Lymphatic vessel regulates tertiary lymphoid structure formation and inflammatory intensity in peripheral nerve allografts.

Peripheral nerve allografting is accompanied by complex immune responses. Lymphatics serve as transportation channels for immune cells and are an essential component of the immune system's functionality. However, the role of lymphatic vessels in peripheral nerve allograft was unclear. In this study, we established a sciatic nerve allograft model to investigate the dynamic relationship between lymphangiogenesis and tertiary lymphoid structure (TLS) formation. We found that TLS development was temporally associated with lymphatic remodeling, and that modulation of lymphangiogenesis significantly affected the number and size of TLSs. Inflammatory cell infiltration was further assessed, which exhibited a synchronous variation trend with the dynamics of lymphatics and TLSs. In addition, we confirmed that lymphangiogenesis inhibition significantly accelerated axonal regeneration with superior outcomes compared to the control group, whereas lymphangiogenesis promotion induced an excessive immune-inflammatory response. These findings suggest that lymphatic remodeling is associated with TLS formation and inflammatory-cell infiltration in peripheral nerve allografts and may contribute to changes in donor-derived cell preservation and subsequent nerve regeneration.