T-Helper Cell–Mediated Islet Inflammation Contributes to β-Cell Dysfunction in Chronic Pancreatitis

Abstract

Objectives 

Beta-cell dysfunction and endocrine insufficiency in chronic pancreatitis (CP) is considered as a late manifestation emanating from fibrosis. To ascertain the role of T-helper cells in β-cell dysfunction, we enumerated circulating T-cell subsets, examined their infiltration into pancreatic islets, and assessed islet functions.

Methods 

Pancreatic tissues and peripheral blood were obtained from CP patients with/without diabetes. T cells were enumerated on flow cytometry and by immunostaining. Islets were assessed for glucose-stimulated insulin release (GSIR) and apoptosis (Annexin V/caspase-3). Islet proteins were probed for insulin gene transcription factor.

Results 

Circulating T-helper type 1 (Th1) cells were higher (P < 0.003) in CP patients with diabetes in comparison with control and CP patients without diabetes. Intra-islet colocalization of Th1 and Th17 cells was evident. In comparison with the controls, 2% ± 0.87% β cells from CP patients without diabetes were apoptotic whereas GSIR was decreased by 60% ± 12%, and 40% ± 9% from CP patients with diabetes were apoptotic, with minimal GSIR (1.42% ± 0.9%) in the remaining 60% viable cells. Western blots of islet proteins revealed an increase in STAT1 (signal transducer and activator of transcription 1) and a decrease in phosphorylated pancreatic duodenal homeobox (Pdx-1).

Conclusions 

T cell–mediated inflammation is associated with β-cell dysfunction during progression of CP.