By Marilynn Larkin
NEW YORK (Reuters Health) - 13/2/2019
Crohn's disease (CD) symptoms may be reduced if an agonist of the retinoic acid receptor alpha (RARA) can be used to traffic T-regulatory (Treg) cells to inflamed intestinal tissues, researchers suggest.
"We are due to start a clinical trial of this therapy within the next six months," Dr. Graham Lord of Kings College London, UK, told Reuters Health by email. (http://bit.ly/2Ia3kYQ)
CD is characterized by an imbalance of effector (proinflammatory) and regulatory T cells (generally immunosuppressive) in the intestinal mucosa, Dr. Lord and colleagues explained online January 30 in Gastroenterology.
In their paper, they report on their efforts to investigate whether impaired trafficking of Treg cells contributes to the pathogenesis of CD and whether proper functioning could be restored.
The researchers measured levels of the integrin alpha4beta7 on Treg cells isolated from the peripheral blood or lamina propria of CD patients and healthy controls. The cells were expanded in the laboratory, incubated with rapamycin with or without agonists of the retinoic acid receptor alpha (RARA), and their gene expression profiles were analyzed. The researchers also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts.
Treg cells from CD patients expressed lower levels of alph4beta7 than those from control patients, the researchers found.
When Treg cells from patients with CD were incubated with rapamycin and an agonist of RARA (RAR568), they expressed high levels of integrin alpha4beta7, as well as other immune system proteins, compared to cells incubated with rapamycin alone or rapamycin and all-trans retinoic acid (ATRA).
These Treg cells had increased suppressive activity in assays and did not produce inflammatory cytokines. Further, they were significantly more likely to traffic to intestinal xenografts than Treg cells that were expanded in control medium.
Summing up, the authors state, "We have identified a primary defect in the number of Tregs expressing the gut-homing molecule alpha4beta7 in CD (and) the optimal conditions for licensing highly suppressive and phenotypically stable autologous Tregs to traffic to the inflamed gut. These cells maintain their function both in vitro and in vivo and therefore form the optimal therapeutic option for adoptive cell-based therapy of CD."
Dr. Jordan Axelrad, a gastroenterologist at NYU Langone Health's Inflammatory Bowel Disease Center in New York City, commented by email, "The exploratory data in the present study were tested in intestinal mouse xenographs and not in human tissues, so it's not clear how these experiments will perform in real-life Crohn's disease."
"As such," he told Reuters Health, "much additional research is needed not only to confirm the above findings but also to verify that this approach to Treg induction is safe and effectively reduces intestinal inflammation in human tissues."
"Clinicians should know that T cell trafficking is an area of clinical investigation in inflammatory bowel disease," he said. "While vedolizumab, a monoclonal antibody to alpha4beta7 integrin, is already approved for use in inflammatory bowel disease, a greater understanding of these specific T cell regulatory pathways and how they contribute or mitigate inflammation will likely yield further therapeutic options."
SOURCE: http://bit.ly/2Ib5F5M Gastroenterology 2019.