Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide

OBJECTIVE Many patients with long-standing type 1 diabetes have remaining functional beta-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after >= 10 years duration of disease. RESEARCH DESIGN AND METHODS Patients (n = 113; >= 18 years of age) with type 1 diabetes and with disease duration of >= 10 years were recruited at Uppsala University Hospital. Residual beta-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide-positive patients and 12 of the C-peptide-negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells. RESULTS The blood concentration of the cytokine IL-35 was markedly lower in C-peptide-negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35(+) regulatory T cells (Tregs), IL-35+ regulatory B cells, and IL-35-producing CD8(+)Foxp3(+) cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults tob-cells. We found that the proportions of IL-17a(+) cells among the Tregs, CD4(+) T cells, and CD8(+) T cells were lower in the C-peptide-positive patients. CONCLUSIONS Patients with remaining endogenous beta-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.