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Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Iijima H, Neurath MF, Nagaishi T, Glickman JN, Nieuwenhuis EE, Nakajima A, Chen D, Fuss IJ, Utku N, Lewicki DN, Becker C, Gallagher TM, Holmes KV, Blumberg RS - J. Exp. Med. (2004)

Bottom Line: We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo.Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production.These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

ABSTRACT
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

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Effect of anti–IL-4 mAb and CC1 mAb injection on the induction of oxazolone colitis. (a) Body weight of mice treated with anti–IL-4 mAb together with CC1 mAb (♦), anti–IL-4 mAb and control mouse IgG1 (□), or control rat IgG and mouse IgG1 (▴). Prevention of body weight loss was significant (*, P < 0.05; **, P < 0.01) in mice administered anti–IL-4 and CC1 mAb when compared with the control Ab–treated group. Data shown are expressed as mean values ± SEM from six mice per group. Representative macroscopic (b) and microscopic (c; ×100) pictures of mice treated with or without anti–IL-4 and CC1 mAbs are shown.
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fig3: Effect of anti–IL-4 mAb and CC1 mAb injection on the induction of oxazolone colitis. (a) Body weight of mice treated with anti–IL-4 mAb together with CC1 mAb (♦), anti–IL-4 mAb and control mouse IgG1 (□), or control rat IgG and mouse IgG1 (▴). Prevention of body weight loss was significant (*, P < 0.05; **, P < 0.01) in mice administered anti–IL-4 and CC1 mAb when compared with the control Ab–treated group. Data shown are expressed as mean values ± SEM from six mice per group. Representative macroscopic (b) and microscopic (c; ×100) pictures of mice treated with or without anti–IL-4 and CC1 mAbs are shown.

Mentions: The studies described above suggested that CEACAM1a ligation specifically impacts upon Th1 but not Th2 pathways in these models. Given that oxazolone colitis represents a mixed Th1/Th2 colitis in C57BL/6 mice as shown above, we examined the effects of administering the CC1 mAb and/or anti–IL-4 mAb to inhibit both Th1 and Th2 pathways, respectively. If oxazolone colitis was indeed due to both Th1 and Th2 cytokines and CEACAM1a was specific for the Th1 pathway, it would be predicted that more complete clinicopathologic protection would be provided by blocking both pathways. Protection as defined by body weight loss was nearly complete when mice received treatment with an anti–IL-4 mAb in combination with the CC1 mAb (Fig. 3 a, ♦) in comparison to either the control Ab–treated (Fig. 3 a, ▴) or anti–IL-4– and control Ab–treated (Fig. 3 a, □) groups. Notably, an essential role for IL-4 in this model was suggested by the fact that blockade of IL-4 either alone or together with CEACAM1a ligation via treatment with the CC1 mAb afforded significant macroscopic protection in comparison to the control rat IgG and mouse IgG1–treated group (Fig. 3 b). Microscopic analysis clearly supported a role for both IL-4 and IFN-γ in the pathogenesis of oxazolone colitis and a specific role for CEACAM1a in IFN-γ regulation. Specifically, treatment with the anti–IL-4 mAb with or without the CC1 mAb resulted in less severe histologic features of colitis compared with the control group (Fig. 3 c). However, the greatest protection from histologic injury was provided by a combination of the CC1 and IL-4 mAbs because the mean colitis score of this group was 3.8 in comparison to scores of 5.0 and 11.3 for the anti–IL-4 plus control and control Ab–treated groups, respectively (P < 0.01, anti–IL-4 and CC1 mAb vs. control mAbs; P < 0.05, anti–IL-4 plus mouse IgG1 mAb vs. control mAbs). In addition, anti–IL-4 and CC1 mAb treatment, but not either alone, suppressed the levels of both IFN-γ and IL-4 to baseline levels in the colonic lamina propria in the context of oxazolone colitis (unpublished data). These results confirm that oxazolone colitis is caused by both Th1 and Th2 cytokine pathways such that blockade of both provides optimal protection from clinical evidence of colitis and immunopathology, and that CEACAM1a is specifically linked to Th1 pathways allowing for an enhancement of the protective effect provided by anti–IL-4 mAb treatment.


Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Iijima H, Neurath MF, Nagaishi T, Glickman JN, Nieuwenhuis EE, Nakajima A, Chen D, Fuss IJ, Utku N, Lewicki DN, Becker C, Gallagher TM, Holmes KV, Blumberg RS - J. Exp. Med. (2004)

Effect of anti–IL-4 mAb and CC1 mAb injection on the induction of oxazolone colitis. (a) Body weight of mice treated with anti–IL-4 mAb together with CC1 mAb (♦), anti–IL-4 mAb and control mouse IgG1 (□), or control rat IgG and mouse IgG1 (▴). Prevention of body weight loss was significant (*, P < 0.05; **, P < 0.01) in mice administered anti–IL-4 and CC1 mAb when compared with the control Ab–treated group. Data shown are expressed as mean values ± SEM from six mice per group. Representative macroscopic (b) and microscopic (c; ×100) pictures of mice treated with or without anti–IL-4 and CC1 mAbs are shown.
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Related In: Results  -  Collection

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fig3: Effect of anti–IL-4 mAb and CC1 mAb injection on the induction of oxazolone colitis. (a) Body weight of mice treated with anti–IL-4 mAb together with CC1 mAb (♦), anti–IL-4 mAb and control mouse IgG1 (□), or control rat IgG and mouse IgG1 (▴). Prevention of body weight loss was significant (*, P < 0.05; **, P < 0.01) in mice administered anti–IL-4 and CC1 mAb when compared with the control Ab–treated group. Data shown are expressed as mean values ± SEM from six mice per group. Representative macroscopic (b) and microscopic (c; ×100) pictures of mice treated with or without anti–IL-4 and CC1 mAbs are shown.
Mentions: The studies described above suggested that CEACAM1a ligation specifically impacts upon Th1 but not Th2 pathways in these models. Given that oxazolone colitis represents a mixed Th1/Th2 colitis in C57BL/6 mice as shown above, we examined the effects of administering the CC1 mAb and/or anti–IL-4 mAb to inhibit both Th1 and Th2 pathways, respectively. If oxazolone colitis was indeed due to both Th1 and Th2 cytokines and CEACAM1a was specific for the Th1 pathway, it would be predicted that more complete clinicopathologic protection would be provided by blocking both pathways. Protection as defined by body weight loss was nearly complete when mice received treatment with an anti–IL-4 mAb in combination with the CC1 mAb (Fig. 3 a, ♦) in comparison to either the control Ab–treated (Fig. 3 a, ▴) or anti–IL-4– and control Ab–treated (Fig. 3 a, □) groups. Notably, an essential role for IL-4 in this model was suggested by the fact that blockade of IL-4 either alone or together with CEACAM1a ligation via treatment with the CC1 mAb afforded significant macroscopic protection in comparison to the control rat IgG and mouse IgG1–treated group (Fig. 3 b). Microscopic analysis clearly supported a role for both IL-4 and IFN-γ in the pathogenesis of oxazolone colitis and a specific role for CEACAM1a in IFN-γ regulation. Specifically, treatment with the anti–IL-4 mAb with or without the CC1 mAb resulted in less severe histologic features of colitis compared with the control group (Fig. 3 c). However, the greatest protection from histologic injury was provided by a combination of the CC1 and IL-4 mAbs because the mean colitis score of this group was 3.8 in comparison to scores of 5.0 and 11.3 for the anti–IL-4 plus control and control Ab–treated groups, respectively (P < 0.01, anti–IL-4 and CC1 mAb vs. control mAbs; P < 0.05, anti–IL-4 plus mouse IgG1 mAb vs. control mAbs). In addition, anti–IL-4 and CC1 mAb treatment, but not either alone, suppressed the levels of both IFN-γ and IL-4 to baseline levels in the colonic lamina propria in the context of oxazolone colitis (unpublished data). These results confirm that oxazolone colitis is caused by both Th1 and Th2 cytokine pathways such that blockade of both provides optimal protection from clinical evidence of colitis and immunopathology, and that CEACAM1a is specifically linked to Th1 pathways allowing for an enhancement of the protective effect provided by anti–IL-4 mAb treatment.

Bottom Line: We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo.Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production.These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

ABSTRACT
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus