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Targeting Bcl-6 prevents sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper
Xiaomei Chen1, Yulian Wang1, Xin Huang1
1Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University. Guangzhou, Guangdong 510080, PR China.
Insights
Bcl-6 inhibition effectively treats sclerodermatous chronic graft-versus-host disease (cGVHD) in mice by reducing T follicular helper cell differentiation and germinal center B cell function. This suggests Bcl-6 inhibitors are a promising therapy for cGVHD patients.
Area of Science:
- Immunology
- Transplantation Biology
- Molecular Medicine
Background:
- Chronic graft-versus-host disease (cGVHD) is a major cause of non-relapse mortality post-allogeneic hematopoietic stem cell transplantation (allo-HSCT).
- CD4+ follicular helper T (Tfh) cells are critical in GVHD pathogenesis, with B-cell lymphoma-6 (Bcl-6) being essential for their function.
- This study investigates Bcl-6's role in sclerodermatous cGVHD (scl-cGVHD) and the efficacy of Bcl-6 inhibitors (Bcl-6i).
Purpose of the Study:
- To evaluate the effect of Bcl-6 on Tfh cell function in a murine model of scl-cGVHD.
- To assess the therapeutic efficacy of Bcl-6 inhibitors (Bcl-6i) in treating scl-cGVHD.
Main Methods:
- A minor histocompatibility haploidentical model of scl-cGVHD was established.
- Mice were treated with 79-6, a small-molecule inhibitor of Bcl-6.
- Clinical outcomes, survival, histopathology, Tfh and germinal center B cell populations, and cytokine levels (IL-21) were analyzed.
Main Results:
- Bcl-6 inhibition with 79-6 significantly improved clinical manifestations and prolonged survival in scl-cGVHD mice.
- Histopathological damage, particularly fibrosis, was markedly reduced following 79-6 treatment.
- 79-6 suppressed Tfh and Tph cell development and function, reduced Tfh cell survival in the spleen, and decreased germinal center plasmocytes and IL-21 levels.
Conclusions:
- Bcl-6 inhibition prevents murine sclerodermatous cGVHD by inhibiting T follicular helper cell differentiation and germinal center B cell function.
- Bcl-6 inhibitors represent a potential therapeutic strategy for patients suffering from cGVHD.
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.
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