Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

Balasubramanian Krishnamurthy, Nadine L. Dudek, Mark D. McKenzie, Anthony W. Purcell, Andrew G. Brooks, Shane Gellert, Peter G. Colman, Leonard C. Harrison, Andrew M. Lew, Helen E. Thomas, Thomas W.H. Kay

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166 Citations (Scopus)

Abstract

Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic β cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP.

Original languageEnglish
Pages (from-to)3258-3265
Number of pages8
JournalJournal of Clinical Investigation
Volume116
Issue number12
DOIs
Publication statusPublished - 1 Dec 2006
Externally publishedYes

Cite this

Krishnamurthy, B., Dudek, N. L., McKenzie, M. D., Purcell, A. W., Brooks, A. G., Gellert, S., ... Kay, T. W. H. (2006). Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. Journal of Clinical Investigation, 116(12), 3258-3265. https://doi.org/10.1172/JCI29602
Krishnamurthy, Balasubramanian ; Dudek, Nadine L. ; McKenzie, Mark D. ; Purcell, Anthony W. ; Brooks, Andrew G. ; Gellert, Shane ; Colman, Peter G. ; Harrison, Leonard C. ; Lew, Andrew M. ; Thomas, Helen E. ; Kay, Thomas W.H. / Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 12. pp. 3258-3265.
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abstract = "Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic β cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP.",
author = "Balasubramanian Krishnamurthy and Dudek, {Nadine L.} and McKenzie, {Mark D.} and Purcell, {Anthony W.} and Brooks, {Andrew G.} and Shane Gellert and Colman, {Peter G.} and Harrison, {Leonard C.} and Lew, {Andrew M.} and Thomas, {Helen E.} and Kay, {Thomas W.H.}",
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Krishnamurthy, B, Dudek, NL, McKenzie, MD, Purcell, AW, Brooks, AG, Gellert, S, Colman, PG, Harrison, LC, Lew, AM, Thomas, HE & Kay, TWH 2006, 'Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP', Journal of Clinical Investigation, vol. 116, no. 12, pp. 3258-3265. https://doi.org/10.1172/JCI29602

Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. / Krishnamurthy, Balasubramanian; Dudek, Nadine L.; McKenzie, Mark D.; Purcell, Anthony W.; Brooks, Andrew G.; Gellert, Shane; Colman, Peter G.; Harrison, Leonard C.; Lew, Andrew M.; Thomas, Helen E.; Kay, Thomas W.H.

In: Journal of Clinical Investigation, Vol. 116, No. 12, 01.12.2006, p. 3258-3265.

Research output: Contribution to journalArticleResearchpeer-review

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