The latest study by Dr. Sophie Paczesny and others at MUSC Hollings Cancer Center revealed a new class of immune cell biomarkers, which may reveal which patients are most at risk of graft-versus-host disease (GVHD). This study was published on Science Translational Medicine.
Paczesny, director of the Department of Microbiology and Immunology at MUSC, explained: “Allogeneic HSCT remains the only effective therapy for leukemia. In HSCT, donor-matched cells are injected into the blood of diseased patients and eventually enter the bone marrow. Some of these cells differentiate into immune cells that help eliminate residual leukemia cancer cells that are not killed by chemotherapy. However, some donors’ immune cells may attack the patient’s own healthy tissue at the same time, which is called graft-versus-host disease.”
GVHD affects up to 50% of patients undergoing HSCT and can manifest in multiple organs. About one-third of people with GVHD experience localized effects in the gastrointestinal tract (GI-GVHD), posing the highest risk of death.
This phenomenon was further described by Paczesny. “For leukemia patients, the donor cells you provide have different biological or antigenic characteristics than the recipients. This is how these immune cells recognize leukemia and destroy leukemia. However, these antigens are also present in normal tissues especially in body regions with the most microbiota (such as the gut). Therefore, donor immune cells flare up there and symptoms are most difficult to treat.”
Bone marrow stem cells are called pluripotent stem cells, which means that they can mature into many different types of cells. This includes red and white blood cells and other immune cell types responsible for balancing immunity and tolerance, such as dendritic cells and T cells.
Dendritic cells are able to exchange information with T cells through antigen molecules presented by MHC complexes on the cell surface. T cells are activated in recognition of “non-self” antigens and then play a key role in triggering the body’s other defense systems against foreign invaders, which may include transplanted cells from different hosts.
Previous work from the Paczesny laboratory has shown that immune cell signaling pathways in GI-GVHD increase the number of “hyperactivated” pathogenic T cells (Th17 cells) in the blood of these patients. The presence of these aggressive T cells was associated with lower survival compared to patients lacking GVHD or with milder forms of GVHD in the skin. These cells are also unique in their ability to induce ICOS, a class of T cell signaling coreceptors.
Paczesny said. “We are trying to understand where the activation of these T cells comes from. What antigen-presenting cells are?”
Since ICOS ligands are located on the surface of antigen-presenting cells, such as dendritic cells, they can be easily detected using existing technologies, such as flow cytometry, which can scan the blood for external labeling on cells. In this way, individuals who develop GI-GVHD symptoms after treatment may be flagged out.
Paczesny’s group showed that GI-GVHD patients had increased levels of dendritic cells expressing ICOS ligands (specifically a population called plasmacytoid dendritic cells) compared to controls. Crucially, patients with high levels of these cells had a much lower three-year survival compared to low levels of cells.
Dr. Djamilatou Adom, a postdoctoral researcher working with Paczesny, further investigated the role of ICOS signaling using mice in GI-GVHD. First, they showed that genetic abrogation of ICOS ligand production before transplantation of donor mouse bone marrow cells into recipient mice could protect recipient mice from GvHD related death. In addition, the researchers used “humanized” mice with a non-functional immune system and found that transplanting plasmacytoid dendritic cells expressing human ICOS ligands into these mice (whose own bone marrow has been destroyed by radiation) resulted in increased levels of Th17 cells within GVHD.
The involvement of plasmacytoid dendritic cells (pDCs) in GVHD is an interesting finding, Paczesny says. “If these cells are not stimulated, they are generally considered to be tolerogenic. In other words, they can reduce the severity of GVHD. However, if they activate T cells, for example by binding ICOS activation, they become more toxic and may drive the development of GVHD.”