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PMID: 11781358 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Multiple immuno-regulatory defects in type-1 diabetes.

The Journal of clinical investigation ·Vol. 109 ·No. 1 ·2002-01-00 ·Pages 131-40

Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, Porcelli S, Maclaren N

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-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.

MeSH Terms
Adolescent Adult Animals Antigens, CD1/genetics Antigens, CD1d Base Sequence CD4-Positive T-Lymphocytes/immunology Case-Control Studies Child Diabetes Mellitus, Type 1/genetics,immunology Diabetes Mellitus, Type 2/genetics,immunology Female Humans Interferon-gamma/biosynthesis Killer Cells, Natural/immunology Lymphocyte Subsets/immunology Male Mice Mice, Inbred NOD Middle Aged RNA, Messenger/genetics,metabolism Receptors, Antigen, T-Cell, alpha-beta/genetics Receptors, Interleukin-2/metabolism
Chemicals
Antigens, CD1 Antigens, CD1d CD1D protein, human RNA, Messenger Receptors, Antigen, T-Cell, alpha-beta Receptors, Interleukin-2 Interferon-gamma
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kukreja Anjli
Department of Pediatrics, Weill College of Medicine of Cornell University, New York, New York, USA.
Cost Giulia
Marker John
Zhang Chenhui
Sun Zhong
Lin-Su Karen
Ten Svetlana
Sanz Maureen
Exley Mark
Wilson Brian
Porcelli Steven
Maclaren Noel
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI13605
Published
2002-01-00
Pages
131-40
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC150819
Subset
IM
Grants
NCRR NIH HHS · M01-RR06020 · United States
External Links
PubMed source DOI: 10.1172/JCI13605 PMC Full Text View journal details
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