Rejection and regulation: a tight balance.

Achieving allograft tolerance is the holy grail of transplantation. However, tolerance and rejection are two extreme ends of a scale that can be tipped in either direction. We review the novel effector and regulatory mechanisms involved and factors that tip the balance in favor of rejection or regulation. It is increasingly recognized that established T cell phenotypes could change their commitments. New data point to the plasticity of Th17 cells in vivo with a reciprocal balance of Th17 cells and regulatory T cells driven by the local cytokine environment. Regulatory T cell profiles have been linked to acute and chronic allograft outcomes, and emerging data also indicate a novel role of a regulatory B cell population. Current research efforts are looking into factors that tip the balance towards allograft tolerance by targeting cytokines, novel co-stimulatory pathways such as T cell Ig mucin molecules, and components of innate immunity, particularly dendritic cells. The balance of effector and regulatory mechanisms contributing to allograft outcome is very complex. It is likely that targeting multiple pathways will be required to achieve tolerance. Further studies are warranted to define this balance and identify optimal combination of therapeutic interventions.

实现同种异体移植物耐受是移植领域的“圣杯”。然而，耐受和排斥是一个天平的两个极端，天平可能向任何一方倾斜。我们综述了所涉及的新型效应和调节机制以及使平衡向排斥或调节方向倾斜的因素。 人们越来越认识到，已确定的T细胞表型可能会改变其功能。新的数据表明体内Th17细胞具有可塑性，Th17细胞和调节性T细胞受局部细胞因子环境驱动而相互平衡。调节性T细胞的特征与同种异体移植物的急性和慢性结果相关，新出现的数据还表明调节性B细胞群具有一种新的作用。当前的研究工作正在探究通过靶向细胞因子、新型共刺激通路（如T细胞免疫球蛋白黏蛋白分子）以及固有免疫成分（特别是树突状细胞）使平衡向同种异体移植物耐受倾斜的因素。 影响同种异体移植物结果的效应和调节机制的平衡非常复杂。很可能需要靶向多个通路才能实现耐受。有必要进一步研究来明确这种平衡并确定治疗干预的最佳组合。