Multiple immuno-regulatory defects in type-1 diabetes.

نویسندگان

  • Anjli Kukreja
  • Giulia Cost
  • John Marker
  • Chenhui Zhang
  • Zhong Sun
  • Karen Lin-Su
  • Svetlana Ten
  • Maureen Sanz
  • Mark Exley
  • Brian Wilson
  • Steven Porcelli
  • Noel Maclaren
چکیده

Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.

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عنوان ژورنال:
  • The Journal of clinical investigation

دوره 109 1  شماره 

صفحات  -

تاریخ انتشار 2002