The Effects of Growth Hormone on Nerve Regeneration, Functional Recovery and the Immune Response in Vascularized Composite Allotransplantation
Jennifer Rath, BS1,2, Xianyu Zhou, MD2, Philip Hanwright, MD2, Neha Amin, BS3, Nicholas von Guionneau, MBBS2, Karim Sarhane, MD2, Chia Na Min, MS2, Thomas Harris, BSc2, Sai Pinni4, WP Andrew Lee, MD2, Gerald Brandacher, MD2, Sami Tuffaha, MD2.
1University at Buffalo Jacobs School of Medicine, Buffalo, NY, USA, 2Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3University of Maryland School of Medicine, Baltimore, MD, USA, 4Johns Hopkins University, Baltimore, MD, USA.
PURPOSE: Functional recovery following upper extremity transplantation remains poor, primarily as a result of prolonged denervation and resultant muscle atrophy. Growth hormone (GH) has well-established trophic effects on neurons, myocytes, and Schwann cells and represents a promising therapeutic strategy to accelerate axonal regeneration and also maintain muscle and Schwann cells prior to reinnervation. The aims of this study were to confirm the positive effects of GH on nerve regeneration and functional recovery and to evaluate the effects of GH treatment on the immune response in the setting of vascularized composite allotransplantation.
METHODS: Rats underwent orthotopic forelimb transplantation with full MHC-mismatch (Brown Norway to Lewis) and were randomly assigned to receive either porcine-derived growth hormone (0.6 mg/kg/day) or no treatment (n=10 per group). All animals received tacrolimus (2 mg/kg/day) for graft maintenance. Animals underwent functional assessments every four weeks using electrically-stimulated grip strength testing. Animals were monitored for clinical signs of rejection. Skin biopsies and serum cytokine levels were obtained at the mid- and end-point to evaluate for subclinical rejection. Animals were sacrificed at 16 weeks or if they demonstrated advanced rejection (grades III/IV). Quantitative histological assessments of axonal regeneration, neuromuscular junction reinnervation, muscle atrophy, and Schwann cell proliferation were performed on muscle and nerve specimens upon sacrifice.
RESULTS: Grip strength was improved in the growth hormone-treated animals as compared to the control group at weeks 4 and 16 (p=0.03 and p=0.05, respectively; Figure 1). Preliminary quantitative analysis of axon histomorphometry revealed trends towards a greater degree of myelination and increased axon counts in the GH-treated group (p>0.05). Animals receiving GH treatment also demonstrated decreased muscle atrophy and increased nerve conduction velocity (p>0.05). Rates of clinical rejection did not significantly differ among groups. Remaining data is pending.
CONCLUSION: Growth hormone treatment improved functional recovery in rats undergoing allogenic orthotopic forelimb transplantation while not significantly affecting the rates of clinical rejection. GH treatment may allow for improved functional outcomes in VCA via accelerated axonal regeneration and maintenance of denervated muscle.
Figure 1: Post-transplantation functional recovery as measured by grip strength. Error bars depict standard error.
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