Metabolic

Researchers Display New Technique of Treating Crohn’s Illness, Well being Information, ET HealthWorld

Washington: A study conducted by the University of Alabama showed a new way to treat Crohn’s disease using a mouse model and immunoreactive T cells from patients with the same disease.

Researcher Charles O Elson, MD, a professor of medicine from Birmingham, focused on a subset of T cells known as T memory or Tm cells. The UAB researchers used a triple punch treatment to remove Tm cells and increase the number of T regulatory or Treg cells.

Both results were able to prevent colitis in a T-cell transfer mouse model, and they had similar inhibitory effects on immunoreactive CD4-positive T cells isolated from blood samples from patients with Crohn’s disease.

These results, according to Elson, support potential immunotherapy to prevent or relieve inflammatory bowel disease. Some background information is needed to understand how and why the triple punch treatment reported in the journal Science Immunology works.

Inflammatory bowel disease results from an overactivation of the immune response against gut microbes in genetically susceptible hosts. A specific microbial antigen that causes this overreaction by short-lived effector T cells is flagellin, the protein subunit of bacterial flagella, the long tail-like structures that spin like a propeller to make some bacteria mobile.

One group of immunodominant flagellins are those in the Lachnospiraceae family, including CBir1; More than half of Crohn’s disease patients show increased serological reactivity to CBir1 and related flagellins.

In contrast to the short-lived T-effector cells, which act as soldiers to fight infections, T-storage cells serve as sentinels, reminding of a previous encounter with flagellins. They are long-lived and calm and have a low metabolism. When reactivated by a new encounter with flagellin antigens, they undergo a profound metabolic transition and quickly expand into a large number of pathogenic effector T cells.

This metabolic switch is controlled by a signaling protein, mTOR, which is located in the Tm cell. Therefore, activation of mTOR is required for T cell expansion, making it an inescapable metabolic checkpoint to generate activated Tm cells. It is also the checkpoint for T-naïve cells who first encounter flagellin.

Elson and colleagues therefore hypothesized that activation of CD4-positive Tm or T-naive cells by flagellin antigens, while at the same time switching off the metabolic checkpoint through the use of mTOR inhibition, resulted in death or the lack of normal Immune system would respond to an antigen called energy.

These effects include two parts of the triple punch treatment, with the third part being the induction of Treg cells.

Activation was triggered by a synthetic peptide that had multiple repeats of a CBir1 epitope. Such a peptide can selectively stimulate memory cells without activating an innate immune response.

To turn off the metabolic checkpoint, the UAB researchers used two existing drugs, rapamycin and metformin. Rapamycin directly inhibits mTOR, and metformin increases that inhibition by activating a kinase called AMPK, which negatively regulates mTOR activity.

Elson calls this treatment cell activation with simultaneous inhibition of the metabolic checkpoint, or CAMCI. Parenteral application of CAMCI in mice successfully targeted microbiota flagellin-specific CD4-positive T cells, resulting in significant antigen-specific CD4-positive T cell death, an impaired development and impairment resulted in reactivation of CD4-positive memory responses and substantial induction of a CD4-positive Treg cell response.

It prevented colitis in the mouse model and had similar inhibitory effects on microbiota flagellin-specific CD4-positive T cells isolated from patients with Crohn’s disease.

For a possible future treatment for patients with Crohn’s disease, it is unlikely that a single flagellin would have much effect, Elson says.

In the developed world, three in 1,000 people suffer from inflammatory bowel disease. The main forms, Crohn’s disease and ulcerative colitis, have significant morbidity and high health care costs, and no current therapy alters the natural course of these diseases.

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