Bone marrow transplantation can be a life-saving procedure, but also a grueling one. Once a compatible donor is found, a recipient must undergo nonspecific radiation or chemotherapy to destroy their own bone marrow, which may leave them weak and vulnerable to infection.
Bone marrow recipients usually also require lifelong treatment with immunosuppressive agents that help them tolerate the donation but may increase their risk of infection and cancer.
In a new paper(link is external) published February 6 in Nature Communications, researchers from NIAID and Harvard University describe a way to better prepare a recipient to tolerate bone marrow donation, using an antibody-drug conjugate that combines a cell-targeting antibody with a cell toxin, which the antibody carries as cargo. Using this approach, they were able to selectively kill bone marrow stem cells in mice, making the mice much more likely to tolerate donor stem cells in bone marrow and to accept skin grafts, without complications or the need for long-term immunosuppression.
The technique uses a combination of a monoclonal antibody and a cell toxin to kill off the recipient’s original stem cells. The monoclonal antibody binds to a protein, CD117, which is common on the outside of the recipient’s blood-producing stem cells. This allows the drugs to selectively kill the stem cells while leaving most other cells unharmed, clearing the way for the donor stem cells to take hold after the transplant.
In a separate paper(link is external) also published in the same issue of Nature Communications, the Harvard team used NIAID funding to test the same antibody-drug combination on mice whose immune system proteins were very similar to those of donor mice. In the recipient mice, one dose of the antibody-drug combination removed over 99 percent of bone marrow stem cells, allowing new donor cells to easily take hold without serious complications. The recipient immune systems were later shown to function well when challenged with fungal spores and viruses.
In their collaborative study, NIAID and Harvard researchers took this idea a step further by testing the antibody-drug combination on mice whose immune system proteins were very different from those of the donor mice, a situation that can make rejection symptoms more likely. Fourteen out of fifteen mice that received bone marrow transplants using the antibody-drug combination remained healthy for almost two years—nearly the entire normal lifespan of a mouse. Most of the mice that were given the antibody-drug combination treatments before receiving skin grafts also did well. In mice receiving no treatments, the skin grafts were rapidly rejected.
Although the antibody-drug combination technique has not yet been tested in humans, these early results are remarkable, the researchers say, and the technique merits further investigation. Content last reviewed on February 26, 2019
Article published courtesy of the NIH