Whole Eye Allograft Transplantation And Immunosuppression: Survival Of The Transplanted Rodent Eye Using Tacrolimus Monotherapy
Wendy Chen, MD, MS1, Jila Noori, MD2, Lin He, MD3, Chiaki Komatsu, MD1, Maxine R. Miller, MD1,4, Ian A. Rosner, BS5, Wensheng Zhang, MD, PhD1, Kira L. Lathrop, MAMS4,6, Joshua Barnett, B.S.1,7, Yong Wong, MD1, Bing Li, M.D.1, Mario G. Solari, M.D.1, Charleen T. Chu, MD,PhD8,9, Kia M. Washington, M.D.1,10.
1University of Pittsburgh Department of Plastic Surgery, Pittsburgh, PA, USA, 2University of Miami Health System Bascom Palmer Eye Institute, Miami, FL, USA, 3The First Affiliated Hospital of Xi’an Jiaotong University Department of Plastic, Aesthetic and Craniofacial Surgery, Xi'An, China, 4University of Pittsburgh Department of Ophthalmology, Pittsburgh, PA, USA, 5Carnegie Mellon University Department of Biological Sciences, Pittsburgh, PA, USA, 6University of Pittsburgh Swanson School of Engineering Department of Bioengineering, Pittsburgh, PA, USA, 7University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 8University of Pittsburgh Department of Pathology, Pittsburgh, PA, USA, 9McGowan Institute for Regenerative Medicine, Pittsburgh, PA, USA, 10Veterans Adminitration Pittsburgh Medical Center , Pittsburgh, PA, USA.
Visual impairment and blindness present significant social and economic burdens around the world. Whole eye transplantation (WET) is a potential solution. Our lab has established a viable rodent model and demonstrated promising results in syngeneic transplants. To establish allograft transplantation, a successful immunosuppressive pharmacotherapy regimen is required. Tacrolimus monotherapy is successful in rodent vascularized composite allotransplantation (VCA), but its efficacy in WET is unknown. Here, we present survival of allograft WET treated with Tacrolimus mono therapy.
METHODS: Brown-Norway to Lewis rat whole eye transplantations were performed (n=6), followed by daily intraperitoneal 1mg/kg Tacrolimus (FK-506) monotherapy injection. Animals were examined at post-operative week 1, 3, 5, and 6. Ocular structure and retinal blood flow were studied using Optical Coherence Tomography (OCT). A retina specialist ophthalmologist performed anterior segment examination, fundoscopy, indirect ophthalmoscopy, and tonometry for intraocular pressures. Animals were sacrificed at 6 weeks. Specimens of the transplanted globe, external ear, eyelid, bone and vessel anastomoses were stained with H&E and interpreted by an ocular pathologist.
RESULTS: All composite grafts survived without signs of infection or necrosis (Figure 1, 2). OCT demonstrated generally normal cornea, relative structural maintenance of the retina, and preserved blood flow in the central retinal artery and vein (Figure 3). At one week after transplantation, most (n=3 out of 5 examined) of transplanted allograft eyes exhibited normal perfusion with pink optic nerve heads. At three weeks, the eyes trended toward increased ischemia, with atrophic fundi or 3+ ischemia (n=3 out of 5 examined). By five weeks, there was some improvement in retinal ischemia, but optic nerve heads remained pale and moderate fundus ischemia was sustained to the study endpoint of 6 wks. In previous syngeneic transplants, fundus ischemia and pale optic nerves were present but uncommon. Intraocular pressures (IOPs, Figure 4) in the transplanted eye were within normal range, with a single exception. Average IOPs in the transplanted eyes were 10.9 mmHg (SD 2.2), 15.5 mmHg (SD 7.7), 9.9 mmHg (SD 2.7), and 10.7 mmHg (SD 2.3) at week 1, 3, 5, and 6, respectively. Histologically, inflammation and neovascularization were seen in the cornea. There were no inflammatory cells in the anterior chamber. Central retinal degeneration was noted. Chronic inflammation was observed at the optic nerve. By comparison, the unoperated eye was normal.
CONCLUSION: With Tacrolimus monotherapy, transplanted globes survived for 6 weeks, with grossly intact cornea and retinal structures and normal IOPs. On ophthalmologic examination, some degree of fundus ischemia was present despite the presence of retinal blood flow as confirmed by OCT. Allografts may be less vascularized than syngeneic whole eye transplantations. In addition, histopathology reveals some inflammation and neovascularization to the cornea and central degeneration of the retina. These findings serve as targets for future, therapies, improvements and investigation. Future studies of systemic and local immunosuppressive therapies are necessary to support the structural and functional success of whole-eye allotransplantation.
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