T cell roles in regeneration across nerve graft alternatives

项目总结/摘要 在神经缺损修复后实现有意义的功能恢复仍然是一个主要的未满足的临床问题。 挑战.由于神经自体移植的缺点，神经移植物替代品正越来越多地被使用， 用于缺陷修复。但在临床上，这些替代品并不能促进持续的再生和恢复。 此外，我们仍然不知道什么因素对促进持续的神经再生至关重要 修复的神经缺损，产生有意义的恢复。为了了解促进神经 再生跨神经移植替代品和功能恢复，我们已经使用了临床相关的神经 移植替代，脱细胞神经同种异体移植物（ANAs），作为模型。最近，我们确定了一个关键作用， 在ANA再生过程中的适应性免疫系统。我们发现，神经再生跨越短 ANA修复野生型（WT）小鼠的神经缺损是稳健的，而T和B小鼠的ANA再生是稳健的。 细胞缺陷小鼠（RAG 1 KO）受损。RAG 1 KO小鼠中的ANA含有减少的2型 细胞因子（即IL-4）水平与WT ANA相比。IL-4表达通过CD 4 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IL-4的表达促进ANA的神经再生。 因此，在我们的目标中，我们将（1）解剖哪些适应性免疫细胞，包括CD 4 T细胞，影响神经， （2）确定ANA内IL-4表达的调节方式，以及（3）确定ANA内IL-4的表达水平。 IL-4的靶点，促进ANA的神经再生。总之，我们的研究将揭示 适应性免疫系统有助于神经再生，并展示了IL-4信号如何促进 神经移植替代品的再生。

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.