Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
Authors
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.
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.
Publication Date
4-23-2021
Abstract
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.
Publication Source (Journal or Book title)
iScience
Recommended Citation
Mammadli, M., Huang, W., Harris, R., Xiong, H., Weeks, S., May, A., Gentile, T., Henty-Ridilla, J., Waickman, A. T., August, A., Bah, A., & Karimi, M.
(2021). Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT. iScience, 24 (4), 102286.
https://doi.org/10.1016/j.isci.2021.102286
