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
| Autor: | James G. Krueger, Brian V. Jegasothy, Judith R. Abrams, Toyoko Kikuchi, Michael J. Brown, Sewon Kang, Cynthia Guzzo, Elizabeth Hayes, Peter S. Linsley, Susan Kelley, Mark Lebwohl |
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| Rok vydání: | 2000 |
| Předmět: |
Keratinocytes
Integrins Immunoconjugates psoriasis vulgaris Neutrophils T-Lymphocytes T cell Immunology Integrin alphaXbeta2 chemical and pharmacologic phenomena Lymphocyte Activation Abatacept CD28 Antigens Antigens CD Lymphocyte costimulation medicine Humans Psoriasis Immunology and Allergy Cytotoxic T cell CTLA-4 Antigen CTLA4Ig Antigen-presenting cell CD86 CD40 biology CD28 hemic and immune systems Dendritic Cells Flow Cytometry Antigens Differentiation medicine.anatomical_structure Selectins biology.protein Original Article T cell costimulation Endothelium Vascular B7 Immunosuppressive Agents CD80 |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.192.5.681 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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