*Purpose: Mechanisms of rejection of peripheral nerve and optic nerve remains largely unknown. The inability to prevent rejection of the optic nerve has thwarted the successful execution of an eye transplant. Here, we aimed to establish a model for understanding the mechanisms behind the rejection of peripheral and optic nerves and to identify optimal immune therapeutic strategies to halt nerve rejection.

*Methods: Optic and sciatic nerve grafts were transplanted under the kidney capsules of mice and were characterized fully for immune infiltrates and peripheral immune responses were assessed.

*Results: Surprisingly, the optic nerve autografts were better preserved than the sciatic nerve. We confirmed axonal presence inside the optic nerve implant by identifying a positive GFP signal in the nerve after intravitreal injection of a GFP-labeled AAV2 virus. The optic and sciatic nerve allografts showed immune cell infiltrates as early as 3 days post-transplantation. Both allografts contained more CD11b⁺ cells than either CD3⁺ T cells or B220⁺ B cells. Notably, the optic nerve allografts contained more of these cells 7 days post-transplantation as compared to the sciatic implants. The spleens of the sciatic nerve recipients also contained a higher percentage of regulatory B cells than those of optic nerve recipients (0.1950% vs. 0.1250%; p=0.0304). Using Ova nerve implants into Rag host injected with OT1 and OT2 cells, we noted higher CD8⁺ alloreactivity as compared to CD4⁺ alloreactive ones. To gain more insights on the immunogenicity of these nerves, we assessed their cellular compositions. Flow cytometric analysis revealed that the optic nerve contained a lower percentage of MHC class-II⁺ cells (0.0044% vs. 0.0578%; p<0.0001) and higher percentage of PD-L1⁺ cells (0.049% vs. 0.034%; p<0.0001), and sciatic nerve cells induced more alloreactivity in comparison to optic nerve cells in an MLR assay (p<0.0001). Given the higher infiltrates in optic nerve in vivo, we speculate the immunogenicity of optic nerve increases following ischemic injuries. Finally, immunosuppressive treatment with mCTLA4IgG, Rapamycin, or Anti-CD3 failed to protect both allografts from rejection.

*Conclusions: The optic nerve allograft may be subjected to a more pronounced alloimmune response than the sciatic nerve allograft. Both grafts appear resistant to standard immunomodulatory drugs that confer tolerance towards other types of transplanted organs.

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