Investigators at St. Jude Children's Research Hospital have demonstrated in mice a way that might reduce the time it takes for a bone marrow transplant to rebuild a child's immune system, and so reduce the risk of potentially fatal virus infections that can occur during this time.
The St. Jude team showed that the current way of harvesting specific stem cells from donated bone marrow to capture many of the stem cells called CD34+ cells fails to capture many of the cells that might be more vigorous in reproducing and rebuilding the immune system. CD34+ cells give rise to a variety of blood cells including T lymphocytes, a critical part of the immune system that orchestrates the attack on invading microorganisms. The researchers showed in mice that most of the CD34+ stem cells left behind by the current harvesting method are especially vigorous in multiplying and producing T lymphocytes. In humans, the loss of many of these vigorous stem cells from the transplant might contribute to the delay in rebuilding the immune system--a time lag that leaves children exposed to serious infections.
The St. Jude finding is important because children whose own bone marrow stem cells have been destroyed by chemotherapy or radiation treatments for cancer routinely undergo bone marrow transplantation. Therefore, reducing the time it takes for the immune system to regenerate T lymphocytes would be an important step in reducing infection risk in these children and improving their long-term outcomes.
A report on this work appears in the current online issue of the journal Stem Cell.
Stem cells that give rise to T lymphocytes--whether they are a person's own stem cells or donated cells--normally gather in the thymus gland in the chest. There the stem cells receive their "marching orders" as new T lymphocyte warriors against invading bacteria, viruses and other potentially dangerous targets including cancer cells, and they develop a specialized homing mechanism called a T cell receptor that lets them find the specific target they are genetically programmed to attack.
The key to the new finding is the discovery by the St. Jude team that the antibody currently used to seek out and "capture" CD34+ stem cells from the donated bone marrow actually identifies only a certain group of them, according to Raymond Barfield, M.D., Ph.D., assistant member of the Bone Marrow Transplantation division at St. Jude. The antibody usually used to capture CD34+ cells, called a class II antibody, recognizes a particular target on the CD34+ cells, Barfield said. But this antibody does not as easily recognize more vigorous CD34+ cells that mature and reproduce faster. These more aggressive stem cells have a different target on their surface that is best recognized by another type of antibody, called class III.
The St. Jude investigators first demonstrated that class II and III antibodies bind to different populations of CD34+ cells by adding both of these antibodies to pieces of human thymus glands. The pieces of thymus glands used in the study had been removed from children during operations unconnected to this research and would otherwise have been discarded.
Using the different types of antibodies, the scientists determined which one produced T lymphocytes faster by measuring the amount of rings of DNA called sjTRECs the cells released. T lymphocytes discard sjTRECs as they develop from stem cells in the thymus and "learn" to recognize a specific target. (St. Jude researchers previously showed that by measuring sjTRECs clinicians could predict whether a bone marrow stem cell transplant would successfully restore the recipient's T lymphocyte population.)
The investigators found that the lymphocytes captured by class III antibodies produced more sjTRECs than stem cells captured by class II antibodies; that is, the class III antibody stem cells matured faster.
The researchers then infused the cells captured by class II and III antibodies into mice that had been specially bred to lack an immune system. The cells traveled to the thymus, where they were trained to produce different families of T lymphocytes, each of which was genetically programmed to attack a specific target. Half of the mice that received cells selected with class III antibodies produced sjTRECs compared with 14 percent of mice transplanted with cells selected using the class II antibody.
"These findings show that the thymus of mice that got class III antibody stem cells were able to produce T lymphocytes quicker than mice receiving class II antibody stem cells," Barfield noted. "This suggests if we harvest CD34+ cells using class III as well as class II antibodies we are likely to get better results when we transplant them into children." The results also suggest that the time from transplantation to a fully restored immune system might be reduced using this strategy.
The St. Jude team said that more studies are needed to confirm this initial finding and to translate it into better treatment for children. "Such information will help clinicians rethink how they can do bone marrow stem cell transplantation so that the risk of infection is lowered in their patients," Barfield said.
Other authors of this study include Mario Otto (now at Akron Children's Hospital, Ohio); Xiaohua Chen, William J. Martin, Wing Leung, James Knowles, Marti Holladay and Jim Houston (all of St. Jude); and Rupert Handgretinger (University of Tübingen, Germany). This work was supported in part by a Cancer Center Support grant, ALSAC and the Assisi Foundation of Memphis.
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