Targeting Sirt-1 shows preclinical promise in controlling GVHD
By Maria Cuitino
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) that can target the recipient’s cancer cells, helping to protect against tumor relapse.
This procedure, however, is not without risk. Donor T cells can also see the recipient’s tissues as foreign and attack them. This phenomenon, known as graft-vs-host disease (GVHD), can cause serious complications and reduce the quality of life in transplant recipients.
The standard procedure for preventing GVHD is to treat patients with immunosuppressive drugs. However, this makes patients susceptible to infections and increases the risk of tumor relapse. Even with this therapy, 30 to 50 percent of patients develop acute GVHD, and 70 percent develop some degree of chronic GVHD.
“GVHD can be expected to occur in the majority of transplanted patients,” says Xue-Zhong Yu, M.D., professor of Microbiology and Immunology in the College of Medicine at the Medical University of South Carolina (MUSC) and SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy at Hollings Cancer Center. “More treatment options are desperately needed.”
Yu led a team of MUSC researchers who showed that targeting the enzyme Sirt-1 helped control GVHD in mice, without increasing the incidence of tumor relapse. They recently reported their findings in Blood (published online December 4, 2018). In BMT models, mice that received a Sirt-1 inhibitor lived longer and had better clinical scores than those that did not.
“What’s exciting about our study is that Sirt-1 regulates different subsets of T cells differently,” says Yu. “So by inhibiting it, we can suppress T cells that lead to GVHD without affecting those that protect against tumor relapse.”
Acute and chronic GVHD are different diseases. Acute GVHD occurs during the first months after transplant, while chronic GVHD reduces the long-term quality of life of patients. Although treatment options have improved for acute GVHD, chronic GVHD remains a therapeutic dilemma.
In this study, Sirt-1 blockage improved chronic GVHD. The study showed that Sirt-1-deficient T cells reduced B-cell activity in mice with the disease.
“This indicates that Sirt-1 plays a role in T- and B-cell interaction in GVHD development,” says Anusara Daenthanasanmak, Ph.D., who was a postdoctoral fellow in the Yu lab while doing this work and is now at the National Institutes of Health. “By blocking Sirt-1, we could have a treatment for both acute and chronic GVHD.”
Yu’s lab is interested in further exploring the role of Sirt-1 in the regulation of B cells. “B cells are critical in the pathogenesis of chronic GVHD,” says Yu. “That is still a gap we need to fill.”
Although the preclinical results are strong, much needs to be done before they can affect patient care.
“I hope to be able to translate the findings in my lab to the clinic,” says Yu. “But, first, further studies are needed to examine the role of Sirt-1 in human T cells and in a human setting.”
Dr. Xue-Zhong Yu seeks ways to make bone marrow transplant safer.