Researchers have found a potential way to prevent graft-versus-host disease (GVHD), a serious and sometimes fatal complication of the allogeneic hematopoietic cell transplants used to treat leukemia.
Allogeneic hematopoietic cell transplants succeed in fighting leukemia when donated T cells—the immune system's "killer cells," which attack unhealthy cells—attack the cancer cells. Through what is known as graft-versus-leukemia (GVL) activity, these donated T cells work to prevent disease relapse. However, a major complication occurs in 30% to 60% of transplant recipients: GVHD, in which the donated T cells also attack the recipient's healthy tissues and organs, including the liver, intestines, and skin. The immunosuppressants that patients are given to prevent GVHD also reduce the GVL activity that the transplant was meant to produce, thereby diminishing the treatment's effectiveness in fighting leukemia.
"There is an urgent need to understand how to reduce graft-versus-host responses without losing the anticancer effects of the transferred cells," remarked the study's senior author, Burkhard Becher, PhD, Professor of Inflammation Research at the Institute of Experimental Immunology of the University of Zurich.
For their study, published in Science Translational Medicine, the team of researchers from the University of Zurich in Switzerland and the University of Freiburg in Germany investigated the mechanisms behind these two phenomena in order to determine how GVL can be achieved without the dangerous side effect of GVHD.
Using mouse models, the researchers discovered what was causing GVHD: granulocyte-macrophage colony-stimulating factor (GM-CSF). This cytokine, produced by the donated T cells, activates phagocytes—cells that ingest foreign particles, bacteria, and diseased or dead cells—arising from the donated cells. The phagocytes produce various inflammatory mediators, including interleukin-1B and reactive oxygen species, that attack the graft recipient.
Tissue biopsies and peripheral blood mononuclear cells from patients with grade IV GVHD contained increased levels of T cells that produced GM-CSF. However, GM-CSF did not affect donated T cells or their ability to eliminate leukemic cells through GVL response.
"This finding really surprised us, since both types of immune response were previously thought to be mediated through the same mechanisms," commented Sònia Tugues, PhD, one of the study's first authors.
The investigators suggest that blocking GM-CSF in hematopoietic cell transplant recipients might prevent GVHD without negatively impacting GVL responses.
"Targeting this cytokine is therefore a very precise and specific form of immunosuppression, designed to stop the tissue damage caused by graft-versus-host responses," stated Dr. Becher.
The researchers intend to run a clinical trial investigating whether blocking GM-CSF using a monoclonal antibody that has already been developed can prevent GVHD.
"If we can stop the graft-versus-host response while preserving the anticancer effect, this procedure can be employed much more successfully and with fewer risks to the patient," commented Dr. Becher. "This therapeutic strategy holds particular promise for patients with the poorest prognosis and highest risk of fatality."
For More Information
Tugues S, Amorim A, Spath S, et al (2018). Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells. Sci Transl Med, 10(469). PII:eaat8410. DOI:10.1126/scitranslmed.aat8410
Image credit: Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths. Courtesy of National Institutes of Health