Regulatory T cell-associated activity in photopheresis-induced immune tolerance in recent onset type 1 diabetes children.
Extracorporeal photochemotherapy (ECP) has demonstrated immunological effects. The proposed cytotoxic lymphocyte antigen 4 (CTLA-4) involvement, together with forkhead box P3 (FoxP3) and transforming growth factor (TGF)-beta are associated with regulatory T cell activity. The aim of the study was to evaluate the regulatory T cell-associated effect of ECP in recent onset type 1 diabetic (T1D) children. Children (n = 20) with T1D received photopheresis 8-methoxypsoralen + ECP or placebo + shampheresis. Peripheral blood mononuclear cells (PBMC) collected pretreatment (day 1) and post-treatment (day 90) were stimulated with phytohaemagglutinin (PHA) and T1D-associated glutamic acid decarboxylase 65 (GAD(65)) peptide a.a. 247-279. CTLA-4, sCTLA-4, FoxP3 and TGF-beta mRNA transcription was quantified. Photopheresis-treated individuals' relative mRNA expression was generally maintained during the course of the study. Placebo individuals increased in spontaneous CTLA-4 mRNA (P < 0.05) but decreased in expression after stimulation with GAD(65)-peptide (P < 0.05) and PHA (P < 0.05). Spontaneous TGF-beta (P < 0.05) increased whereas PHA- (P < 0.01) and GAD(65)-peptide (P < 0.01)-induced TGF-beta expression decreased in the placebo group, whereas it was maintained in the treated group. Without intervention, expression of CTLA-4 and TGF-beta, stimulated with PHA and GAD(65) peptide, decreased with time, with a parallel reduction of GAD(65)-peptide and PHA-stimulated TGF-beta expression. These parameters were counteracted by ECP. In conclusion, our results indicate that ECP maintains regulatory T cell-associated activity in recent-onset T1D.
Division of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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Jonson
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Pihl
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Nyholm
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Cilio
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Ludvigsson
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Faresjö
D000293:Adolescent; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D015415:Biomarkers; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008297:Male; D017893:Photopheresis; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics
D015703:Antigens, CD; D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005968:Glutamate Decarboxylase