Wrenshall Lucile
Division of Transplantation, University of Nebraska, 983285 Nebraska Medical Center, Omaha, NE 68198-3285, USA.
Springer Semin Immunopathol. 2003 Sep;25(2):199-213. doi: 10.1007/s00281-003-0138-y.
Through the constant interplay of cellular and extracellular components, the microenvironment of tissues directs immune responses. In solid organ transplantation, one factor that significantly alters the microenvironment of tissues is reperfusion injury, which occurs to a certain extent in essentially all cadaver organs. The damage that results from reperfusion injury initiates a cascade of signals to surveillance cells such as macrophages, mast cells, and dendritic cells, augmenting both innate and allo-immune responses. Chemokines, released from surveillance cells and others, orchestrate an influx of cells into the allograft, and subsequently drive the migration of dendritic cells and lymphocytes to proper areas within lymph nodes for the efficient generation of allo-immune responses. Heparan sulfate, a component of the extracellular matrix, binds chemokines and thus regulates their localization within tissues. This association is one of a multitude of examples of the interplay between cells and their extracellular surroundings. In addition to the association with chemokines, heparan sulfate binds cytokines such as IFN-gamma and IL-2. In the spleen, heparan sulfate localizes IL-2 to the marginal zone, red pulp, and interdigitating dendritic cells of the T cell zone. Our laboratory recently determined that the contribution of heparan sulfate-bound IL-2 to immune responses is substantial, finding that bound, rather than free, IL-2 drives immune responses. This finding reiterates the critical nature of the interaction between cells and the extracellular matrix. Disruptions in these interactions may lead to dysregulation of immune responses and, in turn, pathologies such as tissue fibrosis or autoimmunity. Further studies into the exchange between cells and the extracellular matrix will likely lead to new lines of therapies aimed at correcting these abnormalities before irreversible damage occurs.
通过细胞和细胞外成分的持续相互作用，组织的微环境引导免疫反应。在实体器官移植中，显著改变组织微环境的一个因素是再灌注损伤，基本上所有尸体器官在一定程度上都会发生这种损伤。再灌注损伤导致的损害引发了一系列信号传递给监视细胞，如巨噬细胞、肥大细胞和树突状细胞，增强了固有免疫和同种异体免疫反应。从监视细胞和其他细胞释放的趋化因子协调细胞流入同种异体移植物，随后驱动树突状细胞和淋巴细胞迁移到淋巴结内的适当区域，以有效产生同种异体免疫反应。硫酸乙酰肝素是细胞外基质的一种成分，它结合趋化因子，从而调节它们在组织内的定位。这种关联是细胞与其细胞外环境相互作用的众多例子之一。除了与趋化因子的关联外，硫酸乙酰肝素还结合细胞因子，如干扰素-γ和白细胞介素-2。在脾脏中，硫酸乙酰肝素将白细胞介素-2定位到边缘区、红髓和T细胞区的交错树突状细胞。我们实验室最近确定，硫酸乙酰肝素结合的白细胞介素-2对免疫反应的贡献很大，发现结合型而非游离型白细胞介素-2驱动免疫反应。这一发现重申了细胞与细胞外基质之间相互作用的关键性质。这些相互作用的破坏可能导致免疫反应失调，进而导致诸如组织纤维化或自身免疫等病理状况。对细胞与细胞外基质之间交换的进一步研究可能会带来新的治疗方法，旨在在不可逆转的损害发生之前纠正这些异常情况。
