Bone marrow transplant (BMT) offers patients with leukemia and lymphoma a potentially curative treatment. Bone marrow from the donor contains healthy immune cells (T cells and B cells), whose role is to protect the body from invaders. Lymphocytes can target the recipient’s cancer cells as well, helping protect against tumor relapse. This procedure, however, is not without risk: that is T cells can also recognize the host’s tissues as foreign and attack them. This phenomenon, known as graft-vs-host disease (GVHD), can cause serious complications in transplant recipients, significantly reducing their quality of life and may even lead to death. Acute and chronic GVHD are very different diseases, distinguished primarily by time of onset and clinical manifestations. Acute GVHD occurs during the first months after transplant, while chronic GVHD reduces the long-term quality of life of patients. The standard procedure to prevent GVHD is to treat patients with immunosuppressant drugs. However, this makes patients more susceptible to infections and increases the risk of tumor relapse. Even with this therapy, averagely 40% of patients develop acute GVHD and about 70% develop some degree of chronic GVHD.
Xue-Zhong Yu, MD, professor of Microbiology and Immunology in the College of Medicine at the Medical University of South Carolina (MUSC) and Chair in Cancer Stem Cell Biology and Therapy at Hollings Cancer Center, led a new study. With his team of MUSC researchers he discovered that targeting the enzyme Sirt-1 helped control GVHD in mice, without increasing tumor relapse. Sirtuin-1 (SIRT1) is the first of seven member of a class of enzymes that use a vitamin B3 cofactor, NAD, to modify cellular proteins and control phenomena like lipid metabolism, cell proliferation, cellular aging, brain chemistry and immune responses as well. In their experiments with BMT models, mice that received a SIRT1 inhibitor (Ex-527) lived longer and had better clinical scores than those that did not. This effect appears to be mediated through T cells It seems that SIRT1 regulates different subsets of T cells differently; so by inhibiting it, T lymphocytes that lead to GVHD can be suppressed, without affecting those that protect against tumor relapse. Therefore, blocking Sirt-1 could be an effective strategy in preventing both acute and chronic GVHD.
Although treatment options have improved for acute GVHD, chronic GVHD remains a therapeutic dilemma. It causes widespread scarring (fibrosis) of the organs affected, leading to loss of organ function. In chronic GVHD, B lymphocytes are activated and ready in their immune function. In this study, blocking SIRT1 showed a positive effect, even after chronic GVHD had developed: SIRT1-deficient T cells reduced B cell activation and differentiation in chronic GVHD mouse models. This means that this enzyme plays an important role in T- and B-cell interaction for GVHD development. Mechanistic studies revealed that Sirt-1 deficiency in T cells enhanced spleen B-cell reconstitution and reduced follicular T helper cell development. Although the pre-clinical results are strong, much needs to be done before they can affect patient care. The team is interested in exploring further the role of SIRT1 in the regulation of B cells, and hopes to be able to translate the findings to the clinic. But, first, further studies are needed to examine the role of SIRT1 in human T cells and in a human setting, assessing correlations in patients.
This is the first study that directly correlates the SIRT1 protein to the GVHD rejection phenomenon. There is another publication on this and deals with the effects of zinc supplementation in the control of GVHD. Like the Ex-527 inhibitor, excess zinc can inhibit SIRT1 and control the intensity of GVHD in some ways. By exposing mixed cultures of lymphocytes to different doses of zinc, there are cellular and immunological responses that result in the appearance of tolerance. Specific epigenetic analyses that investigated the underlying mechanisms in zinc-treated regulatory T cell (Treg) activation, showed that SIRT1 is involved. The enzyme mediates deacetylation of FoxP3 transcription factor to activate T cells; zinc inhibits SIRT1, accelerating its degradation. when mixed lymphocyte cultures are treated with 50 μM zinc, Tregs are induced causing a decrease in gamma-interferon (IFNγ) production. Interestingly, the expression of other activating cytokines (IL-2 and IL-10) were not affected. This indicates that, though in different settings, SIRT1 may represent a feasible and druggable target to effectively handle GVHD.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry
Daenthanasanmak A et al. Blood. 2019 Jan 17; 133(3):266-279.
Qian Y et al. Mediators Inflamm. 2018 May 27; 2018:8736949.
Rosenkranz E et al. Mol Nutr Food Res. 2016 Mar; 60(3):661-71.