Mechanism Underlying Counterregulation of Autoimmune Diabetes by IL-4

Mueller, Régula; Bradley, Linda M.; Krahl, Troy; Sarvetnick, Nora

doi:10.1016/s1074-7613(00)80362-3

Cited by 98 publications

(59 citation statements)

References 29 publications

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“…NOD͞BDC2.5 mice bear rearranged genes for the TCR-␣(V␣1) and TCR-␤ (V␤4) chains (13). In our colony, NOD͞ BDC2.5 mice do not develop spontaneous diabetes but maintain a large number of resting islet-specific memory T cells (16,17). The diminished incidence of diabetes in the NOD͞BDC2.5 background is consistent with the 10-20% rate seen in published studies (13,16).…”

Section: Pancreata In Cd1 ؊/؊ Mice Harbor Higher Proportions Of the Asupporting

confidence: 88%

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

Shi

Flodström

Balasa

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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159

106

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Quantitative and qualitative defects in CD1-restricted natural killer T cells have been reported in several autoimmune-prone strains of mice, including the nonobese diabetic (NOD) mouse. These defects are believed to be associated with the emergence of spontaneous autoimmunity. Here we demonstrate that both CD1d-null NOD and CD1d-null NOD͞BDC2.5 T cell receptor transgenic mice have an accelerated onset and increased incidence of diabetes when compared with CD1d ؉/؊ and CD1d ؉/؉ littermates. The acceleration of disease did not seem to result from changes in the T helper (Th)1͞Th2 balance because lymphocytes purified from lymphoid organs and pancreatic islets of wild-type and CD1d-null mice secreted equivalent amounts of IFN-␥ and IL-4 after stimulation. In contrast, the pancreata of CD1d-null mice harbored significantly higher numbers of activated memory T cells expressing the chemokine receptor CCR4. Notably, the presence of these T cells was associated with immunohistochemical evidence of increased destructive insulitis. Thus, CD1d-restricted T cells are critically important for regulation of the spontaneous disease process in NOD mice.

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Section: Pancreata In Cd1 ؊/؊ Mice Harbor Higher Proportions Of the Asupporting

confidence: 88%

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

Shi

Flodström

Balasa

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

159

106

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“…It was then suggested by the authors that T cell diversity and expansion of what they defined "nonpathogenic" specificities were required for the counterregulating effect of diabetes induced by IL-4 (31). This conclusion was in support of the hypothesis that locally delivered IL-4 did not act directly on diabetogenic effectors, but rather indirectly through a distinct target cell type (31).…”

Section: Discussionsupporting

confidence: 80%

“…well in keeping with the data showing that, at variance with conventional NOD, ␤ cell overexpression of IL-4 does not protect BDC2.5 TCR transgenic NOD mice from diabetes (31). It was then suggested by the authors that T cell diversity and expansion of what they defined "nonpathogenic" specificities were required for the counterregulating effect of diabetes induced by IL-4 (31).…”

Section: Discussionsupporting

confidence: 67%

The Activity of Immunoregulatory T Cells Mediating Active Tolerance Is Potentiated in Nonobese Diabetic Mice by an IL-4-Based Retroviral Gene Therapy

Yamamoto

Chernajovsky

Lepault

et al. 2001

The Journal of Immunology

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Splenocytes from nonobese diabetic mice overexpressing murine IL (mIL)-4 upon recombinant retrovirus infection lose their capacity to transfer diabetes to nonobese diabetic-scid recipients. Diabetes appeared in 0–20% of mice injected with mIL-4-transduced cells vs 80–100% of controls injected with β-galactosidase-transduced cells. Protected mice showed a majority of islets (60%) presenting with noninvasive peri-insulitis at variance with β-galactosidase controls that exhibited invasive/destructive insulitis. Importantly, in all recipients, the transduced proteins were detected within islet infiltrates. Infiltrating lymphocytes from recipients of mIL-4-transduced cells produced high levels of mIL-4, as assessed by ELISA. In recipients of β-galactosidase-transduced cells, ∼60% of TCRαβ+ islet-infiltrating cells expressed β-galactosidase, as assessed by flow cytometry. The protection from disease transfer is due to a direct effect of mIL-4 gene therapy on immunoregulatory T cells rather than on diabetogenic cells. mIL-4-transduced purified CD62L− effector cells or transgenic BDC2.5 diabetogenic T cells still transferred disease efficiently. Conversely, mIL-4 transduction up-regulated the capacity of purified immunoregulatory CD62L+ cells to inhibit disease transfer. These data open new perspectives for gene therapy in insulin-dependent diabetes using T cells devoid of any intrinsic diabetogenic potential.

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“…Several mechanisms of action have been suggested in the past [6,7,35] for the effect of DC and/or IL-4 in NOD mice. We opted for a different approach, using microarray analysis, to get a broader picture of the impact of DC/IL-4 treatment on gene expression in targeted tissues.…”

Section: Dc/il-4 Treatment Normalizes Gene Expression In the Plnmentioning

confidence: 99%

“…IL-4 may be important in the maintenance of a protective Th2 response [5], but it has also been implicated in the stimulation of a broader T cell repertoire composed of non-pathogenic cells [6] and in differential expression of B7.1 and B7.2 molecules by DCs, affecting the quality of CTL responses [7]. Systemic administration of IL-4 appeared to alleviate a form of unresponsiveness among NOD thymocytes and peripheral T cells, which correlated with disease protection [8].…”

Section: Introductionmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

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A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

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Mechanism Underlying Counterregulation of Autoimmune Diabetes by IL-4

Cited by 98 publications

References 29 publications

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

The Activity of Immunoregulatory T Cells Mediating Active Tolerance Is Potentiated in Nonobese Diabetic Mice by an IL-4-Based Retroviral Gene Therapy

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

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