Embargoed for Release June 2, 1999 6 p.m. Eastern Time
Contact:
Todd Ringler
(617) 632-5357
NEW TECHNIQUE HOLDS PROMISE OF CREATING UNIVERSAL DONOR POOL FOR TRANSPLANTATION
BOSTON In a study with powerful implications for people needing organ and tissue transplants, researchers at Dana-Farber Cancer Institute and Harvard Medical School have devised a new technique that may make transplants available to nearly everyone with a partially matched donor.
The study, published in the June 3 issue of the New England Journal of Medicine, is a direct result of discoveries into the fundamental workings of the immune system, specifically the intricate signaling process that enables some immune cells to identify and resist foreign invaders.
Groundwork for the current study involved research into T cells, immune system cells that fight infection, stand guard against cancer, and attack foreign tissue. It is T cells' hostility to foreign tissues and organs that poses a challenge for transplantation. Transplant recipients typically must take a lifelong course of drugs that essentially paralyzes every T cell in their body -- reducing the chances of tissue rejection but leaving patients highly vulnerable to infection by viruses and bacteria and raising their risk of cancer. The new approach, by contrast, seeks to create a condition of "anergy," in which only those T cells that recognize and attack foreign tissue are deactivated.
"The aim of the new technique is to 'punch a hole' in the immune system to render inactive the specific T cells that are responsible for tissue rejection, but to leave intact the T cells that fight infection and guard against cancer," says Lee Nadler, M.D., chairperson of Adult Oncology at Dana-Farber and Brigham and Women's Hospital, one of the study's authors. "This represents an entirely new approach to transplantation one that holds hope of safer transplants for a larger number of people."
"What makes this study so important," says David G. Nathan, M.D., president of Dana-Farber and professor of medicine at Harvard Medical School, "is that it opens the door to a universal donor pool without extensive and prolonged searches for individuals who lack matched family donors. Parents, siblings, and children may soon be eligible to serve as donors for each other, regardless of how well they match, without the complications that are so often associated with transplantation today."
"It is an excellent illustration of work that began in the laboratory being converted into a new and better treatment for patients," says the study's senior author, John G. Gribben, M.D., Ph.D., of Dana-Farber. "It demonstrates the powerful results that can emerge when scientists from a variety of disciplines collaborate on an idea or therapeutic approach." (See end of release for reactions from Nobel laureates who pioneered the field of transplantation.)
The discoveries that gave rise to the new technique took place in the 1980s and early 1990s, many of them originating in Dana-Farber laboratories.
T cells determine whether other cells are friend or foe based on tiny markings called antigens on the cells' surface. In the setting of transplantation, cells whose antigens are sufficiently similar to those of T cells are considered friendly and left unmolested. Cells whose antigens have fewer resemblances are identified as foreign and destroyed.
T cells respond to antigens when the antigens are displayed on the surface of specialized cells called antigen-presenting cells. The T cells determine whether the antigens are foreign or not after receiving a signal from the antigen-presenting cells -- a stage called the "recognition event." But before the T cells can arm themselves for attack, they must receive a second signal from the antigen-presenting cells a message known as the "costimulatory signal."
Research at a variety of institutions elucidated critical components of this signaling pathway. Researchers at the Fred Hutchinson Cancer Center in Seattle discovered a molecule called CD28 on the surface of T cells where the second signal is received. The molecule was cloned for study by researchers at Massachusetts General Hospital. Researchers at Dana-Farber led by Nadler determined that the critical costimulatory signal originates in a family of molecules called B7 on the surface of antigen-presenting cells.
The discovery of B7 has been called by Charles Janeway, M.D., of Yale University School of Medicine "the holy grail of immunology" because of its essential role in T cell response.
Knowledge of B7 inspired the idea by lead author Eva Guinan, M.D., of Dana-Farber and children's Hospital that if the costimulatory signal could be blocked, T cells in donated tissue could be prevented from launching an attack against the recipient.
"There are a billion T cells in transplanted bone marrow," says Guinan. "Within that number, only one in a thousand are responsible for initiating organ and tissue rejection. If we can suppress those cells, and those cells alone, we can reduce the chances of tissue rejection without impairing patients' immunological competence."
The new study represents the results of the first use of this technique in human patients.
The study involved 12 patients who had bone marrow transplants. Such transplants have become standard treatment for patients who are born with diseases of the blood, who have their bone marrow fail, or who have cancers, such as leukemia, that originate in the bone marrow.
The patients in the study had high-risk acute myelogenous or lymphoblastic leukemia, non-Hodgkin's lymphoma, or inherited diseases of the blood. As in conventional bone marrow transplants for cancer, patients first received high doses of chemotherapy and radiation, which not only kills cancer cells throughout the body but also destroys the bone marrow. Bone marrow transplants from "mismatched" donors that is, people whose tissue is only a 50 percent match of the recipients' were used to replace the destroyed marrow.
One of the main complications of conventional bone marrow transplants is graft-versus-host disease (GVHD), a potentially fatal condition in which T cells in donated bone marrow launch an attack against recipients' tissue.
To reduce the likelihood of GVHD, researchers devised a way to make the T cells in the donated marrow "tolerant" of the recipients' tissue. Marrow from each donor was incubated for 36 hours with cells from the intended recipient and with a protein called CTLA-4-Ig. The incubation gave the CTLA-4-Ig time to bind to the B7 molecule on the recipients' antigen-presenting cells, blocking the costimulatory signal. The marrow was then returned to the recipients intravenously.
Following incubation, researchers found a sharp reduction in the number of T cells capable of recognizing recipients' antigens.
With conventional bone marrow transplants, between 70 and 90 percent of patients with 50 percent mismatched donors would be expected to develop severe GVHD. In the study group, none of the patients developed the severe form of the disease, although three had a milder form which was confined to the gastrointestinal tract.
Although seven of the very high-risk patients have died, none of their deaths was attributable to GVHD, but to other, unrelated complications of transplantation. The remaining five patients are alive, in remission, and free of immunologic problems seven to 31 months after their transplants.
"The results show that inducing tolerance in donated bone marrow can significantly lower the chances that patients will develop GVHD," says Guinan. "This technique suggests that bone marrow transplants can be performed without many of the shortcomings associated with current methods.
"Further studies will be needed to ensure that the T cells that have not been made tolerant of recipients' tissue retain their cancer- and infection-fighting ability," she continues. "If this is in fact borne out, this technique may also prove useful in reducing complications associated with a broad range of organ transplants."
Co-authors with Guinan, Nadler, and Gribben on the study are: Lisa Lavita Brennan, R.N., Vassiliki A. Boussiotis, M.D., Ph.D., Naoto Hirauo, M.D., Ph.D., and Donna Neuberg, D.Sc., of Dana-Farber.
Reaction from Nobel laureates who pioneered the field of transplantation
* Joseph Murray, M.D., a surgeon emeritus at Brigham and Women's Hospital in Boston and co-winner of the 1990 Nobel Prize in Medicine: "This is a well-founded study. By dissecting out the factors that cause graft-versus-host disease, the authors have taken an important step in making bone marrow transplantation a more predictable, universally available procedure."
* E. Donnall Thomas, M.D., of the Fred Hutchinson Cancer Research Center in Seattle and the co-winner of the 1990 Nobel Prize in Medicine: "The report by Guinan et al. is an example of the transfer of findings in basic immunology to clinical application. The possibility of inducing anergy with a non-toxic regimen has implications for wide application to all areas of transplantation. As with all initial studies in human patients, much remains to be done. However, the implications of the approach and the results are indeed exciting."
* Baruj Benacerraf, M.D., president emeritus of Dana-Farber Cancer Institute and recipient of the 1980 Nobel Prize in Medicine: "This is a pioneer work which has a tremendous potential to advance the field of transplantation."
-- end --
RSS