Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
Mahinbanu Mammadli,
Weishan Huang,
Rebecca Harris,
Hui Xiong,
Samuel Weeks,
Adriana May,
Teresa Gentile,
Jessica Henty-Ridilla,
Adam T. Waickman,
Avery August,
Alaji Bah,
Mobin Karimi
Affiliations
Mahinbanu Mammadli
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA
Weishan Huang
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Rebecca Harris
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA
Hui Xiong
Department of Radiology, Jiangxi Health Vocational College, Nanchang, 330052, China
Samuel Weeks
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA
Adriana May
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA
Teresa Gentile
Division of Hematology, translational research, SUNY Upstate Medical University, Syracuse NY 13210, USA
Jessica Henty-Ridilla
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Adam T. Waickman
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA
Avery August
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Alaji Bah
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Mobin Karimi
Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA; Corresponding author
Summary: 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.
