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Differences in Inflamitory Cytokine Production in Nerve Regeneration and Allograft Rejection and Effects on Nerve Regeneration
Sami Tuffaha, MD; K. Sarhane; A. Hoke; G. Brandacher; Damon S. Cooney
Plastic and Reconstructive Surgery, Johns Hopkins Medical Institutions, Baltimore, MD

Purpose: Nerve regeneration is a complicated process made even more complex by the involvement of the immune system. The interaction between nerve regeneration and the immune system is a critical part of nerve regeneration after any injury, and is most dramatic during recovery following limb transplantation. This new field of reconstructive surgery relies on further research to improve patient outcomes and can serve as a powerful model to study the mechanisms of interaction between nerve regeneration and immune function. We have investigated the differences in cytokine signaling during nerve regeneration between the

Methods: Rats underwent sciatic nerve transection and repair in isolation (intact limb) or in the context of syngeneic or allogeneic transplantation. Orthotopic hindlimb transplants were performed between (Lewis) syngeneic or (BN to Lewis) allogeneic rat strain combinations. Allogeneic transplants in different groups were either kept on immunosuppression or allowed to reject. Cytokine levels were analyzed using multiplex assay and quantitative PCR and nerve regeneration quantified by nerve histomorphometry.

Results: Several patterns of pro-inflammatory cytokines were noted to be up-regulated in the distal nerve following cut and repair. Anti-inflamatory cytokines including IL-10 were down regulated in distal nerve segments as well. Differences were seen between inflammation caused by cut and repair and syngeneic transplant vs allogeneic transplants. Several cytokines were found to be specific for inflammation involved in rejection. One of these cytokines IL-6 was also found to up-regulated even in the presence of immunosupresion and no clinical signs of rejection. These findings correlated with impaired nerve regeneration by histomorphometry in allogeneic transplants even while on immunosuppression.

Conclusions: Inflammatory cytokines are activated and anti-inflammatory cytokines down regulated following cut and repair of any nerve. Additionally, specific cytokine patterns are initiated in nerves generating in the context of a limb transplant. These inflammatory changes seem to have a deleterious effect on nerve regeneration even in the absence of clinical rejection. Further understanding of the complex interplay between inflammation and nerve regeneration will allow us to make improvements in the clinical outcomes of patients with both nerve injuries and limb transplants.


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