IMMUNOPATHOLOGICAL ASPECTS OF THREMAL INJURY

描述（由申请方提供）：严重热损伤诱导具有显著炎症/免疫成分的病理生理学反应，导致多种并发症，包括伤口愈合延迟、败血症易感性增加和多器官衰竭。广泛的介质和细胞类型密切调节烧伤后炎症过程。尽管如此，烧伤患者在严重烧伤后维持炎症和抗炎反应之间适当平衡的能力经常被破坏，导致免疫病理学并发症。在这方面，独特的T细胞亚群，γ δ（7/8）T细胞具有调节炎症和愈合过程的能力。γ/δ T细胞可能是患者从烧伤中成功恢复的关键组成部分。我们最近的发现通过证明以下内容支持γ/8 T细胞在烧伤后免疫病理学中的重要多方面作用：它们在损伤后早期被动员和激活;它们调节烧伤后中性粒细胞迁移;以及γ/8 T细胞通过调节损伤部位的生长因子、细胞因子和一氧化氮（NO）产生而有助于烧伤伤口愈合。虽然巨噬细胞NO的产生（在某些条件下由γ/δ T细胞调节）是烧伤后免疫功能障碍的重要介质，但它对伤口修复的许多方面也是至关重要的。烧伤首先是对皮肤的损伤，并且绝大多数烧伤患者具有与烧伤或皮肤移植部位的愈合相关的并发症。尽管如此，虽然γ/δ T细胞对伤口愈合很重要，但它们在烧伤后的这些过程中的作用仍有待明确阐明。我们的假设是γ/8 T细胞在烧伤后皮肤炎症反应和伤口愈合中起关键的调节作用，其部分由iNOS依赖性机制介导。具体目标将确定：1）γ/8 T细胞在烧伤后伤口愈合和皮肤炎症反应中的作用; 2）γ/8 T细胞在烧伤切除和移植中的作用; 3）γ/8 T细胞与人类烧伤后伤口愈合和炎症反应的关系。阐明γ/8 T细胞、皮肤炎症反应和烧伤后伤口愈合之间的关系对于开发针对该危重患者群体的改进的治疗方案将是至关重要的，这可能包括用γ/8 T细胞进行生物治疗或调节天然γ/8 T细胞活性的新概念。

DESCRIPTION (provided by applicant): Major thermal injury induces a pathophysiological response that has a marked inflammatory/immune component which contributes to numerous complications that include delayed wound healing, increased susceptibility to sepsis and multiple organ failure. A wide range of mediators and cell types closely regulate the post-burn inflammatory process. Nonetheless, the ability of the burn patient to maintain an appropriate balance between inflammatory and anti-inflammatory responses following major burn injury is often disrupted leading to immunopathological complications. In this regard, a unique T-cell subset, gamma delta (7/8) T- cells has the ability to regulate inflammatory and healing processes. Gamma/delta T-cells are likely to be a critical component of the patient's successful recovery from burn injury. Our recent findings support an important multi-faceted role for y/8 T-cells in post-burn immunopathology by demonstrating the following: they are mobilized and activated early post-injury; they regulate post-burn neutrophil migration and; 7/8 T- cells contribute to burn wound healing via the regulation of growth factor, cytokine, and nitric oxide (NO) production at the injury site. While macrophage NO production (which is regulated by y/8 T-cells under certain conditions) is an important mediator of post-burn immune dysfunction, it is also critical to many aspects of wound repair. Burn injury is first and foremost an injury to the skin and a vast majority of burn patients have complications related to healing of the burn or skin graft site. Nonetheless, while y/8 T-cells are important to wound healing, their role in such processes post-burn remains to be clearly elucidated. It is our hypothesis that y/8 T-cells play a critical regulatory role in the post-burn dermal inflammatory response and wound healing that is, in part, mediated by an iNOS-dependent mechanism. The specific aims will determine: 1) the role of y/8 T-cells in post-burn wound healing and the dermal inflammatory response; 2) the role of y/8 T-cells in burn excision and grafting and; 3) the relationship of y/8 T-cells to the post burn wound healing and inflammatory responses in humans. Elucidation of the relationships between y/8 T-cells, the dermal inflammatory response and post-burn wound healing will be vital in the development of improved therapeutic regimes for this critically ill patient population, which could include the novel concept of biotherapy with y/8 T-cells or modulation of native y/8 T-cell activity.