Multiple immuno-regulatory defects in type-1 diabetes.
Kukreja, Anjli 1; Cost, Giulia 1; Marker, John 1; Zhang, Chenhui 1; Sun, Zhong 1; Lin-Su, Karen 1; Ten, Svetlana 1; Sanz, Maureen 1; Exley, Mark 2; Wilson, Brian 3; Porcelli, Steven 4; Maclaren, Noel 1
[Miscellaneous Article] Journal of Clinical Investigation. 109(1):131-140, January 2002.

(Format: HTML)

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.

Copyright (C) 2002 The American Society for Clinical Investigation, Inc.