The findings were published in this week’s issue of the Journal of Experimental Medicine.
Inflammatory bowel disease consists of Crohn’s disease and ulcerative colitis, two chronic inflammatory conditions of the intestine. IBD has an immune component, meaning that an out-of-control immune reaction is causing chronic inflammation. However, little is known about the causes of the extreme reaction.
Recent studies have indicated that the cause may be linked to overactive immune cells called “helper T cells,” that produce pro-inflammatory substances known as cytokines. In a normal immune response, cytokines are essential for stimulating other cells to destroy pathogens (i.e. viruses and bacteria) within the body. However, in the case of IBD, the continuous pro-inflammatory cytokine production causes damage to the intestine.
At Albany Medical College, the study led by Dorina Avram, Ph.D., associate professor in the Center for Cell Biology and Cancer Research, focused on BCL11B—a specific transcription factor that Dr. Avram herself discovered several years ago. “Transcription factors are important because they work within the nucleus of the cell to turn on or off genes and help the cell function properly,” explains Dr. Avram. “They are critical for gene expression and regulation.”
Dr. Avram and her team had found that when the transcription factor BCL11B was removed from mouse T cells, the mice developed wasting disease in which they continuously lost weight over time due to an inflamed colon. The colon of the mice revealed infiltrating “helper T cells” that were producing high levels of pro-inflammatory cytokines as well as other potentially damaging reactive cells know as granulocytes.
Furthermore, the research found that when BCL11B was removed from T regulatory cells (a type of white blood cell responsible for suppressing the immune response), the cells not only were unable to suppress the immune response, but they actually gained the characteristics of the unwanted pro-inflammatory cells.
“Perhaps the most important finding in our research, however, was discovering that the absence of BCL11B in conventional CD4 T cells compromised the formation of an important T regulatory cell population, known as inducible T regulatory cells,” says Avram. “Without BCL11B, the CD4 T cells hindered the ability for the helper cells to become induced T regulatory cells which only exacerbated the immune response and therefore the inflammation.”
As a potential therapeutic approach to prevent development of IBD, Dr. Avram and her lab transferred healthy T regulatory cells into young mice that had not developed the disease yet, but were predisposed to it due to the purposeful removal of BCL11B in T cells.
The data showed that the transplanted mice maintained healthy weights, produced lower levels of pro-inflammatory cytokines, and most importantly, had colons comparable to healthy mice with no visible inflammation and minimal tissue damage.
“As a result of these findings, we feel a possible treatment for IBD should focus on transferring T regulatory cells and using their ability to suppress the immune response,” says Avram. “By doing so, we may be able to treat the underlying problems of IBD and not just their symptoms.”
While Dr. Avram says this is an exciting development, further basic research will be needed before this theory could be tested on humans at some point in the future.
The research was funded by a five-year, $1 million grant from the National Institute of Health’s National Institute of Allergy and Infectious Diseases. Dr. Avram’s lab, which also includes research associate Jeff VanValkenburgh and post doctoral fellow Diana Albu, worked in collaboration with Albany Med’s department of pathology and with investigators from the United States, England and Japan.
Albany Medical Center, northeastern New York’s only academic health sciences center, is the largest private employer in the Capital Region. It incorporates the 651-bed Albany Medical Center Hospital, which offers the widest range of medical and surgical services in the region, and the Albany Medical College, which trains the next generation of doctors, scientists and other healthcare professionals, and which also includes a biomedical research enterprise and the region’s largest physicians practice with 325 doctors. Albany Medical Center works with dozens of community partners to improve the region’s health and quality of life.