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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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Expression of keratinocyte proliferation and differentiation markers in ear sections.Immunostaining for keratins was performed on paraffin sections of ear skin of Balb/c females 8–12 weeks of age sensitized and challenged by Oxazolone. Treatments with [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg via i.p. took place 30′ post challenge. Dexamethasone 10 mg/kg sc was used as reference compound. A) Vehicle: important hyperproliferation of keratinocyte layer: K6 is widely expressed and it is found supra-basal, K14 is constitutively expressed. K10 showed an inverse staining compared to K6. B–C) [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg respectively were able to down-modulate K6 and K10 expression and to reduce hyperproliferation in a similar manner. K14 staining showed no changes. D) Dexamethasone 10 mg/kg used as reference compound: clearly no staining is observed. E) Isotype control. In all panels, magnification 20× (scale bar: 16.5 µm).
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pone-0008725-g007: Expression of keratinocyte proliferation and differentiation markers in ear sections.Immunostaining for keratins was performed on paraffin sections of ear skin of Balb/c females 8–12 weeks of age sensitized and challenged by Oxazolone. Treatments with [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg via i.p. took place 30′ post challenge. Dexamethasone 10 mg/kg sc was used as reference compound. A) Vehicle: important hyperproliferation of keratinocyte layer: K6 is widely expressed and it is found supra-basal, K14 is constitutively expressed. K10 showed an inverse staining compared to K6. B–C) [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg respectively were able to down-modulate K6 and K10 expression and to reduce hyperproliferation in a similar manner. K14 staining showed no changes. D) Dexamethasone 10 mg/kg used as reference compound: clearly no staining is observed. E) Isotype control. In all panels, magnification 20× (scale bar: 16.5 µm).

Mentions: A representative picture of the expression of K6, K10 and K14 is depicted in Figure 7. Using an Oxazolone-induced CHS, in the present study, we have investigated on keratinocyte proliferation/differentiation. Fig. 7 panel A shows an important hyperproliferation and differentiation of keratinocytes in the vehicle group. The two antagonists at 0.5 mg/kg were able to down-modulate K6 and K10 expression with a similar potency as shown in Fig. 7 panels B and C. K14 is constitutively express in basal cells and K14 staining showed no changes. No hyperproliferation is observed in ear tissue of animals treated with Dexamethasone (Fig. 7 panel D). Isotype control is shown if Fig. 7 panel E.


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

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

Expression of keratinocyte proliferation and differentiation markers in ear sections.Immunostaining for keratins was performed on paraffin sections of ear skin of Balb/c females 8–12 weeks of age sensitized and challenged by Oxazolone. Treatments with [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg via i.p. took place 30′ post challenge. Dexamethasone 10 mg/kg sc was used as reference compound. A) Vehicle: important hyperproliferation of keratinocyte layer: K6 is widely expressed and it is found supra-basal, K14 is constitutively expressed. K10 showed an inverse staining compared to K6. B–C) [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg respectively were able to down-modulate K6 and K10 expression and to reduce hyperproliferation in a similar manner. K14 staining showed no changes. D) Dexamethasone 10 mg/kg used as reference compound: clearly no staining is observed. E) Isotype control. In all panels, magnification 20× (scale bar: 16.5 µm).
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pone-0008725-g007: Expression of keratinocyte proliferation and differentiation markers in ear sections.Immunostaining for keratins was performed on paraffin sections of ear skin of Balb/c females 8–12 weeks of age sensitized and challenged by Oxazolone. Treatments with [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg via i.p. took place 30′ post challenge. Dexamethasone 10 mg/kg sc was used as reference compound. A) Vehicle: important hyperproliferation of keratinocyte layer: K6 is widely expressed and it is found supra-basal, K14 is constitutively expressed. K10 showed an inverse staining compared to K6. B–C) [44AANA47]-CCL5 and Met-CCL5 0.5 mg/kg respectively were able to down-modulate K6 and K10 expression and to reduce hyperproliferation in a similar manner. K14 staining showed no changes. D) Dexamethasone 10 mg/kg used as reference compound: clearly no staining is observed. E) Isotype control. In all panels, magnification 20× (scale bar: 16.5 µm).
Mentions: A representative picture of the expression of K6, K10 and K14 is depicted in Figure 7. Using an Oxazolone-induced CHS, in the present study, we have investigated on keratinocyte proliferation/differentiation. Fig. 7 panel A shows an important hyperproliferation and differentiation of keratinocytes in the vehicle group. The two antagonists at 0.5 mg/kg were able to down-modulate K6 and K10 expression with a similar potency as shown in Fig. 7 panels B and C. K14 is constitutively express in basal cells and K14 staining showed no changes. No hyperproliferation is observed in ear tissue of animals treated with Dexamethasone (Fig. 7 panel D). Isotype control is shown if Fig. 7 panel E.

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