Immunity mutiny
By Alicia Di Rado
Real life is murkier and more complicated than the movies. Despite all of medicine’s advances, life and death are at stake in a field where so much still remains to be discovered.
Enter City of Hope’s Defu Zeng, M.D., assistant professor in the Division of Diabetes, Endocrinology & Metabolism and the Department of Hematology & Hematopoietic Cell Transplantation. Zeng studies graft-versus-host disease, or GVHD, a complication of hematopoietic cell transplantation, commonly called bone marrow transplantation.
Physicians perform hematopoietic cell transplants to treat patients with serious blood diseases, including leukemia and lymphoma. The transplants use stem cells from healthy donors or from the patients themselves to create new, healthy immune systems and blood cells in these cancer patients, giving them a second chance at life.
Unfortunately, sometimes immune cells from the donor attack the patient’s own tissues and organs as if they were foreign. That results in GVHD.
GVHD remains one of the major causes of complications and death for people who undergo transplants with cells from donors.
The GVHD mystery likely would be easier to solve if scientists knew more about its protagonists. That is where Zeng and his fellow scientists come in. They look for the cells and proteins that play parts in the disease.
Called T cells, these cells form part of the backbone of the immune system, the body’s line of defense. They may seem like key suspects in GVHD, but Zeng’s team has found that the tale is more complicated than that.
The TH-17 story
Special T cells called Th-17 cells might be able to help GVHD, according to research by Tangsheng Yi, Ph.D., of Zeng’s lab. Yi and colleagues published their study in the Sept. 1, 2008, issue of the journal Blood.
At first glance, it would be easy to assume Th-17 cells cause trouble.
“Th-17 cells have been shown to play a critical role in driving inflammatory responses in autoimmune diseases such as multiple sclerosis and psoriasis,” Yi said.
These cells produce a protein called interleukin-17, or IL-17. Some scientists have proposed neutralizing IL-17 as a way to suppress inflammation, and pharmaceutical companies are developing drugs to do that to treat autoimmune diseases.
But in GVHD, Th-17 cells and IL-17 actually protect against a dangerous immune response, Zeng said. The group found that Th-17 cells kept other immune cells in check, and those other immune cells can provoke exacerbated, acute GVHD — a form of GVHD arising soon after transplantation.
Zeng said that should signal caution. “Our data clearly indicate that neutralizing IL-17 will not be good for treating acute GVHD,” Zeng said. “It is a good warning.”
The scientists conducted their lab research by examining what happens in an immune system absent of Th-17 cells. Without these cells around, they saw an abundance of other helper T cells known as Th-1 cells, as well as more of a powerful protein called interferon-gamma. The increased Th-1 cells and interferon-gamma prompted exacerbated, acute GVHD.
Today, the team is trying strategies to push Th-17 production and testing whether neutralizing interferon-gamma can ease acute GVHD.
‘Good’ versus ‘bad’
Another population of potentially helpful T cells appears soon after transplantation, according to Zeng and postdoctoral fellow Dongchang Zhao, M.D., Ph.D.
Writing in the same issue of Blood, the researchers and their colleagues reported that donor T cells can differentiate into two populations — with critical consequences.
“One is pathogenic, or ‘bad,’ and can cause GVHD,” explained Zeng. “The other one is ‘good’ and can regulate and suppress GVHD. We have identified a marker for those good T cells, termed ‘CD103.’
“It is the first time we’ve identified this regulatory T-cell population in hematopoietic cell transplant recipients,” Zeng added.
They saw firsthand in the lab how these T cells work. When they infused “good” CD103-expressing T cells into lab mice with severe chronic GVHD, the infusion markedly improved the disease.
The scientists believe it would be possible to isolate these CD103-expressing “good” T cells from a patient with chronic GVHD, expand them in the laboratory and then reinfuse them back into the patient as a therapy for chronic GVHD — a form of GVHD that starts three or more months after transplantation. Currently, physicians have no effective therapy for chronic GVHD.
“The important discovery here is that before, we thought that all the donor T cells we infused were bad for GVHD; now what we’ve found is that among those ‘bad’ cells, there are some ‘good’ cells that can be used to control their ‘bad’ siblings,” Zeng said.
Scientists have published many papers showing that natural regulatory cells, or Treg cells, can prevent GVHD if they are infused before the disease develops, but they cannot treat it once it starts. “This is the first important study showing that Treg cells — if they are activated in the body — can be used to ameliorate ongoing GVHD,” he said.
Further study is needed to replicate the findings in humans. In the meantime, studies from Zeng’s lab are giving scientists worldwide a better picture of the players involved in GVHD. With greater knowledge about the cast of characters, researchers may be able to write a happier ending.
Related Stories