Veenstra Rachelle G, Flynn Ryan, Kreymborg Katharina, McDonald-Hyman Cameron, Saha Asim, Taylor Patricia A, Osborn Mark J, Panoskaltsis-Mortari Angela, Schmitt-Graeff Annette, Lieberknecht Elisabeth, Murphy William J, Serody Jonathan S, Munn David H, Freeman Gordon J, Allison James P, Mak Tak W, van den Brink Marcel, Zeiser Robert, Blazar Bruce R
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
Blood. 2015 May 21;125(21):3335-46. doi: 10.1182/blood-2014-09-603357. Epub 2015 Mar 26.
Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3(-/-) vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3(-/-) vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications.
B7家族成员已被证明通过提供正向或负向共刺激信号来调节免疫反应。B7-H3的功能一直存在争议。我们发现，B7-H3在移植物抗宿主病（GVHD）的靶器官中上调，包括结肠、肝脏和肺。将同种异体供体T细胞输注到B7-H3基因敲除（-/-）小鼠与野生型（WT）受体中，结果显示GVHD致死率增加，这与T细胞增殖增加、结肠炎性细胞因子以及上皮屏障破坏有关。同种异体B7-H3（-/-）与WT供体T细胞相比，在脾脏中T细胞增殖和GVHD致死率也增加，同时上皮内淋巴细胞炎性细胞因子增加以及肠道通透性增加，并且增殖和细胞因子分泌也增加。静息和活化的调节性T细胞（Tregs）均缺乏B7-H3信使核糖核酸。与这些数据一致，在接受B7-H3（-/-）Treg耗尽移植物的受体中，GVHD加剧。在两个延迟淋巴细胞输注（DLI）模型中，缺乏B7-H3的T细胞能够产生移植物抗白血病（GVL）效应。我们得出结论，B7-H3负责提供负向共刺激信号。我们的研究为开发和测试针对B7-H3途径的新疗法提供了支持，包括在骨髓移植后早期增强宿主B7-H3以预防GVHD，以及在移植后期开发强效拮抗抗体以促进DLI介导的GVL而无GVHD并发症的方法。
