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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.

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Related in: MedlinePlus

IL-23-independent induction of Th17 cells in Treg cell-depleted PLP:OVA-pσ1-dosed mice.SJL mice were nasally dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 relative to EAE induction. Mice were i.p. injected with anti-CD25/rat IgG and anti-IL-23p19 rabbit serum (RS) or normal rabbit serum (NRS). Neutralization of IL-23 did not suppress clinical disease in Treg cell-inactivated PLP:OVA-pσ1-dosed mice. Mean of 5 mice per group is shown. * P<0.05 vs. PLP:OVA-pσ1 + anti-CD25-treated mice.
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pone-0008720-g006: IL-23-independent induction of Th17 cells in Treg cell-depleted PLP:OVA-pσ1-dosed mice.SJL mice were nasally dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 relative to EAE induction. Mice were i.p. injected with anti-CD25/rat IgG and anti-IL-23p19 rabbit serum (RS) or normal rabbit serum (NRS). Neutralization of IL-23 did not suppress clinical disease in Treg cell-inactivated PLP:OVA-pσ1-dosed mice. Mean of 5 mice per group is shown. * P<0.05 vs. PLP:OVA-pσ1 + anti-CD25-treated mice.

Mentions: Aside from TGF-β, IL-23 also has been shown to activate Th17 cells [27]–[29]. To determine the necessity of IL-23 for induction of EAE in PLP:OVA-pσ1 + anti-CD25 mAb-treated mice, mice were co-treated with anti-IL-23p19 serum. Neutralization of IL-23 had no effect on clinical onset and severity of EAE (Figure 6).


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)

IL-23-independent induction of Th17 cells in Treg cell-depleted PLP:OVA-pσ1-dosed mice.SJL mice were nasally dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 relative to EAE induction. Mice were i.p. injected with anti-CD25/rat IgG and anti-IL-23p19 rabbit serum (RS) or normal rabbit serum (NRS). Neutralization of IL-23 did not suppress clinical disease in Treg cell-inactivated PLP:OVA-pσ1-dosed mice. Mean of 5 mice per group is shown. * P<0.05 vs. PLP:OVA-pσ1 + anti-CD25-treated mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0008720-g006: IL-23-independent induction of Th17 cells in Treg cell-depleted PLP:OVA-pσ1-dosed mice.SJL mice were nasally dosed with PLP:OVA-pσ1 or PBS on days −14 and −7 relative to EAE induction. Mice were i.p. injected with anti-CD25/rat IgG and anti-IL-23p19 rabbit serum (RS) or normal rabbit serum (NRS). Neutralization of IL-23 did not suppress clinical disease in Treg cell-inactivated PLP:OVA-pσ1-dosed mice. Mean of 5 mice per group is shown. * P<0.05 vs. PLP:OVA-pσ1 + anti-CD25-treated mice.
Mentions: Aside from TGF-β, IL-23 also has been shown to activate Th17 cells [27]–[29]. To determine the necessity of IL-23 for induction of EAE in PLP:OVA-pσ1 + anti-CD25 mAb-treated mice, mice were co-treated with anti-IL-23p19 serum. Neutralization of IL-23 had no effect on clinical onset and severity of EAE (Figure 6).

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