Tuesday, June 16, 2009
Children born without thymus glands have given Duke University
Medical Center researchers a rare opportunity to watch as a new
immune system develops its population of infection-fighting
T-cells.
Researchers led by Thomas Kepler, Ph.D., Division Chief of
Computational Biology, tracked three young patients after thymus
tissue transplantation to measure the growth of a T cell population
– with all of its diversity. Duke University pioneered thymus
transplantation for children born with DiGeorge Syndrome, lacking a
thymus, under the direction of Louise Markert, M.D., Ph.D.
As transplanted thymus tissue took hold in the children, the team
studied signals related to specific T-cell receptors and more
general resources like cytokine signals or space availability. They
assessed T cell receptor diversity to determine overall T cell
levels and to count T cells of certain kinds.
"What we haven't understood until now is how maintaining the
diversity of T cells with different receptors works while a body
also maintains appropriate T cell numbers overall," said Kepler,
who is senior author of a paper published in PloS Computational
Biology. "Our paper is the first to use information about changes
in T cell receptor diversity to infer properties of the T cell
regulatory mechanisms."
The immune system needs a variety of different T cells to fight all
kinds of pathogens. "The fastest way to grow the total T cell
population is to impede diversity and grow just a few kinds of T
cells," Kepler said. "We set out to understand more about the
regulation of this fine balance."
Kepler and lead author Stanca Ciupe, Ph.D., a postdoctoral fellow
in computational immunology, created mathematical formulas to model
the contribution of resources on the regulation of T cell
population growth and diversity. They found that factors that are
blind to T cell receptors and treat all T cells alike are a
thousand times more common than the factors that regulate
receptor-specific development of T cells.
"The findings open up the possibility of studying the development
of T cells in children with DiGeorge syndrome in a rigorous and
quantifiable way, because we can determine which factors are most
important," said Markert, a Duke Associate Professor of Pediatrics
in the Division of Allergy and Immunology.
For example, one of the transplants appeared not to be functioning,
based on a biopsy. Using the computations devised for this
research, however, the team was able to track the rise in certain
types of T cells – the transplant took longer to develop T cells
than most other cases. In the end, the child's immune system
matured, T cells developed, and the child avoided undergoing a
second transplantation.
"What is novel is our ability to take the results from assays and
quantify them to get a numerical measure of diversity, to get a
picture of what really happens when T cells mature," Ciupe said.
"Secondly, we were able to develop a mathematical model to feed the
data into."
"It will require a significant mathematical effort to see the full
promise of human systems biology come to fruition," Kepler said.
"So much scientific work is done in model organisms, but we can't
manipulate humans in those ways. This paper shows that with more
sophisticated mathematical tools, you can get the information you
need to learn about human biology without enormous amounts of
manipulation of people."
Ciupe said that using applying mathematics to biological systems
and biological engineering will continue to develop new
applications for humans. Mathematics might help to deliberately
design human vaccines, for instance. "Physics and mathematics have
a symbiotic relationship and resulted in the laws of physics," she
said. "Combining biology and math is an iterative process, and
someday we may have laws of biology in the same way."
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Duke University Medical Center
Thanks to Duke University Medical Center for this article.