A potential immunosuppressive treatment for Crohn’s disease, a type of inflammatory bowel disease, was demonstrated in a mouse model and using immune-reactive T cells from patients with Crohn’s disease.
This research, led by the University of Alabama at Birmingham researcher Charles O Elson, MD, professor of medicine, focused on a subset of T cells called T memory, or Tm cells. UAB researchers used a three-punch treatment to remove Tm cells and increase the number of T, or Treg, regulatory cells.
Both of these outcomes were able to prevent colitis in a T-cell-transfused mouse model, and had similar inhibitory effects on immune CD4-positive T cells isolated from blood samples of patients with Crohn’s disease.
These findings, Elson says, support potential immunotherapy to prevent or reduce inflammatory bowel disease.
Some background is needed to understand how and why the three-punch treatment, reported in the journal Science Immunology, works.
Inflammatory bowel diseases result from overexpression of the immune response against gut microbes in genetically susceptible hosts. One particular microbial antigen that causes this overexpression with short-acting T cells is short-lived flagellin, the protein subunit of bacterial flagella, the long tail-like structures that circulate as a propeller to secrete a bacterial motile. to do.
One group of highly controlled flagellins is those from the Lachnospiraceae family, including CBir1; more than half of patients with Crohn’s disease have elevated serological reactivity to CBir1 and related flagellins.
Unlike the short-lived T cells that act as soldiers to help fight disease, T memory cells serve as sentinels reminiscent of previous occurrences with flagellins.
They live long and inquisitive lives, with low levels of metabolism. If they are reactivated by recurrence of flagellin antigens, they undergo a deep metabolic transition and rapidly expand to large numbers of pathogenic T-affected cells.
This metabolic mutation is controlled by a signaling protein, mTOR, located in the Tm cell.
Thus, mTOR activation is required for T cell proliferation, making it an inaccessible metabolic study site to form activated Tm cells. It is also the checkpoint for naive T cells coming into contact with flagellin for the first time.
Thus, Elson and his colleagues hypothesized that activation of CD4-Tm or T naive cells by flagellin antigens, while simultaneously shutting down the metabolic pathway through the use of mTOR inhibitors, leading to death or lack of normal immunity. response to an antigen, called anergy. These effects include two parts of the three-punch treatment, with the third being an entry of Treg cells.
The activation was induced by a synthetic peptide containing multiple repeats of a single CBir1 epitope. Such a peptide can selectively stimulate memory cells without activating an innate immune response.
To shut down the metabolic checkpoint, UAB researchers used two existing drugs, rapamycin and metformin. Rapamycin directly inhibits mTOR, and metformin contributes to that inhibition by activating a kinase called AMPK that negatively regulates mTOR activity.
Elson calls this treatment cell activation by concomitant metabolic point injection, or CAMCI.
Parenteral application of CAMCI in mice successfully targeted CD4-positive flagellin microbiota-specific cells, leading to specific antigen-specific CD4-positive T cell death, atypical development and weak response of CD4-positive memory responses , and substantial entry of CD4- Treg positive response cells.
It prevented colitis in the mouse model and had similar inhibitory effects on microbiota-flagellin-specific CD4-positive cells isolated from patients with Crohn’s disease.
For a possible future treatment for patients with Crohn ‘s disease, just targeting one flagellin is unlikely to have much effect, Elson says.
In developed countries, three out of every 1,000 people have inflammatory bowel disease. Its main forms are Crohn’s disease and ulcerative colitis, high morbidity and high medical care costs, and conventional treatment does not alter the natural history of these diseases.
(This story was published from a wire group group without text modification.)
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