Jeff Davies, MD, PhD, and Eva Guinan, MD
A new technique being tested in stem-cell transplants from
imperfectly matched donors has revealed a striking, unforeseen response
that can suppress graft-versus-host disease, a common and dangerous
complication of mismatched transplants, report scientists from
Dana-Farber Cancer Institute.
Analysis of blood samples from a small number of clinical trial
patients showed that the novel method — which inactivates specific
immune cells from the donor that would attack the recipient's body —
also unleashes a surge of T-cells that further dampen the immune
The previously unrecognized specificity of these regulatory T-cells
(also called Tregs) helps explain why the patients treated with the new
strategy — known as "co-stimulatory blockade" — have shown a
gratifyingly low level of graft-vs-host disease, according to the report published online by the new journal Science Translational Medicine.
The findings also suggest that optimizing the activity of Tregs in
this manner might prove valuable in transplants of kidneys and other
solid organs, as well as in treating autoimmune disease, say the
scientists, led by Eva Guinan, MD,
senior author, of Dana-Farber and Children's Hospital Boston, and Jeff
Davies, MD, PhD, first author, of Dana-Farber. Both are also on the
Harvard Medical School faculty.
The innovative method for improving mismatched bone-marrow and
stem-cell transplants was first described clinically 10 years ago in the
New England Journal of Medicine by Guinan, Lee Nadler, MD, also at Dana-Farber and a co-author on the new publication, and others.
They employed a technique called "co-stimulatory blockade" to prevent
certain T-cells in the donor material from recognizing and attacking
cells in the patient's body, causing graft-vs-host inflammatory
reactions that can affect the gastrointestinal system, skin, and other
The need for techniques that can reduce complications in mismatched
transplants is great; the odds of a patient having a perfectly matched
sibling for a donor are only about 25 percent.
"Originally we thought that using this method to specifically block
the harmful response by donor T-cells explained the decrease in
graft-vs-host disease and the rapid recovery of immune function we have
seen in the clinical trials," said Guinan.
"Now we learn that there is another powerful mechanism that is
induced — the generation and rapid expansion of Treg cells in the three
months following the transplant."
Regulatory T-cells are a special population of T-cells that suppress
immunity. They have two important functions: Turning off immune
reactions following a successful defense against infectious organisms,
and preventing immune cells from attacking the body's own tissues, which
are identified by distinctive "self-antigen" markers.
In the past five years or so, scientists have used new tools to study
Tregs and consider ways they could be harnessed for therapy in
transplantation and autoimmune disease.
In 2008, Davies and Guinan reported low levels of graft-vs-host
disease in a small number of mismatched transplants using co-stimulatory
blockade, which not only neutralized the T-cells that cause the harmful
graft-vs-host response but also led to rapid reconstitution of the
patients' bone marrow.
The researchers then designed experiments to learn more molecular
details about how the blockade strategy had reduced graft-vs-host
complications. Based on few reports in the literature, "We wondered
whether Tregs were playing an additional role," said Davies.
Davies analyzed frozen blood samples taken from five patients and
donors at various intervals after the transplants. The analysis showed
that during the first three months, the level of Tregs in the patients
rapidly rose to very high levels, which helped explain why the
recipients experienced only mild graft-vs-host symptoms.
The Tregs, they confirmed, were generated from the donated T-cells — not remnants of the recipient's immune system.
"We found there was something about co-stimulatory blockade that
caused this rapid expansion of Tregs," said Davies, adding that further
studies are exploring this question.
Importantly, the researchers noted, the Tregs acted in a highly
specific fashion: They turned off only the donor T-cells that would have
triggered the immune attack on the recipient's tissues — other T-cells
that help the patients fight off infections were spared.
This specificity appears to have developed in the recipient's body,
where the Tregs were "educated" to respond only to a harmful T-cell
As a result, said Guinan, this technique "creates a good balance of
effects — inactivating the T-cells that cause graft-vs-host disease
(GVHD), revving up the Tregs to turn off any incipient GVHD, while
bringing about a rapid reconstitution of the recipient's immune system."
The scientists expect the new findings to influence the design of
further clinical tests of the co-stimulatory blockade technique.
And, they said, it opens a window on other potential applications of
co-stimulatory blockade, which is already being used clinically to treat
rheumatoid arthritis (an autoimmune disease) and is being tested in
mismatched kidney transplants.
Guinan is the associate director of the Center for Clinical and
Translational Research at Dana-Farber and an associate professor of
pediatrics at Harvard Medical School.
The research was funded by grants from the National Institutes of
Health, the Leukemia & Lymphoma Society, and the American Society of
Blood and Marrow Transplantation.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National
Cancer Institute. It is the top ranked cancer center in New England,
according to U.S. News & World Report, and one of the
largest recipients among independent hospitals of National Cancer
Institute and National Institutes of Health grant funding.