Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

Biondo, Mark; Nasa, Zeyad; Marshall, Aiden C J; Toh, Ban Hock; Alderuccio, Frank

doi:10.4049/jimmunol.166.3.2090

Cited by 71 publications

(47 citation statements)

References 60 publications

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“…Our results demonstrate that GM-CSF expressed within the g -cells of the islets of Langerhans enhanced disease incidence in male NOD mice due to an increase in the availability of islet antigen. Recent studies have shown diverse functions of GM-CSF in the immune system [20,21,27,[32][33][34]. Our results suggest that in ins-GM-CSF mice, this height-ened response is mediated by increased numbers of APC infiltrating the pancreas as well as enhanced expression of B7-1 in CD11b + cells.…”

Section: Discussionmentioning

confidence: 56%

“…Transgenic expression of GM-CSF in the stomach of gastritis-susceptible BALB/cCrSlc mice results in development of autoimmune gastritis. In this latter model, the first stage of disease is associated with proliferation and activation of APC, which leads to migration of pathogenic CD4 + T cells into the gastric mucosa [20]. Recent work by our laboratory showed that the expression of GM-CSF in the pancreas of BALB/c mice greatly enhanced the recruitment and activation of APC within this organ [21].…”

Section: Introductionmentioning

confidence: 99%

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Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

et al. 2004

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is frequently used in preclinical and clinical protocols to modulate autoimmune responses, bone marrow transplants, and recovery from immune ablative therapies. The immunological outcome of such therapies is not fully understood. We tested the hypothesis that GM-CSF would enhance the maturation of antigen-presenting cells, facilitating presentation of g -cell autoantigens to autoreactive T cells. We found that islet expression of GM-CSF greatly enhanced disease in male mice. Islet-derived APC but not splenic APC showed markedly enhanced capacity to stimulate in vitro proliferative responses of islet-antigen-specific autoreactive T cells. In vivo transfer of CD8 + and CD4 + T cells demonstrate that autoreactive T cells undergo extensive division in pancreatic lymph nodes of GM-CSF-transgenic mice compared with wild-type NOD male mice. Together, the results presented here demonstrate that expression of GM-CSF in the pancreas can enhance autoimmunity in disease-susceptible mice.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

et al. 2004

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“…47 The role of GM-CSF in immune regulation, however, is less clear. 48 Transgenic mice in which GM-CSF was expressed in the stomach epithelium developed gastritis, 49 whereas GM-CSF expression in the islets either exacerbated or inhibited diabetes, depending on the genetic background. 50,51 GM-CSF-deficient mice displayed reduced susceptibility to collagen-induced arthritis and experimental allergic encephalomyelitis, which correlated with the induction of weaker autoreactive T-cell responses, but preserved antibody reactions.…”

Section: Discussionmentioning

confidence: 99%

Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

Enzler

Gillessen

Dougan

et al. 2007

Blood

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The pathogenesis of type 1 diabetes (T1D) involves the immune-mediated destruction of insulin-producing ␤ cells in the pancreatic islets of Langerhans. Genetic analysis of families with a high incidence of T1D and nonobese diabetic (NOD) mice, a prototypical model of the disorder, uncovered multiple susceptibility loci, although most of the underlying immune defects remain to be delineated. Here we report that aged mice doubly deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) manifest insulitis, destruction of insulin-producing ␤ cells, and compromised glucose homeostasis. Macrophages from mutant mice produce increased levels of p40 after LPS stimulation, whereas concurrent ablation of interferon-␥ (IFN-␥) ameliorates the disease. The administration of antibodies that block cytotoxic T lymphocyte associated antigen-4 (CTLA-4) to young mutant mice precipitates the onset of insulitis and hyperglycemia. These results, together with previous reports of impaired hematopoietic responses to GM-CSF and IL-3 in patients with T1D and in NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes. IntroductionType 1 diabetes (T1D) is a chronic autoimmune disease in which a loss of tolerance to insulin-producing ␤ cells in the pancreatic islets results in impaired glucose homeostasis. 1 T1D clusters in families and is frequently associated with other autoimmune disorders, suggesting that an underlying genetic susceptibility compromises tolerance to multiple normal tissues. Nonobese diabetic (NOD) mice are widely used as a model for T1D because they display many similar aspects of disease pathogenesis and harbor a general predisposition to autoimmunity, which is modulated by genetic background. 2 In NOD mice, the development of diabetes proceeds from an initial phase of insulitis, characterized by T and B cell infiltrates in the absence of ␤-cell damage, to an aggressive stage in which ␤ cells are destroyed and glucose homeostasis is disrupted.Extensive linkage analysis of families with T1D and NOD mice yielded more than 20 genetic susceptibility loci. 3 Among these, the major histocompatibility (MHC) class II locus exerts the most potent influence on disease development. Several non-MHCrelated genes have also been implicated, including insulin, CTLA-4, IL-2, CD25, the protein tyrosine phosphatase PTPN22, and the membrane transporter NRAMP-1. Nonetheless, multiple additional loci remain to be identified, although characterization of these gene products has been hampered by the large number of immune defects associated with disease and a limited understanding of the key pathogenic mechanisms.Antigen-presenting cells are thought to play an important role in the development of diabetes. 4 Dendritic cells and macrophages contribute to the maintenance of tolerance through central deletion of autoreactive thymocytes and the induction of recessive and dominant modes of suppression in the periphery. 5 Among the phenotypic abnormalities observed in patients ...

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“…GM-CSF treatment in humans has not been implicated in the induction of autoimmune disease, but instead in the activation of pre-existing disease (52)(53)(54). In addition, studies in mouse models performed in genetically susceptible stains have implicated a role for GM-CSF in autoimmune disease severity (55,56). Together these studies argue that GM-CSF alone is insufficient to induce autoimmunity, but that in the presence of pre-existing autoimmune disease or predisposing factors, GM-CSF can aggravate disease symptoms.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Hornell

Beresford

Bushey

et al. 2003

The Journal of Immunology

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GM-CSF stimulates the growth and differentiation of hematopoietic progenitors and also affects mature cell function. These effects have led to the use of GM-CSF as a vaccine adjuvant with promising results; however, the mechanisms underlying GM-CSF-mediated immune potentiation are incompletely understood. In this study, we investigated the hypothesis that the immune stimulatory role of GM-CSF is in part due to effects on class II MHC Ag presentation. We find that, in primary human monocytes treated for 24–48 h, GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40, but not the differentiation marker CD1a or CD16. Furthermore, GM-CSF-treated monocytes are better stimulators in a mixed leukocyte reaction. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOα. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA.

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Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

Cited by 71 publications

References 60 publications

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

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