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Mar 1, 2013

BMTs Without the GVHD

  • While bone marrow transplants (BMTs) are sometimes the only hope for patients with diseases like leukemia and other blood disorders, they come with the significant risk of the patient developing graft-vs-host disease (GVHD). Now, University of Michigan researchers say that inhibiting the Notch signaling pathway in some of the transplanted cells could prevent GVHD. Antibodies inhibiting specific elements of the Notch pathway can prevent the disease in mice, without serious side effects and without substantially compromising the cancer-fighting ability of the transplanted cells, the team reports.

    After a BMT, donor T cells can recognize and destroy tumor cells in the patient. However, in GVHD, the donor T cells also recognize the recipient’s normal tissues as foreign and begin to attack organs like the intestine, liver, lungs, and skin. Conventional methods for preventing the disease include removing T cells from the donor graft and treating the patient with global immunosuppressive drugs. However, this often doesn’t work.

    Inhibiting the Notch signaling pathway might be a new intervention that prevents the disease, says Ivan Maillard, M.D., Ph.D., assistant research professor in the U-M Life Sciences Institute. Upon finding that one of the functions of Notch is to regulate the T cell response that causes GVHD, the researchers experimented with blocking Notch signaling in mice to prevent the complication. But inhibiting Notch throughout the body had significant side effects, particularly in the intestine.

    The team found that Notch signals are mediated by the interaction between five ligands and four receptors on cell membranes. “We were able to identify two ligands and two receptors that account for all the effects of Notch signaling in GVHD, with a dominant role for just one ligand-receptor pair,” Dr. Maillard explains.

    That ligand-receptor pair became the target for inhibition. Maillard collaborated with Genentech, which had developed antibodies to block individual Notch ligands and receptors. When the researchers used antibodies to inhibit the target Notch ligands, mice had none of the gastrointestinal side effects that came with global inhibition of Notch—and they did not develop GVHD.

    “Importantly, the Notch blockade did not prevent donor T cells from being efficient at recognizing and destroying cancer cells, which is the ultimate goal of bone marrow transplantation in human patients,” Dr. Maillard says.

    According to the researchers, the treatment was only necessary short-term, although its beneficial effects were long lasting. “This suggests that there is a pulse of Notch signaling in immune cells immediately after transplantation that presents a window of time for intervention. If we can block that pulse, we could induce long-term benefits without having to block Notch permanently.”

    The effects of Notch blockade could be traced to decreased inflammation as well as increased expansion of regulatory T cells that suppress GVHD, Dr. Maillard says. “These findings open perspectives for studying Notch inhibition in the treatment of T cell-mediated disorders including graft-versus-host disease in patients. A next step will be to define the approach and schedule of inhibition most likely to succeed in patients.”

    The Maillard lab is also investigating the mechanisms of Notch action in T cells and whether Notch also plays an important role in other T cell-mediated immune disorders, such as multiple sclerosis and other autoimmune diseases.

    Details of the study are published online today in the Journal of Clinical Investigation.


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