Drug combo may make organ, tissue matching unnecessary
Monday, March 04, 2019
Tissue-matching means organ recipients have a better chance of a successful transplant, but patients will still need to take anti-rejection medications, possibly for the remainder of their lives. While effective, these drugs can cause the body's immune system to be vulnerable to infection, and they often have unpleasant side effects.
However, a new study offers evidence that an antibody-drug conjugate may serve the same purpose as traditional anti-rejection drugs. Led by a Stanford University physician, the research team found that the conjugate eliminates blood-producing stem cells in mice. To this point, only anti-rejection drugs have kept the production of stem cells at bay.
The team published a pair of papers in Nature Communications on Feb. 6. The studies were led by Dr. Agnieszka Czechowicz, an assistant professor of pediatrics at the Stanford School of Medicine.
Czechowicz conducted the research as a graduate student at Stanford and while completing her fellowship and residency at the Dana Farber Cancer Institute/Boston Children's Cancer Institute and Blood Disorders Center. Other researchers were based at Harvard, Boston Children’s Hospital and the National Institute of Allergy and Infectious Diseases.
The study findings are particularly important since they may eliminate the need to use chemotherapy to eliminate blood-producing stem cells from transplant patients. Studies have shown that when blood-producing stem cells are replaced with the organ donor's blood-producing cells, the body's immune acceptance of the organ or tissues increases.
However, the blood-producing stem cells must first be removed. To this point, toxic chemotherapy has been used to achieve this, but the process can have lingering side effects and leave the organ recipient susceptible to infection while the cells graft.
The first study showed that the antibody conjugate effectively eliminates blood-producing stem cells in mice without damaging side effects. One dose of the antibody-drug combination targeted blood-forming stem cells, killing nearly 100 percent of them.
No harm was done to other types of cells in the process. Transplanted stem cells were then able to live in the mice's bone marrow. The mice's immune reactions were not compromised.
In the second study, researchers found the animal's stem cells did not have to be replaced with those of a matching donor. Instead, the recipient’s original stem cells mixed with the donated cells, forming a chimera. The mice did not develop complications and accepted a skin transplant from the stem-cell donor several months after the stem cell donation.
“Using this technique to make recipients tolerant to donor organs is incredibly exciting,” Czechowicz said. “It indicates that we could have a relatively safe method of inducing tolerance without the need for chronic immune suppression, and do that without needing to match donors and recipients for tissue type. This approach could be transformative for the transplant field.”
While the work is promising, it has only completed in mice so far, Czechowicz said. Even so, it may be possible to restore organ recipients’ blood and immune systems without the need for chemotherapy or radiation, or give patients tissues and organs from an unmatched donor, with minimal immunosuppression.
Other lead authors of these studies include Rahul Palchaudhuri, Ph.D., a former postdoctoral scholar at Harvard. Derrick Rossi, Ph.D., associate professor of stem cell and regenerative biology at Harvard and Dr. David Scadden, co-director of the Harvard Stem Cell Institute, are the senior authors.
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