Bone marrow abnormalities in the non-obese diabetic mouse

Langmuir, Peter; Bridgett, Margot M.; Bothwell, Alfred L.M.

doi:10.1093/intimm/5.2.169

Cited by 52 publications

(35 citation statements)

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“…In contrast, the red blood cell count was increased in diabetic children when compared to controls (Table 1). Our study complements previous reports suggesting decreased lymphocyte number (lymphopenia) in patients with autoimmune diseases [30], and decreased lymphocytes, myeloid cells and DC but not erythromyeloid cells in nOD mice before the onset of insulitis [31,32].…”

Section: Proportions Of T N T CM T Em T Emra and T Reg Cells Arsupporting

confidence: 91%

Type 1 Diabetic Children and Siblings Share a Decrease in Dendritic Cell and Monocyte Numbers but are Differentiated by Expansion of CD4+T Cells Expressing IL-17

Wilkinson¹,

Bian²,

Khalil³

et al. 2011

J Clin Cell Immunol

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Type 1 diabetes (T1D) is an autoimmune disease characterised by multiple defects of immune cells which allow the expansion of pathogenic β cell-specific T effector cells and subsequent T1D development. We performed immunomonitoring assays on blood immune cells in T1D children, their siblings and controls with the supposition that the results would elucidate the sequence of abnormalities in peripheral immune cells leading to the progression of autoimmunity from non-diabetic siblings to diabetic children. We assessed myeloid dendritic cell (MDC), plasmacytoid (P)DC, monocyte, CD4 + monocytes that may result from shared genetic or environmental factors. However, this reduction of blood immune cells requires combination with the proinflammatory cytokine IL-17 to allow disease expression in diabetic children.

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Section: Proportions Of T N T CM T Em T Emra and T Reg Cells Arsupporting

confidence: 91%

Type 1 Diabetic Children and Siblings Share a Decrease in Dendritic Cell and Monocyte Numbers but are Differentiated by Expansion of CD4+T Cells Expressing IL-17

Wilkinson¹,

Bian²,

Khalil³

et al. 2011

J Clin Cell Immunol

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“…With regard to the intrinsic defects in BM DC precursors, a deficient up-regulation of the GM-CSF receptor or an abnormal downstream signaling from the receptor are good candidates for the abnormal cell maturation and increased cell death in culture, particularly in view of the defective response of NOD myeloid precursors to GM-CSF and IL-5, which share the signaling chain of the receptor (34). However, we show that aberrant myeloid DC also develop when Flt3-L is used as the stimulator, signaling through a different receptor.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Precursors of Nonobese Diabetic Mice Develop into Defective Macrophage-Like Dendritic Cells In Vitro

Nikolić

Bunk

Drexhage

et al. 2004

The Journal of Immunology

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The NOD mouse spontaneously develops autoimmune diabetes. Dendritic cells (DC) play a crucial role in the autoimmune response. Previous studies have reported a defective DC generation in vitro from the NOD mouse bone marrow (BM), but a deviated development of myeloid precursors into non-DC in response to GM-CSF was not considered. In this study, we demonstrate several abnormalities during myeloid differentiation of NOD BM precursors using GM-CSF in vitro. 1) We found reduced proliferation and increased cell death in NOD cultures, which explain the previously reported low yield of DC progeny in NOD. Cell yield in NOR cultures was normal. 2) In a detailed analysis GM-CSF-stimulated cultures, we observed in both NOD and NOR mice an increased frequency of macrophages, identified as CD11c+/MHCII− cells with typical macrophage morphology, phenotype, and acid phosphatase activity. This points to a preferential maturation of BM precursors into macrophages in mice with the NOD background. 3) The few CD11c+/MHCIIhigh cells that we obtained from NOD and NOR cultures, which resembled prototypic mature DC, appeared to be defective in stimulating allogeneic T cells. These DC had also strong acid phosphatase activity and elevated expression of monocyte/macrophage markers. In conclusion, in this study we describe a deviated development of myeloid BM precursors of NOD and NOR mice into macrophages and macrophage-like DC in vitro. Potentially, these anomalies contribute to the dysfunctional regulation of tolerance in NOD mice yet are insufficient to induce autoimmune diabetes because they occurred partly in NOR mice.

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“…nsulin-dependent or type 1 diabetes (T1D) 3 results from autoimmune destruction of insulin-secreting ␤ cells in the pancreatic islets of Langerhans. The nature of immune dysregulation leading to ␤ cell destruction remains poorly understood.…”

mentioning

confidence: 99%

“…The nature of immune dysregulation leading to ␤ cell destruction remains poorly understood. However, phenotypic and functional abnormalities of dendritic cells (DC) and myeloid-lineage development have previously been identified in humans at risk for or with T1D (1, 2), as well as in the most widely used animal model of T1D, the nonobese diabetic (NOD) mouse (3,4).…”

mentioning

confidence: 99%

Increased Generation of Dendritic Cells from Myeloid Progenitors in Autoimmune-Prone Nonobese Diabetic Mice

Steptoe

Ritchie

Harrison

2002

The Journal of Immunology

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Aberrant dendritic cell (DC) development and function may contribute to autoimmune disease susceptibility. To address this hypothesis at the level of myeloid lineage-derived DC we compared the development of DC from bone marrow progenitors in vitro and DC populations in vivo in autoimmune diabetes-prone nonobese diabetic (NOD) mice, recombinant congenic nonobese diabetes-resistant (NOR) mice, and unrelated BALB/c and C57BL/6 (BL/6) mice. In GM-CSF/IL-4-supplemented bone marrow cultures, DC developed in significantly greater numbers from NOD than from NOR, BALB/c, and BL/6 mice. Likewise, DC developed in greater numbers from sorted (lineage−IL-7Rα−SCA-1−c-kit+) NOD myeloid progenitors in either GM-CSF/IL-4 or GM-CSF/stem cell factor (SCF)/TNF-α. [3H]TdR incorporation indicated that the increased generation of NOD DC was due to higher levels of myeloid progenitor proliferation. Generation of DC with the early-acting hematopoietic growth factor, flt3 ligand, revealed that while the increased DC-generative capacity of myeloid-committed progenitors was restricted to NOD cells, early lineage-uncommitted progenitors from both NOD and NOR had increased DC-generative capacity relative to BALB/c and BL/6. Consistent with these findings, NOD and NOR mice had increased numbers of DC in blood and thymus and NOD had an increased proportion of the putative myeloid DC (CD11c+CD11b+) subset within spleen. These findings demonstrate that diabetes-prone NOD mice exhibit a myeloid lineage-specific increase in DC generative capacity relative to diabetes-resistant recombinant congenic NOR mice. We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice.

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Bone marrow abnormalities in the non-obese diabetic mouse

Cited by 52 publications

References 0 publications

Type 1 Diabetic Children and Siblings Share a Decrease in Dendritic Cell and Monocyte Numbers but are Differentiated by Expansion of CD4+T Cells Expressing IL-17

Type 1 Diabetic Children and Siblings Share a Decrease in Dendritic Cell and Monocyte Numbers but are Differentiated by Expansion of CD4+T Cells Expressing IL-17

Bone Marrow Precursors of Nonobese Diabetic Mice Develop into Defective Macrophage-Like Dendritic Cells In Vitro

Increased Generation of Dendritic Cells from Myeloid Progenitors in Autoimmune-Prone Nonobese Diabetic Mice

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