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Therapeutic efficacy and immunological response of CCL5 antagonists in models of contact skin reaction.

Canavese M, Altruda F, Silengo L - PLoS ONE (2010)

Bottom Line: The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals.In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears.These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. miriamcanavese@yahoo.com

ABSTRACT
Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44)AANA(47)-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

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Evaluation of CD3 infiltrates in ear sections.Immunostaining with CD3 antibody on ear (paraffin sections) of Balb/c females 8–12 weeks of age sensitized and challenged in a Oxazolone-induced CHS. In all panels, magnification 40× (scale bar: 20 µm). A) Vehicle group: the CD3 staining on ear section revealed an important T cells involvement. B) No reduction of T cell infiltrates in ear sections is observed for [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg. C–D) [44AANA47]-CCL5 and Met-CCL5 at 0.5 and 1 mg/kg respectively were able to reduce T cell involvement to similar level as Dexamethasone. E) Dexamethasone 10 mg/kg was used as reference compound: clearly no staining is observed. F) Isotype control.
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pone-0008725-g006: Evaluation of CD3 infiltrates in ear sections.Immunostaining with CD3 antibody on ear (paraffin sections) of Balb/c females 8–12 weeks of age sensitized and challenged in a Oxazolone-induced CHS. In all panels, magnification 40× (scale bar: 20 µm). A) Vehicle group: the CD3 staining on ear section revealed an important T cells involvement. B) No reduction of T cell infiltrates in ear sections is observed for [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg. C–D) [44AANA47]-CCL5 and Met-CCL5 at 0.5 and 1 mg/kg respectively were able to reduce T cell involvement to similar level as Dexamethasone. E) Dexamethasone 10 mg/kg was used as reference compound: clearly no staining is observed. F) Isotype control.

Mentions: Figure 6 is representing CD3 infiltrates in ear sections in a Oxazolone-induced CHS. The staining of the vehicle group revealed an important involvement of T cells (Fig. 6a). [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg (Fig. 6b) were not able to reduce T cell recruitment. Both variants at 0.5 and 1 mg/kg reduced T-cells infiltrates to similar level as Dexamethasone (Fig. 6c/d). The staining revealed no presence of T cells in ear tissue of animals treated with Dexamethasone 10 mg/kg (Fig. 6e). Isotype control is shown in Fig. 6f.


Therapeutic efficacy and immunological response of CCL5 antagonists in models of contact skin reaction.

Canavese M, Altruda F, Silengo L - PLoS ONE (2010)

Evaluation of CD3 infiltrates in ear sections.Immunostaining with CD3 antibody on ear (paraffin sections) of Balb/c females 8–12 weeks of age sensitized and challenged in a Oxazolone-induced CHS. In all panels, magnification 40× (scale bar: 20 µm). A) Vehicle group: the CD3 staining on ear section revealed an important T cells involvement. B) No reduction of T cell infiltrates in ear sections is observed for [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg. C–D) [44AANA47]-CCL5 and Met-CCL5 at 0.5 and 1 mg/kg respectively were able to reduce T cell involvement to similar level as Dexamethasone. E) Dexamethasone 10 mg/kg was used as reference compound: clearly no staining is observed. F) Isotype control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2806914&req=5

pone-0008725-g006: Evaluation of CD3 infiltrates in ear sections.Immunostaining with CD3 antibody on ear (paraffin sections) of Balb/c females 8–12 weeks of age sensitized and challenged in a Oxazolone-induced CHS. In all panels, magnification 40× (scale bar: 20 µm). A) Vehicle group: the CD3 staining on ear section revealed an important T cells involvement. B) No reduction of T cell infiltrates in ear sections is observed for [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg. C–D) [44AANA47]-CCL5 and Met-CCL5 at 0.5 and 1 mg/kg respectively were able to reduce T cell involvement to similar level as Dexamethasone. E) Dexamethasone 10 mg/kg was used as reference compound: clearly no staining is observed. F) Isotype control.
Mentions: Figure 6 is representing CD3 infiltrates in ear sections in a Oxazolone-induced CHS. The staining of the vehicle group revealed an important involvement of T cells (Fig. 6a). [44AANA47]-CCL5 and Met-CCL5 at 0.05 mg/kg (Fig. 6b) were not able to reduce T cell recruitment. Both variants at 0.5 and 1 mg/kg reduced T-cells infiltrates to similar level as Dexamethasone (Fig. 6c/d). The staining revealed no presence of T cells in ear tissue of animals treated with Dexamethasone 10 mg/kg (Fig. 6e). Isotype control is shown in Fig. 6f.

Bottom Line: The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals.In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears.These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. miriamcanavese@yahoo.com

ABSTRACT
Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44)AANA(47)-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

Show MeSH
Related in: MedlinePlus