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B-Cell Gene Therapy for Tolerance Induction: Host but Not Donor B-Cell Derived IL-10 is Necessary for Tolerance.

Su Y, Zhang AH, Noben-Trauth N, Scott DW - Front Microbiol (2011)

Bottom Line: We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model.Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients.Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naïve or primed B cells with an antigen-immunoglobulin G (peptide-IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy.

No MeSH data available.


Related in: MedlinePlus

IL-10 produced by the host is required for tolerance induction by transgenic tolerogenic B cells. One × 107 B LPS-activated mOVA or wt B cells were injected into wt C57BL/6 mice. Tolerance induction protocol, anti-IL-10R treatment, and assay method are same as described in Figures 1 and 3 (n = 4). Data are representative of two independent experiments.
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Figure 4: IL-10 produced by the host is required for tolerance induction by transgenic tolerogenic B cells. One × 107 B LPS-activated mOVA or wt B cells were injected into wt C57BL/6 mice. Tolerance induction protocol, anti-IL-10R treatment, and assay method are same as described in Figures 1 and 3 (n = 4). Data are representative of two independent experiments.

Mentions: To confirm these results, we used another model in which mOVA transgenic B cells were used as APCs. We have found that both resting and LPS-activated mOVA B cells are tolerogenic in vivo (Su et al., in preparation). In this study, we first transferred LPS-activated mOVA B cells to wt mice and challenged these recipients 1 week later. The recipients were treated with anti-IL-10R or control mAb four times on day −3, 0, 7, and 14. We assayed T-cell and antibody responses on day 21. Again, the tolerogenicity of mOVA B cells was abrogated by in vivo IL-10R blockade (Figure 4). Together, our data in both systems suggest that host IL-10 production is required for genetic engineered B-cell mediated tolerance induction.


B-Cell Gene Therapy for Tolerance Induction: Host but Not Donor B-Cell Derived IL-10 is Necessary for Tolerance.

Su Y, Zhang AH, Noben-Trauth N, Scott DW - Front Microbiol (2011)

IL-10 produced by the host is required for tolerance induction by transgenic tolerogenic B cells. One × 107 B LPS-activated mOVA or wt B cells were injected into wt C57BL/6 mice. Tolerance induction protocol, anti-IL-10R treatment, and assay method are same as described in Figures 1 and 3 (n = 4). Data are representative of two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3139928&req=5

Figure 4: IL-10 produced by the host is required for tolerance induction by transgenic tolerogenic B cells. One × 107 B LPS-activated mOVA or wt B cells were injected into wt C57BL/6 mice. Tolerance induction protocol, anti-IL-10R treatment, and assay method are same as described in Figures 1 and 3 (n = 4). Data are representative of two independent experiments.
Mentions: To confirm these results, we used another model in which mOVA transgenic B cells were used as APCs. We have found that both resting and LPS-activated mOVA B cells are tolerogenic in vivo (Su et al., in preparation). In this study, we first transferred LPS-activated mOVA B cells to wt mice and challenged these recipients 1 week later. The recipients were treated with anti-IL-10R or control mAb four times on day −3, 0, 7, and 14. We assayed T-cell and antibody responses on day 21. Again, the tolerogenicity of mOVA B cells was abrogated by in vivo IL-10R blockade (Figure 4). Together, our data in both systems suggest that host IL-10 production is required for genetic engineered B-cell mediated tolerance induction.

Bottom Line: We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model.Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients.Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naïve or primed B cells with an antigen-immunoglobulin G (peptide-IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy.

No MeSH data available.


Related in: MedlinePlus