Regulatory T cell Transfer in Crohn’s Disease

For my first blog post, I found articles focusing on regulatory T cells (Treg). These cells have a special place in my heart, as they were the focus of my doctoral research. At that time, everyone hoped that in the future they could be used therapeutically in a transfer setting. It looks like that day has come!

Main Points: 

  • A pilot trial using adoptively transferred regulatory T cells in Crohn’s disease patients has shown some promise.
  • Two studies have determined that Neuropilin-1 is a marker for natural regulatory T cells.

Take home message: New research on regulatory T cells is bringing us closer to a therapy for IBD patients.

The immune system doesn’t only promote inflammation; it also has ways to dampen inflammation. One way that this is done is through Treg. These cells are great at limiting the actions of other cells responsible for inflammation. Therefore, researchers wanted to use them to control chronic inflammatory diseases. Treg were isolated and re-injected into Crohn’s disease patients.  The treatment led to a temporary, but significant, improvement in disease symptoms in 8 out of the 20 patients tested.

This study is described in the latest edition of Gastroenterology. The research, performed in France at a multitude of hospitals, used patient peripheral blood mononuclear cells (PBMCs) as the source of the Treg. They first stimulated the PBMCs with ovalbumin (OVA) and then cloned OVA-reactive T cells by limiting dilution. Treg cells were identified by examining the secreted cytokines. The team looked for a cytokine profile associated with induced Treg (iTreg), which is characterized by high IL-10 production. 20 patients received a single dose of autologous Treg, ranging from one million to one billion cells. To make sure that the cells would see their cognate antigen in the gastrointestinal tract, the patients were fed OVA-enriched diets.

Eight out of the 20 patients improved their Crohn’s disease activity index (CDAI) at both 5 and 8 weeks post treatment. These changes were significant but not extremely huge (less than 100 points). Surprisingly, the patients with the lowest dose (one million) had the best results. CRP levels also improved after one week and reductions in peripherally circulating monocytes (CD14+CD16+) and CD4+Foxp3+ T cells were also measured.

This study is impressive. Almost a decade of research on Treg cells has lead up to this point and scientists have been speculating for a long time that Treg transfers would help IBD. It’s great to finally see that this concept has potential. Browsing in the Journal of Experimental Medicine, I also came across another Treg breakthrough, this time in the form of parallel articles that describe a new marker to distinguish thymus-derived natural Treg (nTreg) from induced Treg. This marker is Neuropilin-1 (Nrp1).

Treg come in two main types called induced Treg (iTreg) and natural Treg (nTreg). The difference has to do with how they develop in the body. The researchers found that nTreg express a protein called Neuropilin-1 (Nrp1). This marker, if it behaves similarly in humans, may help future clinical studies better characterize Treg cells and improve the outcome.

Both teams made their discovery via the examination of Treg developed in T cell receptor transgenic mice. Using their respective models, they were able to isolate iTreg and nTreg and perform microarrays to analyze gene transcription in each population. Nrp1 expression was strikingly different between the two populations, with iTreg having low or no expression, and nTreg having a high expression.

Nrp1 expression appears to be stable under most conditions. However, in vivo and in vitro conditions were found that could alter Nrp1 expression that did not really agree with each other. In vivo, iTreg will express Nrp1 under pro-inflammatory conditions, while in in vitro culture, TGFβ drives the expression of Nrp1 as opposed to other cytokines. Thus, there are still some questions to be addressed. Also, not all Nrp1+ cells are Treg. Activated T cells also express it.

This discovery of a new marker to help distinguish nTreg and iTreg is a interesting considering the adoptive transfer experiment in humans. The researchers performing the transfer used iTreg because they could easily culture and recognize them in stimulated PBMC. With this new marker, the option now exists to perform the same kind of study with nTreg. It could be that nTreg may be better for Crohn’s disease patients. Nrp-1 will help address these questions. However, studies have to be done looking at Nrp-1 expression in human Treg.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

Sources:

Desreumaux P, Foussat A, Allez M, Beaugerie L, Hébuterne X, Bouhnik Y, Nachury M, Brun V, Bastian H, Belmonte N, Ticchioni M, Duchange A, Morel-Mandrino P, Neveu V, Clerget-Chossat N, Forte M, Colombel JF. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012 Nov;143(5):1207-1217.e2. doi: 10.1053/j.gastro.2012.07.116. Epub 2012 Aug 8.

Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P, Weiss D, Von Schack D, Bluestone JA. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012 Sep 24;209(10):1713-22, S1-19. Epub 2012 Sep 10.

Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG, Yang Y, Floess S, Huehn J, Oh S, Li MO, Niec RE, Rudensky AY, Dustin ML, Littman DR, Lafaille JJ. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med. 2012 Sep 24;209(10):1723-42, S1. Epub 2012 Sep 10.

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