The establishment of clinically applicable strategies for inducing donor-specific tolerance to allow nerve allograft transplantation is the long term objective of this proposal. 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. Parameters for nerve allograft preservation have been established and cold graft preservation is seen to decrease systemic Cyclosporin A (CsA) requirements. Monoclonal antibodIes (mAbs) against adhesion molecules, ICAM-1 and LFA-1, suppress the nerve allograft response but do not tolerize the animal. By contrast, donor-specific antigen pretreatment with UV-B irradiated spleen cells induces tolerance in the rat allograft model. Anti-CD4 mAbs inactivate functional T cells and thus, result in host unresponsiveness. A reliable sheep model has 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. Seven days of cold preservation of the nerve allograft decreases the antigenicity of the allograft and allows nerve regeneration. Thus, unlike solid organ transplantation, preservation of the allograft makes recipient pretreatment with UV-B irradiated donor antigen(7 days) prior to allotransplantation clinically feasible.
The aims of this proposal are: 1) to establish an immunosuppressive strategy that uses pretransp- lant administration of donor antigen in combination with anti-CD4 mAb therapy to induce donor-specific tolerance in a short nerve allograft rat model; and 2) to study the merits of cold nerve preservation CsA therapy and the administration of donor antigen to confer immunotolera- nce to along nerve allograft sheep model. Assessment techniques will include mixed lymphocyte culture, cytotoxic T lymphocyte assays and limiting dilutional analysis, in conjunction is histological, morpho- logical, electrophysiological and functional assessment of nerve regeneration. The broad objective of this proposal is to improve the results following nerve allografting and thus allow the establishment of a nerve bank and the facilitation of clinical nerve allotransplanta- tion.
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| 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 |
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| 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 |
| Jesuraj, Nithya J; Santosa, Katherine B; Newton, Piyaraj et al. (2011) A systematic evaluation of Schwann cell injection into acellular cold-preserved nerve grafts. J Neurosci Methods 197:209-15 |
| Ray, Wilson Z; Kasukurthi, Rahul; Kale, Santosh S et al. (2011) Costimulation blockade inhibits the indirect pathway of allorecognition in nerve allograft rejection. Muscle Nerve 43:120-6 |
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