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Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.

Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG - J. Exp. Med. (2000)

Bottom Line: Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies.Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs.Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. judith.abrams@pharma.novartis.com

ABSTRACT
Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

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Changes in psoriatic lesional T cell numbers and keratinocyte hyperplasia across the 11 patients accrued to the CTLA4Ig 25 and 50 mg/kg dose groups. (A) Mean percent decrease in values for epidermal thickness (black squares) and numbers of T cells within the epidermis (red diamonds) or dermis (blue circles) compared with baseline (day 1) are illustrated over the first 78 d of the study period. Asterisks indicate statistical significance (*P < 0.05; **P < 0.001). P values were based on a two-sided t test for no change at the indicated study day compared with day 1. (B) Correlation plots of the percent change in infiltrating epidermal or dermal T cells versus percent change in epidermal thickness for each patient at all sampling time points. Individual data points are an average derived from triplicate analyses. Epidermal thickness was calculated by quantitating the cross-sectional surface area beneath a 1-mm linear region of a representative histological section using computer-assisted image analysis. Positive correlations between the change in T (CD3+) cell numbers and epidermal thickness were evident (epidermal CD3+: r = 0.73; dermal CD3+: r = 0.61). Discordant responses characterized by reductions in epidermal thickness that were not accompanied by similar reductions in T cell numbers within a specific compartment are indicated (open red squares).
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Figure 2: Changes in psoriatic lesional T cell numbers and keratinocyte hyperplasia across the 11 patients accrued to the CTLA4Ig 25 and 50 mg/kg dose groups. (A) Mean percent decrease in values for epidermal thickness (black squares) and numbers of T cells within the epidermis (red diamonds) or dermis (blue circles) compared with baseline (day 1) are illustrated over the first 78 d of the study period. Asterisks indicate statistical significance (*P < 0.05; **P < 0.001). P values were based on a two-sided t test for no change at the indicated study day compared with day 1. (B) Correlation plots of the percent change in infiltrating epidermal or dermal T cells versus percent change in epidermal thickness for each patient at all sampling time points. Individual data points are an average derived from triplicate analyses. Epidermal thickness was calculated by quantitating the cross-sectional surface area beneath a 1-mm linear region of a representative histological section using computer-assisted image analysis. Positive correlations between the change in T (CD3+) cell numbers and epidermal thickness were evident (epidermal CD3+: r = 0.73; dermal CD3+: r = 0.61). Discordant responses characterized by reductions in epidermal thickness that were not accompanied by similar reductions in T cell numbers within a specific compartment are indicated (open red squares).

Mentions: Soluble factors released from activated T lymphocytes are believed to contribute to the hyperproliferation of keratinocytes within psoriatic lesions 67. Therefore, intralesional T lymphocyte counts were correlated with epidermal thickness in serial lesional biopsies obtained from patients accrued to the 25 and 50 mg/kg dose groups. Peak reductions in intralesional T lymphocytes were observed at day 78 with an 88% mean decrease in the epidermal compartment (P < 0.001) and a 73% mean reduction in the dermal compartment compared with baseline examination (P < 0.001) (Fig. 2 A). A statistically meaningful decline in epidermal thickness was observed as early as day 8 (19% reduction; P = 0.016); at day 78, a 56% mean percent reduction from baseline epidermal thickness was observed (P < 0.001). The decrease in lesional epidermal T lymphocytes correlated most closely with the observed reductions in epidermal thickness (r = 0.73). Individual patient correlation plots for each of the four biopsies obtained after the day 1 infusion are illustrated in Fig. 2 B.


Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.

Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG - J. Exp. Med. (2000)

Changes in psoriatic lesional T cell numbers and keratinocyte hyperplasia across the 11 patients accrued to the CTLA4Ig 25 and 50 mg/kg dose groups. (A) Mean percent decrease in values for epidermal thickness (black squares) and numbers of T cells within the epidermis (red diamonds) or dermis (blue circles) compared with baseline (day 1) are illustrated over the first 78 d of the study period. Asterisks indicate statistical significance (*P < 0.05; **P < 0.001). P values were based on a two-sided t test for no change at the indicated study day compared with day 1. (B) Correlation plots of the percent change in infiltrating epidermal or dermal T cells versus percent change in epidermal thickness for each patient at all sampling time points. Individual data points are an average derived from triplicate analyses. Epidermal thickness was calculated by quantitating the cross-sectional surface area beneath a 1-mm linear region of a representative histological section using computer-assisted image analysis. Positive correlations between the change in T (CD3+) cell numbers and epidermal thickness were evident (epidermal CD3+: r = 0.73; dermal CD3+: r = 0.61). Discordant responses characterized by reductions in epidermal thickness that were not accompanied by similar reductions in T cell numbers within a specific compartment are indicated (open red squares).
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Related In: Results  -  Collection

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Figure 2: Changes in psoriatic lesional T cell numbers and keratinocyte hyperplasia across the 11 patients accrued to the CTLA4Ig 25 and 50 mg/kg dose groups. (A) Mean percent decrease in values for epidermal thickness (black squares) and numbers of T cells within the epidermis (red diamonds) or dermis (blue circles) compared with baseline (day 1) are illustrated over the first 78 d of the study period. Asterisks indicate statistical significance (*P < 0.05; **P < 0.001). P values were based on a two-sided t test for no change at the indicated study day compared with day 1. (B) Correlation plots of the percent change in infiltrating epidermal or dermal T cells versus percent change in epidermal thickness for each patient at all sampling time points. Individual data points are an average derived from triplicate analyses. Epidermal thickness was calculated by quantitating the cross-sectional surface area beneath a 1-mm linear region of a representative histological section using computer-assisted image analysis. Positive correlations between the change in T (CD3+) cell numbers and epidermal thickness were evident (epidermal CD3+: r = 0.73; dermal CD3+: r = 0.61). Discordant responses characterized by reductions in epidermal thickness that were not accompanied by similar reductions in T cell numbers within a specific compartment are indicated (open red squares).
Mentions: Soluble factors released from activated T lymphocytes are believed to contribute to the hyperproliferation of keratinocytes within psoriatic lesions 67. Therefore, intralesional T lymphocyte counts were correlated with epidermal thickness in serial lesional biopsies obtained from patients accrued to the 25 and 50 mg/kg dose groups. Peak reductions in intralesional T lymphocytes were observed at day 78 with an 88% mean decrease in the epidermal compartment (P < 0.001) and a 73% mean reduction in the dermal compartment compared with baseline examination (P < 0.001) (Fig. 2 A). A statistically meaningful decline in epidermal thickness was observed as early as day 8 (19% reduction; P = 0.016); at day 78, a 56% mean percent reduction from baseline epidermal thickness was observed (P < 0.001). The decrease in lesional epidermal T lymphocytes correlated most closely with the observed reductions in epidermal thickness (r = 0.73). Individual patient correlation plots for each of the four biopsies obtained after the day 1 infusion are illustrated in Fig. 2 B.

Bottom Line: Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies.Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs.Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. judith.abrams@pharma.novartis.com

ABSTRACT
Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

Show MeSH
Related in: MedlinePlus