Importance of epigenetic regulation in the recovery of T cells

In stem cell transplants for leukemia treatment, the patient’s hematopoietic system is removed and replaced with hematopoietic cells from donors. Despite the fact that the number of complications in this process is gradually decreasing as a result of medical progress, the precise mechanisms for the restoration of the immune system in these patients have yet to be clarified.

Researchers at MedUni Vienna, the Austrian Academy of Sciences’ CeMM Research Centre for Molecular Medicine, and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases have found processes that can contribute to the success and improvement of stem cell transplantation. The study’s findings were recently published in the journal Clinical Immunology.

The team of researchers led by Georg Stary from the Department of Dermatology at MedUni Vienna and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences examined immune cells in the blood and skin of stem cell transplant recipients for their research. The researchers discovered regulatory processes involved in restoring the balance of T cells in the immune system in sequential samples, which is important for the success of stem cell transplantation.

Histone deacetylases (HDACs) proved to be important players in this process. HDAC inhibition is already being used successfully in cancer therapy. To investigate the potential application of this approach after stem cell transplantation, the researchers introduced HDAC inhibitors to isolated cells.

“By inhibiting different classes of HDACs in isolated T cells from patients after stem cell transplantation, we could modulate the imbalance of T cell subsets,” noted

first authors Ram Vinay Pandey and Johanna Strobl from the Department of Dermatology at MedUni Vienna.

Further findings regarding complications

The study’s framework allowed researchers to learn more about graft-versus-host disease (GVHD), which can take place after stem cell transplantation. The blood and skin analysis showed a fast recovery of immune cells important for GVHD (such as effector T cells), but a delay in the appearance of “protective” regulatory T cells.

The concurrent examination of the transcriptome, or all the genes that are actively read from the DNA, and the epigenome, or the “readiness” of individual genes, on the other hand, revealed significant differences between skin and blood cells. This imbalance between body tissues, as well as regulatory and non-regulatory cell types, may contribute to complications following stem cell transplantation, such as GVHD.

New approach for therapeutic options

Allogeneic hematopoietic stem cell transplantation is used as a therapy for patients with serious diseases of the hematopoietic system (e.g., acute leukemia). Following the replacement of the patient’s diseased hematopoietic system with healthy hematopoietic cells from donors, about 40% of patients develop GVHD, which most commonly affects the skin.

With the potential of HDAC inhibitors to modulate T cells after stem cell transplantation, we have discovered an innovative approach to influence the epigenetics of T cells at specific time points after stem cell transplantation and to increase the safety of the therapy. Our study underlines the importance of epigenetic regulators in restoring the immune system and shows new therapeutic possibilities for achieving T-cell balance after stem cell transplantation.”

Georg Stary, Department of Dermatology, Medical University of Vienna

The results of the research will be tested in clinical trials.