The long term goal of this proposal is to combine donor- specific immune unresponsiveness, nerve graft injection with cultured autologous Schwann cells, and the immunosuppressive agent FK506 to promote regeneration across nerve allografts. Injury to major peripheral nerves can result in significant and permanent functional deficits. The use of allogeneic nerve graft material would avoid the morbidity associated with harvesting nerve autografts, such as scars, numbness or painful neuroma formation, and offer a limitless source of nerve graft material to reconstruct large, multiple and complex nerve injuries. The systemic immunosuppressive agent FK506 significantly enhances nerve regeneration. Allograft injection with cultured autologous Schwann cells permits axonal regeneration in a rodent model. Administration of anti-CD40 ligand monoclonal antibody alone facilitates nerve allotransplantation in a murine model. Pre- treatment with UVB-irradiated donor antigen prior to nerve allotransplantation induces immune unresponsiveness and facilitates nerve regeneration in both rodent and swine models. Reliable swine and nonhuman primate models have been developed to study nerve allograft regeneration across a long nerve gap that more closely resembles the clinical challenge of reconstruction of extensive nerve injuries.
The aims of this proposal are: 1.) To investigate the effects of combining the neuroenhancing immunosuppressive drug FK506 with anti-CD40 ligand monoclonal antibody induced donor-specific immune unresponsiveness on regeneration across short nerve allografts in a murine model. 2.) To investigate the effects of graft injection with cultured autologous Schwann cells on immunosuppressive requirements and axonal regeneration in long nerve allografts in swine and nonhuman primate models. Assessment techniques include mixed lymphocyte culture, cytotoxic T-lymphocyte assays and limiting dilutional analysis, in conjunction with histological, morphological, electrophysiological, and functional assessments of nerve regeneration. The broad objective of this proposal is to improve the results following human nerve allotransplantation.
| Jesuraj, Nithya J; Santosa, Katherine B; Macewan, Matthew R et al. (2014) Schwann cells seeded in acellular nerve grafts improve functional recovery. Muscle Nerve 49:267-76 |
| Saheb-Al-Zamani, Maryam; Yan, Ying; Farber, Scott J et al. (2013) Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp Neurol 247:165-77 |
| Yan, Ying; MacEwan, Matthew R; Hunter, Daniel A et al. (2013) Nerve regeneration in rat limb allografts: evaluation of acute rejection rescue. Plast Reconstr Surg 131:499e-511e |
| Farber, Scott J; Glaus, Simone W; Moore, Amy M et al. (2013) Supercharge nerve transfer to enhance motor recovery: a laboratory study. J Hand Surg Am 38:466-77 |
| Fox, Ida K; Brenner, Michael J; Johnson, Philip J et al. (2012) Axonal regeneration and motor neuron survival after microsurgical nerve reconstruction. Microsurgery 32:552-62 |
| Jesuraj, Nithya J; Nguyen, Peter K; Wood, Matthew D et al. (2012) Differential gene expression in motor and sensory Schwann cells in the rat femoral nerve. J Neurosci Res 90:96-104 |
| Gustafson, Tiffany P; Yan, Ying; Newton, Piyaraj et al. (2012) A NIR Dye for Development of Peripheral Nerve Targeted Probes. Medchemcomm 3:685-690 |
| Yan, Ying; Sun, Hank H; Hunter, Daniel A et al. (2012) Efficacy of short-term FK506 administration on accelerating nerve regeneration. Neurorehabil Neural Repair 26:570-80 |
| Glaus, Simone W; Johnson, Philip J; Mackinnon, Susan E (2011) Clinical strategies to enhance nerve regeneration in composite tissue allotransplantation. Hand Clin 27:495-509, ix |
| Fox, Ida K; Mackinnon, Susan E (2011) Adult peripheral nerve disorders: nerve entrapment, repair, transfer, and brachial plexus disorders. Plast Reconstr Surg 127:105e-118e |
Showing the most recent 10 out of 69 publications
