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CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells.

Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N - J. Exp. Med. (2008)

Bottom Line: The beneficial effect included selection of antigen-specific T cells that were CD4(+)CD25(-)Foxp3(-)IL-10(high), which could adoptively transfer disease resistance, and suppression of Th17 selection.However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig-induced tolerance is IL-10 dependent, IL-10-independent mechanisms may also contribute to their regulatory function.Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell-derived factor 1alpha), redirects the polarization of effector Th1 cells into CD4(+)CD25(-)Foxp3(-)interleukin (IL) 10(high) antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10-deficient mice. Anti-IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4(+)CD25(-)Foxp3(-)IL-10(high), which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig-induced tolerance is IL-10 dependent, IL-10-independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

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Neutralization of CXCL12 during ongoing EAE aggravates ongoing EAE. C57BL/6 female mice (n = 6 per group) were subjected to active induction of MOGp35-55-induced EAE, and at the onset of disease (day 10) were separated into three equally sick groups (n = 6 mice per group). On days 11, 13, 15, and 17 after the induction of disease, mice were injected i.v. either with PBS (open circles), 50 μg/mouse of anti-CXCL12 mAb (closed circles), or control antibody (open squares). An observer blind to the experimental protocol monitored the development and progression of disease. The results of one out of three independent experiments (n = 6 mice per each group) are shown as the mean maximal score ± SE. The arrow indicates the first day of anti-CXCL12 antibody administration.
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fig1: Neutralization of CXCL12 during ongoing EAE aggravates ongoing EAE. C57BL/6 female mice (n = 6 per group) were subjected to active induction of MOGp35-55-induced EAE, and at the onset of disease (day 10) were separated into three equally sick groups (n = 6 mice per group). On days 11, 13, 15, and 17 after the induction of disease, mice were injected i.v. either with PBS (open circles), 50 μg/mouse of anti-CXCL12 mAb (closed circles), or control antibody (open squares). An observer blind to the experimental protocol monitored the development and progression of disease. The results of one out of three independent experiments (n = 6 mice per each group) are shown as the mean maximal score ± SE. The arrow indicates the first day of anti-CXCL12 antibody administration.

Mentions: We first explored the possibility that the endogenously produced CXCL12 participates in the natural regulation of disease. To test this hypothesis, EAE mice were administered with a mAb to CXCL12, or an isotype-matched control IgG, after the onset of disease. Our results (Fig. 1) indicate that these mice, but not those administered with the control antibodies, developed an exacerbated, long-term form of disease (mean maximal score of 3 ± 0.28 vs. 2.166 ± 0.18 in both control groups; P < 0.03). The data shown represent one out of three experiments with very similar observations. These results suggest that CXCL12 may function as an antiinflammatory chemokine in regulating an ongoing disease.


CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells.

Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N - J. Exp. Med. (2008)

Neutralization of CXCL12 during ongoing EAE aggravates ongoing EAE. C57BL/6 female mice (n = 6 per group) were subjected to active induction of MOGp35-55-induced EAE, and at the onset of disease (day 10) were separated into three equally sick groups (n = 6 mice per group). On days 11, 13, 15, and 17 after the induction of disease, mice were injected i.v. either with PBS (open circles), 50 μg/mouse of anti-CXCL12 mAb (closed circles), or control antibody (open squares). An observer blind to the experimental protocol monitored the development and progression of disease. The results of one out of three independent experiments (n = 6 mice per each group) are shown as the mean maximal score ± SE. The arrow indicates the first day of anti-CXCL12 antibody administration.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571938&req=5

fig1: Neutralization of CXCL12 during ongoing EAE aggravates ongoing EAE. C57BL/6 female mice (n = 6 per group) were subjected to active induction of MOGp35-55-induced EAE, and at the onset of disease (day 10) were separated into three equally sick groups (n = 6 mice per group). On days 11, 13, 15, and 17 after the induction of disease, mice were injected i.v. either with PBS (open circles), 50 μg/mouse of anti-CXCL12 mAb (closed circles), or control antibody (open squares). An observer blind to the experimental protocol monitored the development and progression of disease. The results of one out of three independent experiments (n = 6 mice per each group) are shown as the mean maximal score ± SE. The arrow indicates the first day of anti-CXCL12 antibody administration.
Mentions: We first explored the possibility that the endogenously produced CXCL12 participates in the natural regulation of disease. To test this hypothesis, EAE mice were administered with a mAb to CXCL12, or an isotype-matched control IgG, after the onset of disease. Our results (Fig. 1) indicate that these mice, but not those administered with the control antibodies, developed an exacerbated, long-term form of disease (mean maximal score of 3 ± 0.28 vs. 2.166 ± 0.18 in both control groups; P < 0.03). The data shown represent one out of three experiments with very similar observations. These results suggest that CXCL12 may function as an antiinflammatory chemokine in regulating an ongoing disease.

Bottom Line: The beneficial effect included selection of antigen-specific T cells that were CD4(+)CD25(-)Foxp3(-)IL-10(high), which could adoptively transfer disease resistance, and suppression of Th17 selection.However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig-induced tolerance is IL-10 dependent, IL-10-independent mechanisms may also contribute to their regulatory function.Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell-derived factor 1alpha), redirects the polarization of effector Th1 cells into CD4(+)CD25(-)Foxp3(-)interleukin (IL) 10(high) antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10-deficient mice. Anti-IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4(+)CD25(-)Foxp3(-)IL-10(high), which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig-induced tolerance is IL-10 dependent, IL-10-independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

Show MeSH
Related in: MedlinePlus