New Frontiers Campaign Gift Helps Recruit Scientist

A single protein interferes with the efficient transplantation of blood stem cells, researchers reported in the Aug. 13 edition of Science, flagging a new potential pharmaceutical target in the treatment of severe blood diseases such as leukemia.

Kent Christopherson, Ph.D.

By inhibiting or eliminating the troublesome protein in mice, scientists enhanced all measures of blood stem cell transplant success in the recipients, with a significant jump in survival rates at a low dose of transplanted stem cells, said study lead author Kent Christopherson, Ph.D., an assistant professor of molecular medicine at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM).

Christopherson joined the IMM at The University of Texas Health Science Center at Houston in December, thanks to a $250,000 gift from the Fort Worthbased Amon G. Carter Foundation to the New Frontiers Campaign for stem cell research. The $200 million campaign to build a new home for the IMM and to recruit and support talented scientists like Christopherson recently reached $182 million.

“Improving the efficiency of blood stem cell transplants would permit transplant of fewer cells. That in turn presents the possibility of using umbilical cord blood for transplants in adults,” Christopherson said of the longer-term implications of the team’s research for human beings.

People with life-threatening blood diseases must have their diseased blood replaced by healthy donor blood. Blood stem cells, known scientifically as hematopoietic stem cells, are found mainly in the bone marrow and differentiate into all types of blood cells: red cells, platelets and white cells that form the basis of the immune system.

Adults with these diseases must rely on bone marrow transplants that precisely match a donor’s marrow to the recipient to avoid rejection. Umbilical cord blood is another source of transplantable hematopoietic stem cells. “Cord” blood works well in children but does not provide the massive number of stem cells required for all but the smallest adults.

“Cord blood is readily available as what used to be a discarded byproduct of delivering a baby and additionally does not require a perfect match with the recipient, so there are reasons you would prefer to use cord blood if you could,” Christopherson said.

The research team targeted the protein known as CD26 because it is known to damage another protein that is important to a number of blood stem cell processes.

They conducted blood stem cell transplants in four groups of mice: two groups were treated with two known inhibitors of CD26; a third had no CD26 because the gene that expresses the protein had been knocked out; and in a group of control mice CD26 was unhindered.

In a measure of short-term success of the transplant known as homing efficiency that shows the percentage of donor cells embedded in the recipient’s bone marrow, and a longer-term measure that reflects the percentage of circulating donor blood cells (engraftment), mice treated with CD26 inhibitors and the knockout mice showed significantly higher percentages of donor stem cells at work in the recipient than did the control group.

The knockout mice had the most dramatic shortterm improvement, showing 35 percent of blood stem cells in recipient bone marrow were from the donor compared with 14 percent in the control group in the short-term.

In the longer term, at the lowest dose of stem cells transplanted, all the control mice died within 21 days. At the same dose, 80 percent of the CD26 knockout mice lived past 60 days.

The CD26 inhibitors used in the experiments work very briefly, Christopherson said, but a second generation of compounds with a longer half-life would be promising.

Christopherson conducted the experiments as a post-doctoral fellow in the Department of Microbiology and Immunology and the Walther Oncology Center at Indiana University. He is following up the mouse research by studying CD26 in human samples from cord blood, bone marrow and mobilized peripheral blood stem cells.

He also recently authored a chapter on hematopoietic stem cell transplantation in a new book, Cord Blood Biology, Immunology, Banking and Clinical Transplantation, published this year by the American Association of Blood Banks. The book is edited by Hal Broxmeyer, Ph.D., professor and chairman of microbiology and immunology at the Indiana University School of Medicine, who also is senior author of the Science paper.

— By Scott Merville, Public Affairs