The Journal of Experimental Medicine
Rockland Immunochemicals for Research
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 5 September 2000.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 874K)
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abrams, J. R.
Right arrow Articles by Krueger, J. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abrams, J. R.
Right arrow Articles by Krueger, J. G.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
© The Rockefeller University Press, 0022-1007/2000/9/681/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 681-694

Original Article

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

Judith R. Abramsa, Susan L. Kelleya, Elizabeth Hayesb, Toyoko Kikuchib, Michael J. Browna, Sewon Kangc, Mark G. Lebwohld, Cynthia A. Guzzoe, Brian V. Jegasothyf, Peter S. Linsleyg, and James G. Kruegerb
a Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492
b Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York 10021
c Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109
d Department of Dermatology, Mount Sinai Medical Center, New York, New York 10029
e Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
f Department of Dermatology, University of Pittsburgh Medical Center, Montefiore University Hospital, Pittsburgh, Pennsylvania 15213
g Rosetta Inpharmatics, Kirkland, Washington 98034

Correspondence to: Judith R. Abrams, Novartis Pharmaceuticals Corporation, 59 Route 10, Bldg. 122, Rm. S320, East Hanover, NJ 07936-1080. Tel:973-781-5085 Fax:973-781-6318 E-mail:judith.abrams{at}pharma.novartis.com.

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.

Key Words: psoriasis vulgaris, T cell costimulation, B7, CTLA4Ig, dendritic cells


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS