Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice.

Abstract

BACKGROUND & AIMS:

Treatment with ex vivo expanded regulatory T cells (Tregs) is regarded as a promising therapeutic approach in inflammatory bowel disease but is hampered by impaired Treg accumulation and function at inflammatory sites. We aim to study whether antigen-specific redirected Tregs can overcome these limitations.

METHODS:

We developed transgenic mice whose T cells, including Tregs, express chimeric receptor (CR) made of antibody variable region as recognition unit and T-cell stimulatory and costimulatory domains to activate specifically in response to the predetermined model antigen 2,4,6-trinitrophenol (TNP).

RESULTS:

TNP-specific CR-bearing Tregs were potently and specifically activated by exogenous TNP and suppressed effector T cells in the absence of costimulatory B7-CD28 interaction. TNP-specific transgenic (Tg) mice were resistant to 2,4,6-trinitrobenzene sulphonic acid (TNBS) colitis but not to other hapten-mediated colitis. Adoptive transfer of CR-bearing Tregs to wild-type mice with TNBS colitis was associated with significant amelioration of colitis and improved survival. Although TNP-specific CR-bearing Tregs did not suppress oxazolone colitis, they cured it after addition of traces of TNBS to oxazolone-inflamed colons, demonstrating a "bystander" effect. In vivo imaging of adoptively transferred CR-bearing Tregs demonstrated that they preferentially migrate to TNBS-induced colonic mucosal lesions within hours of induction of colitis.

CONCLUSIONS:

Tregs can be redirected with specificity distinct from that of pathogenic lymphocytes, accumulate at colonic inflammatory lesions, and suppress effector T cells in a specific, nonmajor histocompatibility complex-restricted, and noncostimulatory-dependent manner, resulting in significant amelioration of colitis. Hopefully, this approach will lead to a novel therapy for inflammatory bowel disease, as well as other inflammatory diseases.

• Authors: Eran Elinav, Tova Waks, Zelig Eshhar
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 7 Pg. 2014-24 (Jun 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18424268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD28 Antigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Histocompatibility Antigens
• Immunoglobulin Variable Region
• Picrates
• Receptors, Antigen, T-Cell
• Receptors, IgG
• Recombinant Fusion Proteins
• Oxazolone
• Trinitrobenzenesulfonic Acid
• picric acid

Topics

• Animals
• Bystander Effect
• CD28 Antigens (immunology)
• Cell Line
• Cell Movement
• Colitis (chemically induced, immunology, pathology, prevention & control, therapy)
• Colon (immunology, pathology)
• Disease Models, Animal
• Forkhead Transcription Factors (metabolism)
• Histocompatibility Antigens (immunology)
• Immunity, Mucosal
• Immunoglobulin Variable Region (immunology)
• Immunotherapy, Adoptive
• Intestinal Mucosa (immunology)
• Lymphocyte Activation
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Oxazolone
• Picrates (immunology)
• Receptors, Antigen, T-Cell (genetics, immunology)
• Receptors, IgG (immunology)
• Recombinant Fusion Proteins (immunology)
• T-Lymphocytes, Regulatory (immunology, transplantation)
• Time Factors
• Trinitrobenzenesulfonic Acid