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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish
Pages (from-to)2762-2775
Number of pages14
JournalEuropean Journal of Immunology
Issue number9
StatePublished - Sep 2005
Externally publishedYes


  • Autoreactive CD4 T cells
  • Homeostasis
  • MHC II-peptide complexes
  • Type 1 diabetes


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