Immunological Distinctions of Peripheral Nerves May Allow for a Localized Approach to Immunosuppression for Allografts
Jared Shane Bushman, PhD, University of Wyoming, Laramie, WY
Introduction: Regeneration through segmental defects is remains a significant challenge. Engineered bridging devices (e.g. conduits, decellularized allografts) lack the bioactivity of live nerve grafts and thus do not stimulate effective repair in many cases. Much effort has been put toward developing means to improve engineered devices through bioactivation (e.g. addition of cells, growth factors, luminal fillers) in an attempt to make them more like live nerve grafts, but they still fall significantly short of sensory autografts. Live (not decellularized) nerve allografts can be matched to the injury site in terms of size and sensorimotor composition and are highly effective at promoting regeneration, but use is limited because of the risks and expense of systemic immunosuppression. We have been investigating the immunology of the host response to peripheral nerve allografts and discovered several distinctive aspects. These aspects coupled with advances in immunology may make a more localized and temporary approach to immunosuppression possible that may circumvent the risks and much of the expense of systemic immunosuppression.
Materials and Methods: Immunohistochemistry was used to study the timeline and abundance of host immune cells into peripheral nerve autografts and allografts in rats. For localized immunosuppression, allogeneic regulatory T cells (Tregs) were implanted around 2 cm branched nerve allografts sutured into rat hosts, a poly(ethylene glycol) (PEG) hydrogel as a localized Treg delivery vehicle. Migration and the functional effect of Tregs on the host immune response was tracked by immunofluorescence and compound muscle action potentials (CMAPs) were used as a functional measure of regeneration. Terminal measurements include nerve morphometry and muscle mass.
Results: Peripheral nerve allografts in a complete MHC mismatch elicited a host immune response that was only marginally different from that of an autograft. In the test of localized immunosuppression with Tregs, the Tregs infiltrated the allograft and suppressed the host immune response indicated by a significant reduction in host effector immune cells within grafts. CMAPs and nerve morphometry indicate that the degree of functional regeneration achieved with localized immunosuppression and peripheral nerve allografts was equal to the autograft that was immediately sutured back into place. No additional immunosuppression was necessary beyond the initial implantation of Tregs. This was achieved with complex segmental defect that included the peroneal and tibial branch point.
Conclusions: The immunological challenges for the use of peripheral nerve allografts to treat segmental defects may be addressable with a localized regimen of immunosuppression.
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