DOI: 10.1084/jem.192.5.681. 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 [Penn]

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

10.1084/jem.192.5.681

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

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.

Bibliography

Abrams, J. R., Kelley, S. L., Hayes, E., Kikuchi, T., Brown, M. J., Kang, S., Lebwohl, M. G., Guzzo, C. A., Jegasothy, B. V., Linsley, P. S., & Krueger, J. G. (2000). Blockade of T Lymphocyte Costimulation with Cytotoxic T LymphocyteâAssociated Antigen 4âImmunoglobulin (Ctla4ig) Reverses the Cellular Pathology of Psoriatic Plaques, Including the Activation of Keratinocytes, Dendritic Cells, and Endothelial Cells. The Journal of Experimental Medicine, 192(5), 681â694.

Authors 11

Judith R. Abrams (first)
Susan L. Kelley (additional)
Elizabeth Hayes (additional)
Toyoko Kikuchi (additional)
Michael J. Brown (additional)
Sewon Kang (additional)
Mark G. Lebwohl (additional)
Cynthia A. Guzzo (additional)
Brian V. Jegasothy (additional)
Peter S. Linsley (additional)
James G. Krueger (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:48 p.m.)
Deposited	2 years, 1 month ago (July 25, 2023, 6:38 a.m.)
Indexed	3 weeks, 4 days ago (Aug. 2, 2025, 12:12 a.m.)
Issued	24 years, 11 months ago (Sept. 5, 2000)
Published	24 years, 11 months ago (Sept. 5, 2000)
Published Online	24 years, 11 months ago (Sept. 5, 2000)
Published Print	24 years, 11 months ago (Sept. 5, 2000)

Funders 0

None

BibTeX

@article{Abrams_2000, title={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}, volume={192}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.192.5.681}, DOI={10.1084/jem.192.5.681}, number={5}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Abrams, Judith R. and Kelley, Susan L. and Hayes, Elizabeth and Kikuchi, Toyoko and Brown, Michael J. and Kang, Sewon and Lebwohl, Mark G. and Guzzo, Cynthia A. and Jegasothy, Brian V. and Linsley, Peter S. and Krueger, James G.}, year={2000}, month=sep, pages={681–694} }

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  "abstract": "<jats:p>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\u2013associated 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\u2013lysosomal-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.</jats:p>",
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