Details

Autor(en) / Beteiligte

• Preda, Ioana
• McEvoy, Robert C.
• Lin, Marvin
• Bona, Constantin A.
• Rapaport, Robert
• Brumeanu, Teodor D.
• Casares, Sofia

Titel

Soluble, dimeric HLA DR4‐peptide chimeras: An approach for detection and immunoregulation of human type‐1 diabetes

Ist Teil von

• European Journal of Immunology, 2005-09, Vol.35 (9), p.2762-2775

Ort / Verlag

Weinheim: WILEY‐VCH Verlag

Erscheinungsjahr

2005

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Still there are no effective methods to predict or cure type 1 diabetes (T1D) in humans. Soluble, dimeric MHC class II‐peptide (DEF) chimeras have potential for both early diagnosis and immunospecific therapy. DEF chimeras prevent and reverse diabetes in mice by stimulating antigen‐specific type 1 T regulatory cell (Tr1)‐like cells. We also showed that diabetes could be predicted by changes in the phenotype of autoreactive CD4 T cells in peripheral blood. Herein, we demonstrated that human DEF (HLA‐DR*0401/Fcγ1) chimeras expressing peptides of β‐cell antigens stimulate Tr1‐like cells in blood of patients with T1D, non‐diabetic relatives, and controls. Furthermore, the specific and stable binding of DEF chimeras to cognate TCR and CD4 coreceptor allowed quantification and phenotyping of autoreactive CD4 T cells in non‐stimulated blood by FACS. Our results indicate that (1) autoreactive CD4 T cells to GAD65 autoantigen are commonly present in humans expressing diabetes‐susceptible HLA‐DR*0401 molecules; (2) these autoreactive T cells undergo avidity maturation upon encountering the self antigen early in life; (3) the disease is associated with an imbalance between autoreactive CD4+CD25+ and CD4+CD69+ T cells specific for GAD65. Based on this, we propose a model to explain the kinetics of autoreactive CD4 T cells in blood during the natural history of T1D.