Bone marrow transplants save the lives of leukemia, but they have one risky drawback and that is “graft-versus-host disease.” Graft-versus-host disease (GVHD) results when immune cells in the donor’s bone marrow attack the tissues and cells of the recipient’s body as foreign. Almost half of bone marrow transplant recipients develop graft-versus-host disease (GVHD), the main organs affected are the skin, liver and gut. Obviously, finding a way to quell or even prevent GVHD would be a boon for bone marrow transplantations.
By utilizing a mouse model, researchers at Washington University School of Medicine in St. Louis have managed to reduce the risk of GVHD from bone marrow transplants. Since bone marrow transplants are the only available curative treatment when leukemia returns, decreasing the risk of GVHD is the first step to improving the prognosis of leukemia patients.
The main strategy behind decreasing the effects of GVHD is to direct immune cells from the donor’s bone marrow away from healthy tissue and lead them to their intended purpose, which is to kill cancer cells.
“This is the first example of reducing graft-versus-host disease not by killing the T-cells, but simply by altering how they circulate and traffic,” says John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine at Barnes-Jewish Hospital and Washington University School of Medicine. “Donor T-cells do good things in terms of eliminating the recipient’s leukemia, but they can also attack normal tissues leading to death in a number of patients. The goal is to minimize graft-versus-host disease, while maintaining the therapeutic graft-versus-leukemia effect.”
By working in a mouse model, Jaebok Choi, PhD, research assistant professor of medicine, showed that if he eliminated or blocked a particular protein known as the interferon gamma receptor on donor T-cells, these cell were unable to migrate to critical organs such as the intestines. However, these same T-cells were still capable of killing leukemia cells.
“The fact that blocking the interferon gamma receptor can redirect donor T-cells away from the gastrointestinal tract, at least in mice, is very exciting because graft-versus-host disease in the gut results in most of the deaths after stem cell transplant,” DiPersio says. “People can tolerate graft-versus-host disease of the skin. But in the GI tract, it causes relentless diarrhea and severe infections due to gut bacteria leaking into the blood, which can result in severe toxicity, reduction in the quality of life or even death in some patients.”
Interferon gamma has, for some time, been known to play a vital role in inflammation. The signal transduction pathway that works downstream of the receptor is just now being better understood. It is this signal transduction pathway downstream of the receptor that is responsible for activating the T-cells so that they cause GVHD. The signaling cascade initiated when interferon gamma binds its receptor activates molecules known as JAK kinases, followed by another protein called “STAT,” and finally a protein called CXCR3. CXCR3 mediates the trafficking of donor T-cells to the GI tract and other target organs.
Deleting the interferon gamma receptor from donor T-cells steers them away from target organs. This, however, leads to a second question: “Could the same result be observed by inhibiting some of the other molecules that act downstream of the interferon gamma receptor?” To address this question, Choi knocked out CXCR3 and discovered that such a knock out reduced graft-versus-host disease, but did not completely wipe it out.
“There are probably additional downstream targets of interferon gamma receptor signaling other than JAKs, STATs and CXCR3 that are responsible for T-cell trafficking to the GI tract and other target organs,” DiPersio says. “We’re trying to figure out what those are.”
This worked beautifully in mice, but could it work in humans? To make these data more relevant to human biology, Choi and DiPersio used drugs known to block JAK kinases in human cells. These drugs are presently approved by the Food and Drug Administration to treat myelofibrosis, which is a pre-leukemic condition in which bone marrow is replaced with fibrous tissue. Ruxolitinib and pacritinib are two such drugs and Choi and DiPersio showed that treating mice with either of these two drugs could mimic the protective effect of deleting the interferon gamma receptor. The JAK inhibitors definitely redirect the donor T-cells away from target organs and reducing graft-versus-host disease in leukemic mice. Unfortunately, they have yet to determine if these drugs preserve the anti-leukemia effect of these T-cells.
“The proof-of-principle behind these experiments is the exciting part,” DiPersio says. “If you can change where the T-cells go as opposed to killing them, you prevent the life-threatening complications and maintain the clinical benefit of the transplant.”