Mammadli Mahinbanu, Huang Weishan, Harris Rebecca, Xiong Hui, Weeks Samuel, May Adriana, Gentile Teresa, Henty-Ridilla Jessica, Waickman Adam T, August Avery, Bah Alaji, Karimi Mobin
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA.
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
iScience. 2021 Mar 11;24(4):102286. doi: 10.1016/j.isci.2021.102286. eCollection 2021 Apr 23.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8 and CD4 donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8 and CD4 donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment.
异基因造血干细胞移植（allo-HSCT）是治疗血液系统恶性肿瘤的一种治愈性疗法，这归因于同种异体反应性供体T细胞介导的移植物抗白血病（GVL）活性。然而，移植物抗宿主病（GVHD）也是由这些细胞介导的。在此，我们评估了减弱TCR介导的SLP76:ITK相互作用在allo-HSCT后对GVL与GVHD效应的影响。来自在SLP-76中表达Y145F突变的小鼠的CD8和CD4供体T细胞不会引发GVHD，但保留了对B-ALL细胞的GVL效应。SLP76Y145FKI CD8和CD4供体T细胞还显示出炎症细胞因子产生减少以及向GVHD靶器官的迁移减少。我们开发了一种新型肽来特异性抑制SLP76:ITK相互作用，导致PLCγ1和ERK的磷酸化减少、人T细胞中细胞因子产生减少，以及GVHD与GVL效应的分离。总之，我们的数据表明，抑制SLP76:ITK相互作用可能是一种在allo-HSCT治疗后将GVHD与GVL效应分离的治疗策略。
