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

doi:10.1016/j.isci.2021.102286

Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT

iScience. 2021 Mar 11;24(4):102286. doi: 10.1016/j.isci.2021.102286. eCollection 2021 Apr 23.

Authors

Affiliations

¹ Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA.
² Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
³ Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
⁴ Department of Radiology, Jiangxi Health Vocational College, Nanchang, 330052, China.
⁵ Division of Hematology, translational research, SUNY Upstate Medical University, Syracuse NY 13210, USA.
⁶ Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

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.

Keywords: Immunology; Molecular Biology.

Abstract

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