Insulin2 Gene (Ins2) Transcription by NOD Bone Marrow-derived Cells Does Not Influence Autoimmune Diabetes Development in NOD-Ins2 Knockout Mice

A. Martin-Pagola, A. Pileggi, E. Zahr, F. Vendrame, Ruth Molano, I. Snowhite, Camillo Ricordi, G. S. Eisenbarth, M. Nakayama, Alberto Pugliese

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Insulin is a critical autoantigen for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. About 80% of NOD females and 30-40% of NOD males develop diabetes. However, Insulin2 (Ins2) knockout NOD mice develop autoimmune diabetes with complete penetrance in both sexes, at an earlier age, and have stronger autoimmune responses to insulin. The severe diabetes phenotype observed in NOD-Ins2-/- mice suggests that lack of Ins2 expression in the thymus may compromise immunological tolerance to insulin. Insulin is a prototypical tissue specific antigen (TSA) for which tolerance is dependent on expression in thymus and peripheral lymphoid tissues. TSA are naturally expressed by medullary thymic epithelial cells (mTEC), stromal cells in peripheral lymphoid tissues and bone marrow (BM)-derived cells, mainly CD11c+ dendritic cells. The natural expression of TSA by mTEC and stromal cells has been shown to contribute to self-tolerance. However, it is unclear whether this also applies to BM-derived cells naturally expressing TSA. To address this question, we created BM chimeras and investigated whether reintroducing Ins2 expression solely by NOD BM-derived cells delays diabetes development in NOD-Ins2-/- mice. On follow-up, NOD-Ins2-/- mice receiving Ins2-expressing NOD BM cells developed diabetes at similar rates of those receiving NOD-Ins2-/- BM cells. Diabetes developed in 64% of NOD recipients transplanted with NOD BM and in 47% of NOD mice transplanted with NOD-Ins2-/- BM (P = ns). Thus, NOD-Ins2-/- BM did not worsen diabetes in NOD recipients and Ins2 expression by NOD BM-derived cells did not delay diabetes development in NOD-Ins2-/- mice.

Original languageEnglish
Pages (from-to)439-446
Number of pages8
JournalScandinavian Journal of Immunology
Volume70
Issue number5
DOIs
StatePublished - Nov 1 2009

Fingerprint

Inbred NOD Mouse
Type 1 Diabetes Mellitus
Knockout Mice
Bone Marrow Cells
Genes
Bone Marrow
Insulin
Antigens
Lymphoid Tissue
Stromal Cells
Thymus Gland
Epithelial Cells
Self Tolerance
Penetrance
Autoantigens
Autoimmunity
Dendritic Cells
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Insulin2 Gene (Ins2) Transcription by NOD Bone Marrow-derived Cells Does Not Influence Autoimmune Diabetes Development in NOD-Ins2 Knockout Mice. / Martin-Pagola, A.; Pileggi, A.; Zahr, E.; Vendrame, F.; Molano, Ruth; Snowhite, I.; Ricordi, Camillo; Eisenbarth, G. S.; Nakayama, M.; Pugliese, Alberto.

In: Scandinavian Journal of Immunology, Vol. 70, No. 5, 01.11.2009, p. 439-446.

Research output: Contribution to journalArticle

Martin-Pagola, A. ; Pileggi, A. ; Zahr, E. ; Vendrame, F. ; Molano, Ruth ; Snowhite, I. ; Ricordi, Camillo ; Eisenbarth, G. S. ; Nakayama, M. ; Pugliese, Alberto. / Insulin2 Gene (Ins2) Transcription by NOD Bone Marrow-derived Cells Does Not Influence Autoimmune Diabetes Development in NOD-Ins2 Knockout Mice. In: Scandinavian Journal of Immunology. 2009 ; Vol. 70, No. 5. pp. 439-446.
@article{d2b7967cd79d4d3b83403da90693b731,
title = "Insulin2 Gene (Ins2) Transcription by NOD Bone Marrow-derived Cells Does Not Influence Autoimmune Diabetes Development in NOD-Ins2 Knockout Mice",
abstract = "Insulin is a critical autoantigen for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. About 80{\%} of NOD females and 30-40{\%} of NOD males develop diabetes. However, Insulin2 (Ins2) knockout NOD mice develop autoimmune diabetes with complete penetrance in both sexes, at an earlier age, and have stronger autoimmune responses to insulin. The severe diabetes phenotype observed in NOD-Ins2-/- mice suggests that lack of Ins2 expression in the thymus may compromise immunological tolerance to insulin. Insulin is a prototypical tissue specific antigen (TSA) for which tolerance is dependent on expression in thymus and peripheral lymphoid tissues. TSA are naturally expressed by medullary thymic epithelial cells (mTEC), stromal cells in peripheral lymphoid tissues and bone marrow (BM)-derived cells, mainly CD11c+ dendritic cells. The natural expression of TSA by mTEC and stromal cells has been shown to contribute to self-tolerance. However, it is unclear whether this also applies to BM-derived cells naturally expressing TSA. To address this question, we created BM chimeras and investigated whether reintroducing Ins2 expression solely by NOD BM-derived cells delays diabetes development in NOD-Ins2-/- mice. On follow-up, NOD-Ins2-/- mice receiving Ins2-expressing NOD BM cells developed diabetes at similar rates of those receiving NOD-Ins2-/- BM cells. Diabetes developed in 64{\%} of NOD recipients transplanted with NOD BM and in 47{\%} of NOD mice transplanted with NOD-Ins2-/- BM (P = ns). Thus, NOD-Ins2-/- BM did not worsen diabetes in NOD recipients and Ins2 expression by NOD BM-derived cells did not delay diabetes development in NOD-Ins2-/- mice.",
author = "A. Martin-Pagola and A. Pileggi and E. Zahr and F. Vendrame and Ruth Molano and I. Snowhite and Camillo Ricordi and Eisenbarth, {G. S.} and M. Nakayama and Alberto Pugliese",
year = "2009",
month = "11",
day = "1",
doi = "10.1111/j.1365-3083.2009.02316.x",
language = "English",
volume = "70",
pages = "439--446",
journal = "Scandinavian Journal of Immunology",
issn = "0300-9475",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Insulin2 Gene (Ins2) Transcription by NOD Bone Marrow-derived Cells Does Not Influence Autoimmune Diabetes Development in NOD-Ins2 Knockout Mice

AU - Martin-Pagola, A.

AU - Pileggi, A.

AU - Zahr, E.

AU - Vendrame, F.

AU - Molano, Ruth

AU - Snowhite, I.

AU - Ricordi, Camillo

AU - Eisenbarth, G. S.

AU - Nakayama, M.

AU - Pugliese, Alberto

PY - 2009/11/1

Y1 - 2009/11/1

N2 - Insulin is a critical autoantigen for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. About 80% of NOD females and 30-40% of NOD males develop diabetes. However, Insulin2 (Ins2) knockout NOD mice develop autoimmune diabetes with complete penetrance in both sexes, at an earlier age, and have stronger autoimmune responses to insulin. The severe diabetes phenotype observed in NOD-Ins2-/- mice suggests that lack of Ins2 expression in the thymus may compromise immunological tolerance to insulin. Insulin is a prototypical tissue specific antigen (TSA) for which tolerance is dependent on expression in thymus and peripheral lymphoid tissues. TSA are naturally expressed by medullary thymic epithelial cells (mTEC), stromal cells in peripheral lymphoid tissues and bone marrow (BM)-derived cells, mainly CD11c+ dendritic cells. The natural expression of TSA by mTEC and stromal cells has been shown to contribute to self-tolerance. However, it is unclear whether this also applies to BM-derived cells naturally expressing TSA. To address this question, we created BM chimeras and investigated whether reintroducing Ins2 expression solely by NOD BM-derived cells delays diabetes development in NOD-Ins2-/- mice. On follow-up, NOD-Ins2-/- mice receiving Ins2-expressing NOD BM cells developed diabetes at similar rates of those receiving NOD-Ins2-/- BM cells. Diabetes developed in 64% of NOD recipients transplanted with NOD BM and in 47% of NOD mice transplanted with NOD-Ins2-/- BM (P = ns). Thus, NOD-Ins2-/- BM did not worsen diabetes in NOD recipients and Ins2 expression by NOD BM-derived cells did not delay diabetes development in NOD-Ins2-/- mice.

AB - Insulin is a critical autoantigen for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. About 80% of NOD females and 30-40% of NOD males develop diabetes. However, Insulin2 (Ins2) knockout NOD mice develop autoimmune diabetes with complete penetrance in both sexes, at an earlier age, and have stronger autoimmune responses to insulin. The severe diabetes phenotype observed in NOD-Ins2-/- mice suggests that lack of Ins2 expression in the thymus may compromise immunological tolerance to insulin. Insulin is a prototypical tissue specific antigen (TSA) for which tolerance is dependent on expression in thymus and peripheral lymphoid tissues. TSA are naturally expressed by medullary thymic epithelial cells (mTEC), stromal cells in peripheral lymphoid tissues and bone marrow (BM)-derived cells, mainly CD11c+ dendritic cells. The natural expression of TSA by mTEC and stromal cells has been shown to contribute to self-tolerance. However, it is unclear whether this also applies to BM-derived cells naturally expressing TSA. To address this question, we created BM chimeras and investigated whether reintroducing Ins2 expression solely by NOD BM-derived cells delays diabetes development in NOD-Ins2-/- mice. On follow-up, NOD-Ins2-/- mice receiving Ins2-expressing NOD BM cells developed diabetes at similar rates of those receiving NOD-Ins2-/- BM cells. Diabetes developed in 64% of NOD recipients transplanted with NOD BM and in 47% of NOD mice transplanted with NOD-Ins2-/- BM (P = ns). Thus, NOD-Ins2-/- BM did not worsen diabetes in NOD recipients and Ins2 expression by NOD BM-derived cells did not delay diabetes development in NOD-Ins2-/- mice.

UR - http://www.scopus.com/inward/record.url?scp=70350482147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350482147&partnerID=8YFLogxK

U2 - 10.1111/j.1365-3083.2009.02316.x

DO - 10.1111/j.1365-3083.2009.02316.x

M3 - Article

VL - 70

SP - 439

EP - 446

JO - Scandinavian Journal of Immunology

JF - Scandinavian Journal of Immunology

SN - 0300-9475

IS - 5

ER -