Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor.
OBJECTIVE
The therapeutic application of regulatory T cells (Tregs) for the treatment of inflammatory diseases is limited by the scarcity of antigen-specific Tregs. A preferred approach to endow effector T cells (Teff) with a desired specificity uses chimeric immune receptors with antibody-type specificity. Accordingly, employing such chimeric immune receptors to redirect Tregs to sites of inflammation may be a useful therapeutic approach to alleviate a broad scope of diseases in which an uncontrolled inflammatory response plays a major role.


METHODS
To enable application of the approach in clinical setting, which requires the genetic modification of the patient's own Tregs, we describe here a novel protocol that allows the efficient retroviral transduction and 2,4,6-trinitrophenol-specific expansion of murine naturally occurring regulatory T cells (nTregs), with a 2,4,6-trinitrophenol-specific tripartite chimeric receptor.


RESULTS
Transduced Tregs maintained their Foxp3 level, could undergo repeated expansion upon ex vivo encounter with their cognate antigen in a major histocompatibility complex-independent, costimulation-independent, and contact-dependent manner and specifically suppressed Teff cells. Adoptive transfer of small numbers of the transduced nTregs was associated with antigen-specific, dose-dependent amelioration of trinitrobenzenesulphonic acid colitis.


CONCLUSIONS
This study demonstrates that nTregs can be efficiently transduced to express functional, antigen-specific chimeric receptors that enable the specific suppression of effector T cells both in vitro and in vivo. This approach may enable future cell-based therapeutic application in inflammatory bowel disease, as well as other inflammatory disorders.
Elinav
Eran
E
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Adam
Nitzan
N
Waks
Tova
T
Eshhar
Zelig
Z
D019264:Adoptive Transfer; D000818:Animals; D000918:Antibody Specificity; D003092:Colitis / Q000276:immunology / Q000628:therapy*; D005260:Female; D015686:Gene Products, env / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology; D015684:Gene Products, pol / Q000276:immunology; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005822:Genetic Vectors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011946:Receptors, Antigen / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015686:Gene Products, env; D015683:Gene Products, gag; D015684:Gene Products, pol; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins