Study paves way for trial of cell-based treatment for Crohn's disease

Last Updated: 2015-03-06

By Will Boggs MD

NEW YORK (Reuters Health) - In vitro expanded CD45RA+ regulatory T cells have anti-inflammatory effects on cells isolated from Crohn's disease mucosa, researchers from the UK report.

"We are embarking on a phase Ib/IIa trial right now following validation of our GMP flow sorting solution," Dr. Graham M. Lord from King's College London told Reuters Health by email. "If these early trials are successful, this treatment may be useful for other autoimmune diseases, broadening the therapeutic potential."

Enrichment of regulatory T cells (Treg) on the basis of CD45RA+ expression from healthy control blood improves their phenotypic stability, Dr. Lord and colleagues write in Gut, online February 24.

But there are several barriers to their use in treating Crohn's disease, including their potential plasticity to pathogenic interleukin-17+ cells, uncertain homing to mucosal tissue, and possible effector T cell resistance to Treg-mediated suppression in inflamed Crohn's mucosa.

The researchers sought to define the optimal population for regulatory T cell therapy in Crohn's disease. They began by isolating CD45RA+ and CD45RA- Treg from patients' blood and expanding them in vitro using a workflow that could be readily transferred to a good manufacturing (GMP) background.

Unlike Treg expanded from CD45RA- precursors, those expanded from CD45RA+ precursors showed stable FOXP3 expression as well as resistance to interleukin-17 induction, they found.

Moreover, expanded CD45RA+ Treg expressed homing receptors for gut and lymphoid tissue and, in fact, homed to inflamed human small intestine in a severe combined immunodeficiency (SCID) mouse bearing human small intestinal xenotransplants.

The in vitro expanded CD45RA+ Treg also suppressed proliferation and activation of mesenteric lymph nodes and lamina propria lymphocytes isolated from inflamed Crohn's mucosa.

"This study addresses many of the perceived barriers to Treg cell treatment for Crohn's disease and paves the way for a clinical trial of in vitro expanded CD45RA+ Tregs in this therapeutically challenging disease," the researchers conclude.

"The risks are that we are unable to expand Tregs sufficiently to achieve a therapeutic dose," Dr. Lord said. "The other risk (minimized by flow sorting 'naïve' Tregs) is that these cells will be plastic and start to produce proinflammatory cytokines."

"This is a proof of concept study," Dr. Jean-Frederic Colombel from Icahn School of Medicine at Mount Sinai, New York City, told Reuters Health by email. "The strong parts are that the authors are able to zoom in on a population contained within the CD4+CD25+ Tregs. This population of cells, identified by the expression of CD45RA appears to be distinct from CD45RA- cells in that it is stable and does not undergo Th17 conversion. The expression of gut-homing molecules by Tregs and the homing of Treg into a gut xenograft are the somewhat weak aspects of this study and will need to be explored further. Finally, the cells described are not antigen specific."

Dr. Colombel, who recently reviewed immune cell therapy in inflammatory bowel disease, concluded, "This paper increases interest in cell-based therapies in the treatment of inflammatory bowel diseases. While this study should be considered preliminary, it paves the way for similar studies in the future."

He added that he and his colleagues have already (in a study reported in 2012) "demonstrated that autologous Treg expanded in vitro can provide benefit to a small cohort of patients with Crohn's disease."

SOURCE: http://bit.ly/1wa9I69

Gut 2015.