title: CD4+CD25(int) T cells in inflammatory diseases refractory to treatment with glucocorticoids.
abstract: Up to 30% of patients with autoimmune, allergic, and lymphoproliferative diseases are refractory to glucocorticoid therapy. The present study was undertaken to investigate whether such steroid resistance (SR) is limited to a subpopulation of CD4(+) T cells and, as IL-2 is a putative driver of SR, whether T cell SR is associated with CD25 expression. We show that SR patients have a characteristic subgroup of activated CD4(+) T cells that continue to proliferate despite exposure to high-dose Dexamethasone (Dex), demonstrate that CD4(+)CD25(-) cells are exquisitely sensitive to Dex whereas CD4(+)CD25(int) cells are highly SR, and further find that the combination of an anti-CD25 mAb with Dex enhances suppression of T cell proliferation compared with each agent alone. We therefore conclude that SR is not a general property of all lymphocytes but resides in T cell subpopulations, which are prevalent in SR patients and express intermediary levels of CD25. As a result, we propose a new paradigm for SR disease in which glucocorticoid therapy positively selects SR cells, generating a population of drug-resistant lymphocytes that perpetuate on-going inflammation.
authors.affiliation: Academic Unit of Ophthalmology, Department of Clinical Science at South Bristol, University of Bristol, Bristol, UK.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Lee
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Creed
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Schewitz
authors.forename: Paul V
authors.initials: PV
authors.lastname: Newcomb
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Nicholson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000276:immunology*; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012680:Sensitivity and Specificity; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D003907:Dexamethasone