Limits...
IL-28 supplants requirement for T(reg) cells in protein sigma1-mediated protection against murine experimental autoimmune encephalomyelitis (EAE).

Rynda A, Maddaloni M, Ochoa-Repáraz J, Callis G, Pascual DW - PLoS ONE (2010)

Bottom Line: Conventional methods to induce tolerance in humans have met with limited success.To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells.Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.

ABSTRACT
Conventional methods to induce tolerance in humans have met with limited success. Hence, efforts to redirect tolerogen uptake using reovirus adhesin, protein sigma 1 (psigma1), may circumvent these shortcomings based upon the recent finding that when reovirus psigma1 is engineered to deliver chicken ovalbumin (OVA) mucosally, tolerance is obtained, even with a single dose. To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells. IL-10R or IL-4 neutralization reversed protection to EAE conferred by PLP:OVA-psigma1, and adoptive transfer of Ag-specific T(reg) or Th2 cells restored protection against EAE in recipients. Upon assessment of each relative participant, functional inactivation of CD25 impaired PLP:OVA-psigma1's protective capacity, triggering TGF-beta-mediated inflammation; however, concomitant inactivation of TGF-beta and CD25 reestablished PLP:OVA-psigma1-mediated protection by IL-28-producing FoxP3(+)CD25(-)CD4(+) T cells. Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.

Show MeSH

Related in: MedlinePlus

PLP:OVA-pσ1 protects against EAE via IL-10-producing Treg and IL-4-producing Th2 cells.Mice were dosed with PLP:OVA-pσ1, and two weeks later, Treg and CD25−CD4+ Th2 cells were isolated and adoptively transferred to naive recipients. On day 0, mice were induced with EAE and on days −1 and +5 received anti-IL-10R mAb or IgG isotype control Ab. A. In contrast to Treg cells + IgG-treated mice, mice given Treg cells + anti-IL-10R mAb developed clinical EAE. Administration of anti-IL-10R mAb had no effect on the clinical disease in mice adoptively transferred with PLP:OVA-pσ1-derived Th2 cells. * P<0.05 vs. PBS + IgG. B. Mice were sacrificed at the peak of clinical disease, and CD4+ T cells isolated from their LNs were evaluated for production of cytokines by ELISA. Treg cells + anti-IL-10R-treated mice produced significantly more proinflammatory cytokines and less anti-inflammatory cytokines when compared to Treg cells + IgG-treated mice. Mean and SD of 5 mice per group is depicted; * P<0.05 vs. Treg cells + IgG. C. Mice dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 were injected with anti-IL-4 mAb or rat IgG on days −1 and +5. PBS + anti-IL-4-dosed mice developed accelerated and more severe EAE than PBS + IgG-dosed mice. The disease in PLP:OVA-pσ1 + anti-IL-4-dosed mice was less severe than in PBS + IgG-dosed mice, but significantly more severe than in PLP:OVA-pσ1 + IgG-dosed mice. * P<0.05 for PLP:OVA-pσ1 + IgG vs. PBS + IgG or PLP:OVA-pσ1 + anti-IL-4.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2806841&req=5

pone-0008720-g003: PLP:OVA-pσ1 protects against EAE via IL-10-producing Treg and IL-4-producing Th2 cells.Mice were dosed with PLP:OVA-pσ1, and two weeks later, Treg and CD25−CD4+ Th2 cells were isolated and adoptively transferred to naive recipients. On day 0, mice were induced with EAE and on days −1 and +5 received anti-IL-10R mAb or IgG isotype control Ab. A. In contrast to Treg cells + IgG-treated mice, mice given Treg cells + anti-IL-10R mAb developed clinical EAE. Administration of anti-IL-10R mAb had no effect on the clinical disease in mice adoptively transferred with PLP:OVA-pσ1-derived Th2 cells. * P<0.05 vs. PBS + IgG. B. Mice were sacrificed at the peak of clinical disease, and CD4+ T cells isolated from their LNs were evaluated for production of cytokines by ELISA. Treg cells + anti-IL-10R-treated mice produced significantly more proinflammatory cytokines and less anti-inflammatory cytokines when compared to Treg cells + IgG-treated mice. Mean and SD of 5 mice per group is depicted; * P<0.05 vs. Treg cells + IgG. C. Mice dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 were injected with anti-IL-4 mAb or rat IgG on days −1 and +5. PBS + anti-IL-4-dosed mice developed accelerated and more severe EAE than PBS + IgG-dosed mice. The disease in PLP:OVA-pσ1 + anti-IL-4-dosed mice was less severe than in PBS + IgG-dosed mice, but significantly more severe than in PLP:OVA-pσ1 + IgG-dosed mice. * P<0.05 for PLP:OVA-pσ1 + IgG vs. PBS + IgG or PLP:OVA-pσ1 + anti-IL-4.

Mentions: To investigate the relative contribution to protection by these PLP-specific Treg and Th2 cells, naive SJL mice were adoptively transferred with PLP:OVA-pσ1-derived Treg or Th2 cells and treated with anti-IL-10R mAb 1 day prior and 5 days after EAE induction. Adoptive transfer of Ag-specific Treg cells nearly abrogated EAE, whereas, Th2 cells partially ameliorated disease (Figure 3A; Figure S1). Anti-IL-10R mAb treatment had no effect upon PLP:OVA-pσ1-derived Th2 cells to prevent EAE; however, IL-10R blockade in recipients given PLP:OVA-pσ1-derived Treg cells rendered them susceptible to EAE (Figure 3A).


IL-28 supplants requirement for T(reg) cells in protein sigma1-mediated protection against murine experimental autoimmune encephalomyelitis (EAE).

Rynda A, Maddaloni M, Ochoa-Repáraz J, Callis G, Pascual DW - PLoS ONE (2010)

PLP:OVA-pσ1 protects against EAE via IL-10-producing Treg and IL-4-producing Th2 cells.Mice were dosed with PLP:OVA-pσ1, and two weeks later, Treg and CD25−CD4+ Th2 cells were isolated and adoptively transferred to naive recipients. On day 0, mice were induced with EAE and on days −1 and +5 received anti-IL-10R mAb or IgG isotype control Ab. A. In contrast to Treg cells + IgG-treated mice, mice given Treg cells + anti-IL-10R mAb developed clinical EAE. Administration of anti-IL-10R mAb had no effect on the clinical disease in mice adoptively transferred with PLP:OVA-pσ1-derived Th2 cells. * P<0.05 vs. PBS + IgG. B. Mice were sacrificed at the peak of clinical disease, and CD4+ T cells isolated from their LNs were evaluated for production of cytokines by ELISA. Treg cells + anti-IL-10R-treated mice produced significantly more proinflammatory cytokines and less anti-inflammatory cytokines when compared to Treg cells + IgG-treated mice. Mean and SD of 5 mice per group is depicted; * P<0.05 vs. Treg cells + IgG. C. Mice dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 were injected with anti-IL-4 mAb or rat IgG on days −1 and +5. PBS + anti-IL-4-dosed mice developed accelerated and more severe EAE than PBS + IgG-dosed mice. The disease in PLP:OVA-pσ1 + anti-IL-4-dosed mice was less severe than in PBS + IgG-dosed mice, but significantly more severe than in PLP:OVA-pσ1 + IgG-dosed mice. * P<0.05 for PLP:OVA-pσ1 + IgG vs. PBS + IgG or PLP:OVA-pσ1 + anti-IL-4.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2806841&req=5

pone-0008720-g003: PLP:OVA-pσ1 protects against EAE via IL-10-producing Treg and IL-4-producing Th2 cells.Mice were dosed with PLP:OVA-pσ1, and two weeks later, Treg and CD25−CD4+ Th2 cells were isolated and adoptively transferred to naive recipients. On day 0, mice were induced with EAE and on days −1 and +5 received anti-IL-10R mAb or IgG isotype control Ab. A. In contrast to Treg cells + IgG-treated mice, mice given Treg cells + anti-IL-10R mAb developed clinical EAE. Administration of anti-IL-10R mAb had no effect on the clinical disease in mice adoptively transferred with PLP:OVA-pσ1-derived Th2 cells. * P<0.05 vs. PBS + IgG. B. Mice were sacrificed at the peak of clinical disease, and CD4+ T cells isolated from their LNs were evaluated for production of cytokines by ELISA. Treg cells + anti-IL-10R-treated mice produced significantly more proinflammatory cytokines and less anti-inflammatory cytokines when compared to Treg cells + IgG-treated mice. Mean and SD of 5 mice per group is depicted; * P<0.05 vs. Treg cells + IgG. C. Mice dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 were injected with anti-IL-4 mAb or rat IgG on days −1 and +5. PBS + anti-IL-4-dosed mice developed accelerated and more severe EAE than PBS + IgG-dosed mice. The disease in PLP:OVA-pσ1 + anti-IL-4-dosed mice was less severe than in PBS + IgG-dosed mice, but significantly more severe than in PLP:OVA-pσ1 + IgG-dosed mice. * P<0.05 for PLP:OVA-pσ1 + IgG vs. PBS + IgG or PLP:OVA-pσ1 + anti-IL-4.
Mentions: To investigate the relative contribution to protection by these PLP-specific Treg and Th2 cells, naive SJL mice were adoptively transferred with PLP:OVA-pσ1-derived Treg or Th2 cells and treated with anti-IL-10R mAb 1 day prior and 5 days after EAE induction. Adoptive transfer of Ag-specific Treg cells nearly abrogated EAE, whereas, Th2 cells partially ameliorated disease (Figure 3A; Figure S1). Anti-IL-10R mAb treatment had no effect upon PLP:OVA-pσ1-derived Th2 cells to prevent EAE; however, IL-10R blockade in recipients given PLP:OVA-pσ1-derived Treg cells rendered them susceptible to EAE (Figure 3A).

Bottom Line: Conventional methods to induce tolerance in humans have met with limited success.To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells.Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.

ABSTRACT
Conventional methods to induce tolerance in humans have met with limited success. Hence, efforts to redirect tolerogen uptake using reovirus adhesin, protein sigma 1 (psigma1), may circumvent these shortcomings based upon the recent finding that when reovirus psigma1 is engineered to deliver chicken ovalbumin (OVA) mucosally, tolerance is obtained, even with a single dose. To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells. IL-10R or IL-4 neutralization reversed protection to EAE conferred by PLP:OVA-psigma1, and adoptive transfer of Ag-specific T(reg) or Th2 cells restored protection against EAE in recipients. Upon assessment of each relative participant, functional inactivation of CD25 impaired PLP:OVA-psigma1's protective capacity, triggering TGF-beta-mediated inflammation; however, concomitant inactivation of TGF-beta and CD25 reestablished PLP:OVA-psigma1-mediated protection by IL-28-producing FoxP3(+)CD25(-)CD4(+) T cells. Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.

Show MeSH
Related in: MedlinePlus