Limits...
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: Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium.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.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

Diminished immunohistochemical detection of CD40, ICAM-1, HLA-DR, and FXIIIa in psoriatic lesional skin after administration of CTLA4Ig. Keratinocytes within the suprapapillary regions (arrows) and DCs displayed marked upregulation of expression of CD40, ICAM-1 (CD54), and HLA-DR at day 1 (top), which serially decreased at study days 36 (middle) and 78 (bottom). Superficial capillaries in untreated psoriatic lesions also exhibited increased ICAM-1 and CD40 staining (arrowheads; A and D), which was reduced at days 36 (B and E) and 78 (C and F). Phenotypic alterations of lesional DCs stained with mAbs to HLA-DR and FXIIIa are observed at days 36 and 78 after the initial infusion (G–L). Higher magnification views of the boxed regions are shown in the inset areas in G–L, and demonstrate a progressive decrease in the number and length of branching processes radiating from the cell body (dendricity) of the stained cells. Results shown are from serial biopsies of a single lesion in a patient administered CTLA4Ig 25 mg/kg and are representative of the nine patients achieving a 50% or greater improvement in clinical scores. Original magnifications: (A–F) ×400; (G–L) ×200; (G–L, insets) ×800.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2193278&req=5

Figure 3: Diminished immunohistochemical detection of CD40, ICAM-1, HLA-DR, and FXIIIa in psoriatic lesional skin after administration of CTLA4Ig. Keratinocytes within the suprapapillary regions (arrows) and DCs displayed marked upregulation of expression of CD40, ICAM-1 (CD54), and HLA-DR at day 1 (top), which serially decreased at study days 36 (middle) and 78 (bottom). Superficial capillaries in untreated psoriatic lesions also exhibited increased ICAM-1 and CD40 staining (arrowheads; A and D), which was reduced at days 36 (B and E) and 78 (C and F). Phenotypic alterations of lesional DCs stained with mAbs to HLA-DR and FXIIIa are observed at days 36 and 78 after the initial infusion (G–L). Higher magnification views of the boxed regions are shown in the inset areas in G–L, and demonstrate a progressive decrease in the number and length of branching processes radiating from the cell body (dendricity) of the stained cells. Results shown are from serial biopsies of a single lesion in a patient administered CTLA4Ig 25 mg/kg and are representative of the nine patients achieving a 50% or greater improvement in clinical scores. Original magnifications: (A–F) ×400; (G–L) ×200; (G–L, insets) ×800.

Mentions: Keratinocytes, upon activation, are able to express a variety of cell surface proteins that are thought to play an important role in amplifying the cutaneous inflammatory reaction in psoriasis, including the clonal expansion of intralesional T cells 192021222324. Membrane-bound and soluble T cell factors induce these keratinocyte phenotypic alterations 61920. Therefore, a paracrine loop for intralesional T cell activation may be provided by activated lesional keratinocytes. Accordingly, immunohistochemical studies of select keratinocyte accessory molecules were undertaken. At day 1, strong immunostaining with mAbs reactive with CD40 was detected on lesional keratinocytes, particularly in the suprapapillary areas. The CD40 expression on keratinocytes, colocalized with the marked expression of CD54 (intercellular adhesion molecule [ICAM]-1), MHC class II HLA-DR antigens (Fig. 3A, Fig. D, and Fig. G), and the influx of juxtaposed T lymphocytes (Fig. 1A, Fig. D, and Fig. G). At day 78, clinically responding patients displayed weak CD40 reactivity on the basal layer of keratinocytes. CD54 and HLA-DR expression were similarly markedly diminished within the day 78 biopsy specimens (Fig. 3C, Fig. F, and Fig. I). Clinically nonresponding patients did not demonstrate discernible changes in their immunohistology from baseline examination with regard to all serial immunohistochemical studies incorporated in this study.


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)

Diminished immunohistochemical detection of CD40, ICAM-1, HLA-DR, and FXIIIa in psoriatic lesional skin after administration of CTLA4Ig. Keratinocytes within the suprapapillary regions (arrows) and DCs displayed marked upregulation of expression of CD40, ICAM-1 (CD54), and HLA-DR at day 1 (top), which serially decreased at study days 36 (middle) and 78 (bottom). Superficial capillaries in untreated psoriatic lesions also exhibited increased ICAM-1 and CD40 staining (arrowheads; A and D), which was reduced at days 36 (B and E) and 78 (C and F). Phenotypic alterations of lesional DCs stained with mAbs to HLA-DR and FXIIIa are observed at days 36 and 78 after the initial infusion (G–L). Higher magnification views of the boxed regions are shown in the inset areas in G–L, and demonstrate a progressive decrease in the number and length of branching processes radiating from the cell body (dendricity) of the stained cells. Results shown are from serial biopsies of a single lesion in a patient administered CTLA4Ig 25 mg/kg and are representative of the nine patients achieving a 50% or greater improvement in clinical scores. Original magnifications: (A–F) ×400; (G–L) ×200; (G–L, insets) ×800.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193278&req=5

Figure 3: Diminished immunohistochemical detection of CD40, ICAM-1, HLA-DR, and FXIIIa in psoriatic lesional skin after administration of CTLA4Ig. Keratinocytes within the suprapapillary regions (arrows) and DCs displayed marked upregulation of expression of CD40, ICAM-1 (CD54), and HLA-DR at day 1 (top), which serially decreased at study days 36 (middle) and 78 (bottom). Superficial capillaries in untreated psoriatic lesions also exhibited increased ICAM-1 and CD40 staining (arrowheads; A and D), which was reduced at days 36 (B and E) and 78 (C and F). Phenotypic alterations of lesional DCs stained with mAbs to HLA-DR and FXIIIa are observed at days 36 and 78 after the initial infusion (G–L). Higher magnification views of the boxed regions are shown in the inset areas in G–L, and demonstrate a progressive decrease in the number and length of branching processes radiating from the cell body (dendricity) of the stained cells. Results shown are from serial biopsies of a single lesion in a patient administered CTLA4Ig 25 mg/kg and are representative of the nine patients achieving a 50% or greater improvement in clinical scores. Original magnifications: (A–F) ×400; (G–L) ×200; (G–L, insets) ×800.
Mentions: Keratinocytes, upon activation, are able to express a variety of cell surface proteins that are thought to play an important role in amplifying the cutaneous inflammatory reaction in psoriasis, including the clonal expansion of intralesional T cells 192021222324. Membrane-bound and soluble T cell factors induce these keratinocyte phenotypic alterations 61920. Therefore, a paracrine loop for intralesional T cell activation may be provided by activated lesional keratinocytes. Accordingly, immunohistochemical studies of select keratinocyte accessory molecules were undertaken. At day 1, strong immunostaining with mAbs reactive with CD40 was detected on lesional keratinocytes, particularly in the suprapapillary areas. The CD40 expression on keratinocytes, colocalized with the marked expression of CD54 (intercellular adhesion molecule [ICAM]-1), MHC class II HLA-DR antigens (Fig. 3A, Fig. D, and Fig. G), and the influx of juxtaposed T lymphocytes (Fig. 1A, Fig. D, and Fig. G). At day 78, clinically responding patients displayed weak CD40 reactivity on the basal layer of keratinocytes. CD54 and HLA-DR expression were similarly markedly diminished within the day 78 biopsy specimens (Fig. 3C, Fig. F, and Fig. I). Clinically nonresponding patients did not demonstrate discernible changes in their immunohistology from baseline examination with regard to all serial immunohistochemical studies incorporated in this study.

Bottom Line: Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium.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.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