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In December, investigators at St. Jude Children's Research Hospital published preliminary research that demonstrated in mice a way that might reduce the time it takes for a child's immune system to rebuild after a bone marrow transplant, thus also reducing the risk of potentially fatal viral infections.

The research was spawned from developing a cutting edge approach to bone marrow transplantation, haploidentical transplants, which are safer and more effective for children. The experimental haploidentical transplant technique uses a parent donor instead of a matched sibling or matched unrelated donor. The benefit to using a parent is the parent is typically very willing and can be an option if another match cannot be found. However, a parent can only provide half of the needed gene codes to rebuild a child's immune system and the risk for a lethal graft-versus-host disease is far greater.

Initially, physicians selected particular stem cells called CD34 stem cells, yet only selected them in such a way that the cells were very pure and almost free of T-cells in the graft.

CD34 stem cells repopulate from bone marrow or peripheral blood and are capable of repopulating an entire immune system. T-cells, or T lymphocytes, can be both helpful and harmful to the body. T-cells fight off viruses or foreign bodies and are least partially responsible for the anti-leukemia effect seen in transplantation. However, T-cells are also the cells that cause graft-versus-host disease because when transplanted into a new body, they may begin to attack the recipient's own cells.

Eliminating the T-cells from the needed CD34 stem cells makes haploidentical transplants possible. Originally, scientists used a class II antibody to attach to the CD34 cells. However, it takes a long time to get the haploidentical transplants to recover their T lymphocyte immune system. This leaves the bone marrow recipient vulnerable to infection and relapse, both of which can be deadly.

"When we selected CD34 stem cells using the [class II antibody], we knew we were selecting stem cells that can repopulate the entire immune system eventually, but are we missing some cells?" posed Dr. Raymond Barfield, assistant member of the bone marrow transplant division at St. Jude. "Are we missing some T-cell progenitors that are capable of more rapidly populating the thymus?"

The thymus gland, located in the chest, is where T-cells mature. Stem cells that give rise to T-cells, whether they are a person's own stem cells or donated cells, normally gather in the thymus gland.

Barfield explained that the key to this new finding is the discovery that the class II antibody recognizes a particular target on the CD34 cells but does not easily recognize more vigorous CD34 cells that mature and reproduce at a faster rate. These more aggressive stem cells have a different target on their surface that is best recognized by another type of antibody called a class III.

Barfield and others conducted their research on thymus glands that had been removed from children during operations unconnected to this research and would have normally been discarded. They used multiple CD34 antibodies on them, basically any CD34 antibodies, to look at various CD34 positive cells in the thymuses to see what range of CD34 positive cells were present. The purpose was to find a CD34 positive progenitor cell in the thymus that might help reconstitute the T-cell immune system more quickly.

"What we discovered was that when we used a different antibody than the one that's used in clinical practice, when we used a class III antibody, we were able to target significantly more thymus cells than when we used class II," explained Barfield.

With five volunteers, stem cells were mobilized and selected with both class III and class II antibodies. Those stem cells were then placed in mice and followed using a marker. The investigators found the mice that received the class III antibody had significantly more robust T-cell growth than the mice that received the class II. In other words, the class III antibody stem cells matured faster. Not only that, the study uncovered the fact that the CD34 population is not homogenous but heterogeneous, which means investigators have been missing some CD34 positive cell subpopulations because they were only using single antibodies.

Barfield said the findings might suggest they switch to a different antibody in the clinic and use the class III antibody to collect stem cells. But more importantly, he stressed, could there be other very important cells that could contribute to antivirus and anti-leukemia effects that they don't yet know about? Instead of using these positive selection methods (selecting a homogenous stem cell with a single antibody), Barfield suggested using cell depletion techniques.

"Instead of targeting the cell you want, target the cell you don't want and get rid of it," he explained. "You may have cells in there you don't even know exist, but as long as you get rid of the cells that cause overwhelming graft-versus-host disease, you can put these cells more safely into patients and quickly reconstitute their immune systems."

The St. Jude team said more studies are needed to confirm this initial finding and to translate it into better treatment for children. The challenge will be learning more about which subsets of cells cause excessive harm so scientists can be sure they only eliminate cells that will cause problems while leaving in the good, immune recovering cells.

March 2007
March 2007

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