Multiple immuno-regulatory defects in type-1 diabetes

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

Research output: Contribution to journalArticle

577 Citations (Scopus)

Abstract

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-γ in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-γ and IL-4 deficiencies in Vα24+ 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.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalJournal of Clinical Investigation
Volume109
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Type 1 Diabetes Mellitus
Natural Killer T-Cells
Autoimmunity
T-Lymphocytes
Inbred NOD Mouse
Ionomycin
T-Lymphocyte Subsets
Tetradecanoylphorbol Acetate
Regulatory T-Lymphocytes
T-Cell Antigen Receptor
Islets of Langerhans
Interleukin-4
Flow Cytometry
Cell Count
Cytokines
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kukreja, A., Cost, G., Marker, J., Zhang, C., Sun, Z., Lin-Su, K., ... Maclaren, N. (2002). Multiple immuno-regulatory defects in type-1 diabetes. Journal of Clinical Investigation, 109(1), 131-140. https://doi.org/10.1172/JCI200213605

Multiple immuno-regulatory defects in type-1 diabetes. / Kukreja, Anjli; Cost, Giulia; Marker, John; Zhang, Chenhui; Sun, Zhong; Lin-Su, Karen; Ten, Svetlana; Sanz, Maureen; Exley, Mark; Wilson, Brian; Porcelli, Steven A.; Maclaren, Noel.

In: Journal of Clinical Investigation, Vol. 109, No. 1, 2002, p. 131-140.

Research output: Contribution to journalArticle

Kukreja, A, Cost, G, Marker, J, Zhang, C, Sun, Z, Lin-Su, K, Ten, S, Sanz, M, Exley, M, Wilson, B, Porcelli, SA & Maclaren, N 2002, 'Multiple immuno-regulatory defects in type-1 diabetes', Journal of Clinical Investigation, vol. 109, no. 1, pp. 131-140. https://doi.org/10.1172/JCI200213605
Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K et al. Multiple immuno-regulatory defects in type-1 diabetes. Journal of Clinical Investigation. 2002;109(1):131-140. https://doi.org/10.1172/JCI200213605
Kukreja, Anjli ; Cost, Giulia ; Marker, John ; Zhang, Chenhui ; Sun, Zhong ; Lin-Su, Karen ; Ten, Svetlana ; Sanz, Maureen ; Exley, Mark ; Wilson, Brian ; Porcelli, Steven A. ; Maclaren, Noel. / Multiple immuno-regulatory defects in type-1 diabetes. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 1. pp. 131-140.
@article{3eab2d1b515d4e33a33e4d6d50ff4fa8,
title = "Multiple immuno-regulatory defects in type-1 diabetes",
abstract = "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-γ in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-γ and IL-4 deficiencies in Vα24+ 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.",
author = "Anjli Kukreja and Giulia Cost and John Marker and Chenhui Zhang and Zhong Sun and Karen Lin-Su and Svetlana Ten and Maureen Sanz and Mark Exley and Brian Wilson and Porcelli, {Steven A.} and Noel Maclaren",
year = "2002",
doi = "10.1172/JCI200213605",
language = "English (US)",
volume = "109",
pages = "131--140",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Multiple immuno-regulatory defects in type-1 diabetes

AU - Kukreja, Anjli

AU - Cost, Giulia

AU - Marker, John

AU - Zhang, Chenhui

AU - Sun, Zhong

AU - Lin-Su, Karen

AU - Ten, Svetlana

AU - Sanz, Maureen

AU - Exley, Mark

AU - Wilson, Brian

AU - Porcelli, Steven A.

AU - Maclaren, Noel

PY - 2002

Y1 - 2002

N2 - 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-γ in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-γ and IL-4 deficiencies in Vα24+ 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.

AB - 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-γ in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-γ and IL-4 deficiencies in Vα24+ 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.

UR - http://www.scopus.com/inward/record.url?scp=0036141438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036141438&partnerID=8YFLogxK

U2 - 10.1172/JCI200213605

DO - 10.1172/JCI200213605

M3 - Article

C2 - 11781358

AN - SCOPUS:0036141438

VL - 109

SP - 131

EP - 140

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -