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Robert Levy, Casey Lightbourn, Ying Wang, Cameron Bader, Sabrina Copsel, Brent Pfeiffer, Victor L Perez; Use of Post-Transplant Cyclophosphamide Therapy in High Risk Corneal Graft Transplantation: A New Strategy to Prolong Corneal Allograft Survival. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3311.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal transplants performed in recipients with vascularized corneas are considered high risk and the survival rate is dismal. Recently, cyclophosphamide (Cy) given after bone marrow transplants (BMT), i.e. post-transplant Cy (PTCy) has shown very promising results in clinical allogeneic BMT patients. Our lab and others have demonstrated that deletion of allo-reactive T cells together with maintenance of Treg cells underlie the effectiveness of this strategy. In this work, we asked if PTCy would also be effective after solid tissue allografts, including high-risk corneal transplant.
Murine orthotopic corneal allo-transplants were employed using B6 cornea donors and MHC-mismatched BALB/c recipients which typically result in graft rejection rates of >80%. Systemic PTCy treatment was tested at different doses (50-90 mgs/kgs) and time points (days 3-9) after transplantation. Corneal graft survival was assessed weekly by clinical corneal clarity score.
Animals treated with 50mg/kg PTCy at multiple time-points (ex. Days 6,7,+/- 9) delayed rejection of CT. Furthermore, employing escalating PTCy doses (50-90mg/kg) corroborated the timing and correlated with increasing, significant corneal graft survival (Fig.1). As anticipated, decreased MLR reactivity against donor B6 antigens was observed in PTCy treated recipients, consistent with deletion of graft rejecting allo-reactive T cells. Interestingly, we found a dramatic effect on neovascularization in PTCy treated pre-vascularized high-risk CT recipients. Photographic and slit lamp analyses demonstrated markedly diminished overall number, size and location of vessels in PTCy treated CT recipients. Notably, within PTCy treated mice, long-term acceptors-but not rejectors-demonstrated minimal / no corneal neo-vascularization. In total, the findings illustrate that PTCy can effectively and significantly prolong CT.
We hypothesize that PTCy inhibits both graft rejecting T cells and corneal neo-vascularization and that the latter involves reduction of angiogenic signals from infiltrating hematopoietic as well as parenchymal cells. These findings suggest that PTCy can provide a clinically effective treatment to markedly improve corneal allograft survival.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
Fig.1 Dose response demonstrates post transplant cyclophosphamide (PTC) treatment promotes corneal allograft survival.
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