Abstract P9

Kostereva, Nataliya; Lee, Vincent; Tobita, Kimimasa; Unadkat, Jignesh V.; Schnider, Jonas; Komatsu, Chiaki; Solari, Mario G.; Gorantla, Vijay S.

doi:10.1097/01.prs.0000445005.33742.6c

Cited by 1 publication

(1 citation statement)

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“…Nerve repair/coaptation (NR), a major component of VCA, is necessary for peripheral nerve regeneration to restore function to the transplanted tissues, but the effect of nerve coaptation on the inflammatory cascade that causes transplant rejection is presently unknown (4)(5)(6)(7). Nerve coaptation during VCA surgery initiates peripheral nervous system regeneration and ultimately facilitates motor control from recipient to graft and sensory input from graft to recipient, two functions that are crucial to functional transplant outcomes (8).…”

Section: Introductionmentioning

confidence: 99%

Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation

et al. 2023

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IntroductionVascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA.MethodsFor mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods.ResultsIn cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times.DiscussionThus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.

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