Oncotarget

Research Papers: Immunology:

Dissecting the mechanisms involved in anti-human T-lymphocyte immunoglobulin (ATG)-induced tolerance in the setting of allogeneic stem cell transplantation - potential implications for graft versus host disease

Katia Beider, David Naor, Valeria Voevoda, Olga Ostrovsky, Hanna Bitner, Evgenia Rosenberg, Nira Varda-Bloom, Victoria Marcu-Malina, Jonathan Canaani, Ivetta Danilesko, Avichai Shimoni and Arnon Nagler _

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Oncotarget. 2017; 8:90748-90765. https://doi.org/10.18632/oncotarget.21797

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Abstract

Katia Beider1, David Naor2, Valeria Voevoda1, Olga Ostrovsky1, Hanna Bitner1, Evgenia Rosenberg1, Nira Varda-Bloom1, Victoria Marcu-Malina1, Jonathan Canaani1, Ivetta Danilesko1, Avichai Shimoni1 and Arnon Nagler1

1 Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel

2 Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

Correspondence to:

Arnon Nagler, email:

Keywords: ATG, Treg, TGFβ, Immunology and Microbiology Section, Immune response, Immunity

Received: May 12, 2017 Accepted: September 22, 2017 Published: October 11, 2017

Abstract

Polyclonal anti-human thymocyte globulins (ATG) have been recently shown to significantly reduce the incidence of graft versus host disease (GVHD) post allogeneic stem cell transplantation (HSCT) from both sibling and unrelated donors. Induction of regulatory T cells has been suggested as one of the possible mechanisms. The aim of current study was to further characterize the T cell populations induced by ATG treatment and to delineate the mechanisms involved in ATG-induced tolerance. Phenotypic characterization revealed a significant increase in the expression of FoxP3, GITR, CD95, PD-1 and ICOS as well as the complement inhibitory molecules CD55, CD58 and CD59 on CD4+CD25+ T cells upon ATG treatment. Addition of ATG-treated cells to autologous and allogeneic peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3/anti-CD28 antibodies resulted in significant inhibition of proliferation. Moreover, T-cell activation and IFNγ secretion were reduced in the presence of ATG-induced Treg cells. The CD4+CD25+CD127-low Treg fraction sorted from ATG-treated culture demonstrated greater suppressive potency than negative fraction. Conditioned medium produced by ATG-treated but not IgG-treated cells contained TGFβ and suppressed T cell proliferation and activation in a TGFβ receptor-dependent manner. TGFβ receptor kinase inhibitor SB431542 interfered with the suppressive activity of ATG-primed cells, enabling partial rescue of proliferation and IFNγ secretion. Moreover, SB431542 prevented Treg phenotype induction upon ATG treatment. Altogether, our data reveal the role of TGFβ signaling in ATG-mediated immunosuppression and further support the use of ATG, a potent inducer of regulatory T cells, for prevention of GVHD post HSCT and potentially other therapeutic applications.


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