cGvHD

BCL6 inhibition in murine chronic graft-versus-host disease model

Chronic graft-versus-host disease (cGvHD) remains a major cause of high non-relapse mortality and morbidity rates after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Corticosteroids are the currently used standard of care for patients with cGvHD. Previous data suggests that cGvHD may associated with germinal center (GC) reaction, in which T follicular helper cells and germinal center B-cells increase and start to produce antibodies to induce cGvHD. As a consequence, targeting GCs may be a feasible therapy option for patients with cGvHD.

BCL6 is a master transcription factor which supports the differentiation of naive helper T cells in follicular helper T cells and assists GC development with chromatin-associated factors such as the EZH2 lysine methyltransferase or the BRD4 epigenetic reader protein.

Katelyn Paz from the University of Minnesota, Minneapolis, MN, USA, and colleagues evaluated BCL6 expression in both donor T cells and B cells and their role in cGvHD development. The study group utilized a small-molecule, peptidomemidic BCL6 inhibitor, 79-6, for the treatment of cGvHD in a murine model. B6→B10.BR (BO cGvHD) and B10.D2Balb/c (scleroderma cGvHD) models were used.

Key findings:
  • BCL6 expression is mandatory in both donor T- and B-cells for cGvHD
  • 79-6 improves established murine cGvHD
    • 79-6 ameliorated pulmonary function
    • 79-6 decreased splenic GC B-cell frequencies
    • 79-6 decreased plasma cell frequencies in the lung
  • BCL6 KO BM and WT T cells did not cause pathogenic pulmonary dysfunction

In summary, the study group stated that BCL6 expression is essential in donor marrow B and T cells to induce germinal center reaction in chronic GvHD mice. A small-molecule inhibitor of BCL6, 79-6, was found to be efficient for the treatment of mice cGvHD. The authors added that “targeting BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.”

References
  1. Paz K. et al. Small-molecule BCL6 inhibitor effectively treats mice with non-sclerodermatous chronic graft-versus-host disease. 2018 Oct 2. DOI: 10.1182/blood-2018-03-839993. [Epub ahead of print].

 

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