title: APL-1, an altered peptide ligand derived from human heat-shock protein 60, selectively induces apoptosis in activated CD4+ CD25+ T cells from peripheral blood of rheumatoid arthritis patients.
abstract: Rheumatoid arthritis (RA) is a chronic T-cell mediated autoimmune disease that affects primarily the joints. The induction of immune tolerance through antigen-specific therapies for the blockade of pathogenic CD4+ T cells constitutes a current focus of research. In this focus it is attempted to simultaneously activate multiple regulatory mechanisms, such as: apoptosis and regulatory T cells (Tregs). APL-1 is an altered peptide ligand derived from a novel CD4+ T-cell epitope of human heat-shock protein of 60kDa, an autoantigen involved in the pathogenesis of RA. Previously, we have reported that APL-1 induces CD4+ CD25(high)Foxp3+ Tregs in several systems. Here, we investigated the ability of APL-1 in inducing apoptosis in PBMCs from RA patients, who were classified as active or inactive according to their DAS28 score. APL-1 decreased the viability of PBMCs from active but not from inactive patients. DNA fragmentation assays and typical morphological features clearly demonstrated that APL-1 induced apoptosis in these cells. Activated CD4+ CD25+ T cells but not resting CD4+ CD25- T cells were identified as targets of APL-1. Furthermore, CD4+ T-cell responses to APL-1 were found to be dependent on antigen presentation via the HLA-DR molecule. Thus, APL-1 is a regulatory CD4+ T cell epitope which might modulate inflammatory immune responses in PBMCs from RA patients by inducing CD4+ CD25(high)Foxp3+ Tregs and apoptosis in activated CD4+ T cells. These results support further investigation of this candidate drug for the treatment of RA.
authors.affiliation: Biomedical Research Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Havana 11300, Cuba. Electronic address: ariana.barbera@cigb.edu.cu.
authors.forename: Ariana
authors.initials: A
authors.lastname: Barberá
authors.forename: Noraylis
authors.initials: N
authors.lastname: Lorenzo
authors.forename: Greta
authors.initials: G
authors.lastname: Garrido
authors.forename: Yuliet
authors.initials: Y
authors.lastname: Mazola
authors.forename: Viviana
authors.initials: V
authors.lastname: Falcón
authors.forename: Ana María
authors.initials: AM
authors.lastname: Torres
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Hernández
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Hernández
authors.forename: Bram
authors.initials: B
authors.lastname: Margry
authors.forename: A Marit
authors.initials: AM
authors.lastname: de Groot
authors.forename: Joel
authors.initials: J
authors.lastname: van Roon
authors.forename: Ruurd
authors.initials: R
authors.lastname: van der Zee
authors.forename: Femke
authors.initials: F
authors.lastname: Broere
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.forename: Gabriel
authors.initials: G
authors.lastname: Padrón
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Domínguez
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000276:immunology / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008024:Ligands; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: C000591158:APL-1 peptide; D000893:Anti-Inflammatory Agents; D018834:Chaperonin 60; C060293:HSPD1 protein, human; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D010455:Peptides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: APL; Altered peptide ligands; Epitope-specific immunotherapy; HSP60; Heat shock protein 60; RA; Rheumatoid arthritis; T helper; TLR; Th; Tregs; altered peptide ligand; heat shock protein of 60kDa; regulatory T cells; rheumatoid arthritis; toll like receptors