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

iScience (Apr 2021)

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

Journal volume & issue: Vol. 24, no. 4
p. 102286

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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