A newly developed genetic test
may drastically improve the safety of bone marrow transplants.
By looking at the activities of 17 genes, researchers
in Quebec and Ontario found that they could predict
the development of a common, potentially fatal type
of transplant rejection known as graft-versus-host disease
(GVHD).
"We estimate that there have been
over 10,000 Canadian [leukemia and lymphoma] patients
successfully treated with bone marrow transplantation.
The only caveat is the high incidence of [GVHD], whereby
the donor tissue's T cells recognize their new host
as 'non-self' and reject the recipient tissues," says
Dr Claude Perrault, head of research at the new Institute
for Research in Immunology and Cancer at the University
of Montreal and principal investigator of the study,
recently published in the Public Library of Science
Medicine.
TAKING
ODDS
Peripheral blood stem-cell grafts from immunologically-matched
donors, usually siblings, is the gold standard for treating
most hematological cancers. A minority of leukemia and
lymphoma patients who receive bone marrow grafts are
totally cured — about 25% don't even need the lifelong
immunosuppressive treatment normally associated with
transplantation. But GVHD is the reality that up to
60% of these patients must face. It's the major cause
of non-cancer relapse morbidity and mortality in this
group, leading to either a drastically reduced quality
of life due to aggressive immunosuppression, or death.
Until now, doctors have had no
conclusive means of knowing whether donated bone marrow
— essentially, a transplanted immune system —
would have a strong or weak immunological response when
confronted with a host's tissue.
"We asked ourselves why some patients
are affected by [GVHD], while others are not. Our hypothesis
was that there was a genetic basis for the rejection,
so we analysed the genetic profiles of 50 leukemia and
lymphoma patients and their sibling donors," says Dr
Perrault.
REJECTION
RADAR
After performing microarray expression profiling on
19,000 donor T cells' genes, Dr Perrault and his colleagues
isolated 17 genes whose expression levels seemed to
affect the strength of the immunological response to
the graft. Using a genetic assay technique called quantitative
reverse transcriptase polymerase chain reaction, the
researchers found that, by analysing these genes in
the study's participants, they were able to predict
the incidence of GVHD in 80% of cases.
In the coming months, an advanced,
multi-centre phase will begin, expanding the study to
other hospitals in Canada and the US. Dr Perrault believes
this larger study will validate his findings and improve
the test's predictive ability. He foresees the development
of a standard laboratory assay, which would quickly
identify safe bone marrow donors, within two years.
"The process of identifying these
17 genetic markers, which we believe predict the incidence
of GVHD, would be a very simple test that could be done
at any hospital with up-to-date laboratory facilities,"
says Dr Perrault.
And the test doesn't only predict
which donor is the best match — it could be used
to optimize outcomes, too. "If the only available donor
tissue is likely to cause GVHD, the test effectively
warns doctors to preemptively start immunosuppressive
therapy to discourage host tissue rejection," Dr Perrault
explains.
In the not-too-distant future,
his research team hopes to evaluate the possibility
of whether this same assay would be effective in predicting
the likelihood of rejection in solid tissue transplantation.
"It's still early, but I believe this same method is
applicable to preventing rejection in kidney, liver
and other organ transplantation," he says.
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