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Improving the Odds
CHORI Scientists Establish Potential for Novel Technique to Utilize Mismatched Cord blood Stem Cells in Transplantation

June 1, 2011 - CHORI scientists Bindu Kanathezhath, MD, Frans Kuypers, PhD, and their colleagues have demonstrated for the first time the possibility of successfully using mismatched donor-recipient pairs in cord blood stem cell transplantation. The proof of principle study was published recently in Experimental Biology and Medicine, and shows significantly greater engraftment and long-term survival by adding psoralen-treated photochemically inactivated donor T cells to donor cord blood stem cells before transplantation.

“We have shown that we can use completely unrelated donor sources in mice and still have successful cord blood transplantation,” says Dr. Kuypers. “While that kind of risk is something we would never look to undertake in people, the idea is that if you can stretch it that incredibly far in mice, there is a good reason to think that this approach could be used successfully in transplants in humans with a less than perfect match.”

“We have shown that we can use completely unrelated donor sources in mice and still have successful cord blood transplan-
tation.”



The standard procedure in stem cell transplantation, whether using bone marrow or cord blood, is to make sure that the donor and the recipient have as close to perfect a match as possible at what is called the major histocompatibility complex (MHC), a group of genes associated with the body's immune responses. Finding perfect, or near-perfect matches is incredibly difficult, however.

"Thousands and thousands of potential recipients of stem cell transplants in the United States will not be able to find a closely enough matched donor resource. Thousands and thousands of patients die without receiving potentially disease-curing transplants as a result," says Dr. Kuypers.

“What we tried to do here was provide a different way of looking at matching that still allows you to get good engraftment without a donor’s T cells causing graft versus host disease.”

The immune system's T cells recognize foreign matter, such as bacteria, viruses, or, in this case, a donor's cells, as not-self. When they recognize these non-self cells, they start a process by which the body attempts to attack and destroy the not-self cells.

"Obviously this is a good system for infections, but it's not such a good system for transplantation. When the donor stem cells are incorporated into the recipient and begin to reproduce, which is what we call engraftment, those new stem cells create their own T cells that are looking to defend against other, not-self cells," says Dr. Kuypers. "This causes graft versus host disease, in which the new cells attack the recipient's cells, and can be very problematic."

The donor T cells have another role, however, which is integral to the success of transplantation.

While the mechanism is still not clearly understood, the donor T cells help clear recipient cells out of the way for engraftment of the new stem cells to occur.

"T cells fight against the host cells to provide the space necessary for the new donor stem cells to take root and grow," says Dr. Kanathezhath. "So on the one hand, you want the T cells so that engraftment occurs, but on the other hand, you don't want them, because they could result in graft versus host disease."

While the standard procedure has always been to try to balance the positive and negative effects of donor T cells, Drs. Kanathezhath, Kuypers and their colleagues have hit upon an entirely different method to achieve the same, if not better, results.

By adding donor T cells pre-treated with a synthetic psoralen, which makes them susceptible to ultraviolet light, Dr. Kanathezhath and Kuypers were able to photochemically treat the T cells prior to transplantation. Combining these photochemically modified T cells with cord blood stem cells resulted in both superior engraftment of the donor cord blood stem cells and survival without graft versus host disease.

“We don’t kill the donor’s T- cells, we simply modify the response, allowing the donor T cells to clear the space to facilitate engraftment of stem cells, but preventing the same T cells from proliferating and attacking the host cells.”

While the key to translating this revolutionary new process from mice to people will require a much deeper understanding of the mechanisms behind these results, the study clearly shows the potential for a clinical model in which donor-recipient matches don’t have to be so excruciatingly exact.

“Transplantation technology has really improved tremendously over the last couple of decades, but no matter what, you still need a stem cell resource to have a successful transplant,” says Dr. Kuypers. “Being able to lower the need for a perfect match and at the same time provide modern medicine with a larger resource is very important, and ultimately, our long term goal.”

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Wednesday, October 5, 2011 11:23 AM

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