T cell roles in regeneration across nerve graft alternatives

T 细胞在神经移植替代品再生中的作用

• 批准号: 10541239
• 负责人: Matthew D. Wood
• 金额: $ 37.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541239
• 关键词: ACTL6B gene; Adaptive Immune System; Address; Affect; Allografting; Antibodies; Axon; B-Lymphocytes; CD19 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinical; Data; Defect; Disadvantaged; Genes; Goals; Human; Immune; Immune system; Impairment; Injury; Innate Immune System; Interleukin-4; Interleukin-5; Knockout Mice; Knowledge; Length; LoxP-flanked allele; Mediating; Modeling; Motor; Mus; Natural regeneration; Nerve; Nerve Regeneration; Nervous System; Neurons; Outcome; Outcomes Research; Patient Care; Play; Rag1 Mouse; Reconstructive Surgical Procedures; Recovery; Recovery of Function; Regulation; Rodent Model; Role; Scientific Advances and Accomplishments; Signal Transduction; T-Cell Depletion; T-Lymphocyte; Trauma; Wild Type Mouse; Work; clinically relevant; cytokine; eosinophil; humoral immunity deficiency; immunoregulation; improved; innovation; nerve autograft; nerve injury; nerve repair; novel therapeutics; peripheral nerve damage; receptor; repaired; restoration

PROJECT SUMMARY / ABSTRACT Achieving meaningful restoration of function after nerve defects are repaired is still a major unmet clinical challenge. Due to disadvantages of nerve autografting, nerve graft alternatives are being increasingly used and desired for defect repair. But clinically, these alternatives do not promote consistent regeneration and recovery. Furthermore, we still do not understand what factors are critical to promote consistent nerve regeneration across repaired nerve defects that yields meaningful recovery. To understand mechanisms that promote nerve regeneration across nerve graft alternatives and functional recovery, we have used the clinically-relevant nerve graft alternative, acellular nerve allografts (ANAs), as a model. Recently, we determined a critical role for the adaptive immune system during regeneration across ANAs. We found that nerve regeneration across short ANAs repairing nerve defects in wild-type (WT) mice was robust, while regeneration across ANAs in T and B cell deficient mice (RAG1KO) was impaired. The ANAs within RAG1KO mice contained reduced Type 2 cytokine (i.e. IL-4) levels compared to WT ANAs. IL-4 expression was regulated via CD4 T cells and eosinophils. And in IL-4KO mice, regeneration across ANAs was also impaired. Overall, we have evidence that T cells contribute to nerve regeneration across ANAs through regulation of IL-4 expression within ANAs. Therefore, in our aims we will (1) dissect which adaptive immune cells, including CD4 T cells, affect nerve regeneration across ANAs, (2) identify how IL-4 expression is regulated within ANAs, and (3) determine the targets of IL-4 that promote nerve regeneration across ANAs. In summary, our studies will reveal the cells of the adaptive immune system contributing to nerve regeneration and demonstrate how IL-4 signaling promotes regeneration across nerve graft alternatives.

项目概要/摘要 神经缺损修复后实现有意义的功能恢复仍然是临床上一个主要的未满足的问题 挑战。由于自体神经移植的缺点，神经移植替代品的使用越来越多， 需要进行缺陷修复。但在临床上，这些替代方案并不能促进持续的再生和恢复。 此外，我们仍然不明白哪些因素对于促进一致的神经再生至关重要 跨越修复的神经缺陷，产生有意义的恢复。了解促进神经的机制 跨神经移植替代品的再生和功能恢复，我们使用了临床相关的神经 移植替代方案，无细胞神经同种异体移植（ANA）作为模型。最近，我们确定了一个关键角色 ANA 再生过程中的适应性免疫系统。我们发现神经再生在短时间内 ANA 修复野生型 (WT) 小鼠神经缺陷的能力很强，而 T 型和 B 型小鼠中 ANA 的再生能力很强 细胞缺陷小鼠（RAG1KO）受损。 RAG1KO 小鼠体内的 ANA 含有减少的 2 型 与 WT ANA 相比，细胞因子（即 IL-4）水平。 IL-4 表达通过 CD4 T 细胞调节 嗜酸性粒细胞。在 IL-4KO 小鼠中，ANA 的再生也受到损害。总的来说，我们有证据表明 T 细胞通过调节 ANA 内的 IL-4 表达，促进 ANA 神经再生。 因此，在我们的目标中，我们将 (1) 剖析哪些适应性免疫细胞，包括 CD4 T 细胞，影响神经 跨 ANA 的再生，(2) 确定 ANA 内 IL-4 表达的调节方式，以及 (3) 确定 IL-4 的靶标可促进 ANA 神经再生。总之，我们的研究将揭示细胞 适应性免疫系统有助于神经再生，并展示 IL-4 信号如何促进 跨神经移植替代品的再生。