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Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

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Related in: MedlinePlus

Intranasal delivery of E-selectin reduces swelling in a delayed type hypersensitivity reaction.9 week old mice underwent one round (consisting of five intranasal administrations every other day) of 10 µl PBS containing either 5 µg OVA (white bars) or E-selectin (black bars). After sensitization and subsequent challenge with E-selectin, responses to E-selectin were significantly reduced in animals previously receiving E-selectin versus those receiving OVA intranasally (P = 0.007). Swelling was not significantly different in the ears challenged only with PBS between the two treatment groups. N = 5 mice per group, error bars represent SEM.
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pone-0020620-g002: Intranasal delivery of E-selectin reduces swelling in a delayed type hypersensitivity reaction.9 week old mice underwent one round (consisting of five intranasal administrations every other day) of 10 µl PBS containing either 5 µg OVA (white bars) or E-selectin (black bars). After sensitization and subsequent challenge with E-selectin, responses to E-selectin were significantly reduced in animals previously receiving E-selectin versus those receiving OVA intranasally (P = 0.007). Swelling was not significantly different in the ears challenged only with PBS between the two treatment groups. N = 5 mice per group, error bars represent SEM.

Mentions: Previous work from our laboratory demonstrated E-selectin tolerization significantly limits Th1 mediated DTH reactions mounted in rats following sensitization and challenge with human E-selectin [23], [27], [28]. Comparisons to both PBS and OVA- tolerized animals highlighted the specificity of the response to E-selectin. After testing a range (0.1 to 10 µg) of tolerizing doses with a similar regimen in a C57BL/6 mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE; Jacqueline A. Quandt, unpublished data, 2010), the 5 µg dose was found to be most effective at limiting clinical disease and was selected for the current study. In C57BL/6 mice, 5 µg of E-selectin given intranasally significantly reduced ear swelling, a response which was highly specific to E-selectin (Figure 2) with negligible reductions in OVA-tolerized mice. Intranasal E-selectin reduced swelling by more than 50% compared to OVA tolerized animals (P = 0.007) with no significant differences observed in PBS-sensitized ears. Delivery of E-selectin alone to the ear pad did not elicit swelling beyond that measured for PBS in animals naive to E-selectin (data not shown).


Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice.

Li X, Johnson KR, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA - PLoS ONE (2011)

Intranasal delivery of E-selectin reduces swelling in a delayed type hypersensitivity reaction.9 week old mice underwent one round (consisting of five intranasal administrations every other day) of 10 µl PBS containing either 5 µg OVA (white bars) or E-selectin (black bars). After sensitization and subsequent challenge with E-selectin, responses to E-selectin were significantly reduced in animals previously receiving E-selectin versus those receiving OVA intranasally (P = 0.007). Swelling was not significantly different in the ears challenged only with PBS between the two treatment groups. N = 5 mice per group, error bars represent SEM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3119064&req=5

pone-0020620-g002: Intranasal delivery of E-selectin reduces swelling in a delayed type hypersensitivity reaction.9 week old mice underwent one round (consisting of five intranasal administrations every other day) of 10 µl PBS containing either 5 µg OVA (white bars) or E-selectin (black bars). After sensitization and subsequent challenge with E-selectin, responses to E-selectin were significantly reduced in animals previously receiving E-selectin versus those receiving OVA intranasally (P = 0.007). Swelling was not significantly different in the ears challenged only with PBS between the two treatment groups. N = 5 mice per group, error bars represent SEM.
Mentions: Previous work from our laboratory demonstrated E-selectin tolerization significantly limits Th1 mediated DTH reactions mounted in rats following sensitization and challenge with human E-selectin [23], [27], [28]. Comparisons to both PBS and OVA- tolerized animals highlighted the specificity of the response to E-selectin. After testing a range (0.1 to 10 µg) of tolerizing doses with a similar regimen in a C57BL/6 mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE; Jacqueline A. Quandt, unpublished data, 2010), the 5 µg dose was found to be most effective at limiting clinical disease and was selected for the current study. In C57BL/6 mice, 5 µg of E-selectin given intranasally significantly reduced ear swelling, a response which was highly specific to E-selectin (Figure 2) with negligible reductions in OVA-tolerized mice. Intranasal E-selectin reduced swelling by more than 50% compared to OVA tolerized animals (P = 0.007) with no significant differences observed in PBS-sensitized ears. Delivery of E-selectin alone to the ear pad did not elicit swelling beyond that measured for PBS in animals naive to E-selectin (data not shown).

Bottom Line: A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin.This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes.Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke.

Show MeSH
Related in: MedlinePlus