen or 3rd party antigen-primed T cells following re-stimulation with relevant antigen in vitro. Corneal stromal edema was quantified using histological analysis.
Untreated allografts were uniformly rejected (MST 16.6±1.5d, n=9) and, while syn-MSC treatment showed some evidence of attenuation of rejection (MST 18.3±4d, n=9), no clear pattern emerged following this treatment. In contrast, corneal allograft survival was significantly prolonged in approximately 90% of allo-MSC treated and 80% of 3rd party MSC treated allograft recipients. Flow cytometric analysis showed lower percentages of infiltrating NKT cells in corneas of both allo- and 3rd party MSC treated animals, coupled with a significantly higher frequency of splenic CD4+Foxp3+ regulatory T cells (Tregs), compared to controls. Furthermore, in an in vitro recall response assay following re-stimulation of lymphocytes from allo-MSC treated allograft recipients with allo-antigen, a significantly higher percentage of CD4+Foxp3+ Tregs were present compared to allo-antigen re-stimulated lymphocytes from syn-MSC treated recipients.
Systemic administration of both allo- and 3rd party MSCs prolongs corneal allograft survival with between 80 and 90% of allografts surviving for ≥ 30 days. This can be in part explained by the presence of fewer intragraft NKT cells and a higher frequency of splenic Tregs, coupled with antigen-specific modulation in the case of allo-MSC treatment.
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