Targeting Bcl-6 prevents sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation in mice

Abstract

Background: Chronic graft-versus-host disease (cGVHD) is the most common cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD4⁺ follicular helper T (Tfh) cells, specialized providers of T cell help to B cells, play a vital role in GVHD pathogenesis. B-cell lymphoma-6 (Bcl-6) transcription factor has been shown to be required for Tfh-mediated germinal center reactions. In this study, we would like to evaluate the effect of Bcl-6 on Tfh function in sclerodermatous cGVHD and the efficacy of Bcl-6 inhibitors (Bcl-6i) for treating a minor histocompatibility complex (miHC) mismatch model of sclerodermatous cGVHD (scl-cGVHD).

Methods: A minor histocompatibility haploidentical model of scl-cGVHD was established and received intraperitoneal injection of 79-6, a small-molecule inhibitor of Bcl-6. The clinical manifestations and survival times of cGVHD mice were recorded. The histological assessment was performed by hematoxylin-eosin (HE) and Masson's trichrome staining on the skin and lung tissues. Tfh cells and germinal center B cells in the spleen and peripheral blood were detected by flow cytometry. The cellular markers were immunostained in different organs. ELISA was performed to detect cytokine secretion.

Results: Bcl-6 inhibition by 79-6 improved the clinical manifestation of scl-cGVHD mice and prolonged their survival. The histopathologic damage, particular the fibrotic changes of scl-cGVHD mice was significantly relieved after 79-6 treatment. Furthermore, 79-6 treatment not only suppressed the development and function of Tfh and Tph cells in the peripheral blood, but also reduced the survival of Tfh cells in the spleen. Moreover, 79-6 decreased the frequency of GC plasmocytes accompanied by a reduction in IL-21.

Conclusions: Our study demonstrates that Bcl-6 inhibitor could prevent murine sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation and suppressing the function of GC B cells, indicating that Bcl-6 inhibition may be a potential treatment for patients with cGVHD.

Keywords: B cells; Bcl-6; Follicular helper T cells; Peripheral helper T cells; Sclerodermatous cGVHD.