The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF

Metcalf, Donald; Mifsud, Sandra; Rago, L Di; Robb, Lorraine; Nicola, Nicos A.; Ws, Alexander

doi:10.1038/sj.leu.2400926

Cited by 18 publications

(11 citation statements)

References 14 publications

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“…140 These results supported the theory that the effects of cytokines are mediated exclusively by high-affinity receptors. 140 The phenotypes of cytokine and receptor transgenic/knockout mice are summarized in Table 5.…”

Section: Therapy Directed At Cytokine Gene Expressionsupporting

confidence: 79%

“…140 In these mice which over-expressed the GM-CSF gene, the low-affinity GM-CSF␣ receptor chain did not induce the same tissue pathologies that were induced by the ␤ c chain in GM-CSFtransgenic mice. 140 These results supported the theory that the effects of cytokines are mediated exclusively by high-affinity receptors. 140 The phenotypes of cytokine and receptor transgenic/knockout mice are summarized in Table 5.…”

Section: Therapy Directed At Cytokine Gene Expressionmentioning

confidence: 99%

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1999

Leukemia

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Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

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Section: Therapy Directed At Cytokine Gene Expressionsupporting

confidence: 79%

Section: Therapy Directed At Cytokine Gene Expressionmentioning

confidence: 99%

True

1999

Leukemia

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“…GM-CSF could not be detected in the serum even after repeat administration of the MuStDO 5-mGM-CSF vaccine. This finding may not be surprising given the relatively short half-life of GM-CSF in mice (approximately 21 min), 39 presumably due to its rapid clearance by receptormediated uptake in mice. 40 Thus, due to the short serum half-life of GM-CSF, serum levels of GM-CSF may be a misleading index for the occurrence or nonoccurrence of GM-CSF expression following pDNA administration.…”

Section: Discussionmentioning

confidence: 88%

“…The human GM-CSF pDNA was included in the vaccine to increase the immunogenicity as GM-CSF is known to attract dendritic cells to the site of administration and enhance the maturation of dendritic cell precursors which play an important role in antigen presentation. [19][20][21][22][23][24] While co-administration of GM-CSF pDNA has been demonstrated to enhance the immunogenicity of pDNA vaccines, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] the overexpression of GM-CSF in transgenic mice has been demonstrated to result in adverse pathology associated with overaccumulation of macrophages in tissues, accumulation of macrophages in the peritoneal and pleural cavities, retinal damage, muscle wasting, and a fatal tissue damage syndrome. 37 Thus, the inclusion of GM-CSF in the vaccine raised several important theoretical safety concerns which had to be addressed before the vaccine could be taken into a clinical trial with healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Safety of a GM-CSF adjuvant-plasmid DNA malaria vaccine

Monteith

Horton

et al. 2001

Gene Ther

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MuStDO 5 is a multivalent plasmid DNA vaccine for malaria comprised of five plasmid DNAs encoding five proteins from Plasmodium falciparum and one plasmid DNA encoding human GM-CSF. To evaluate the safety of MuStDO 5, a series of pre-clinical studies were conducted in mice and rabbits. In pharmacology studies in mice, GM-CSF could not be detected in the serum following either intramuscular or a combined intramuscular/intradermal administration of the vaccine, but was readily detected in the muscle following

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“…It has been reported that an overexpression of GM-CSF in the lungs of rats resulted in pulmonary fibrosis (13). Transgenic mice with constitutive overproduction of GM-CSF exhibited damage to several organs, including eye, skeletal muscles and lungs, in which alveolar proteinosis and accumulation of lymphocytes in the peribronchial area were observed (14). In a more recent study with transgenic animals, the GM-CSF gene equipped with the promoter and flanking sequences of the human CRP gene was used (15).…”

Section: Introductionmentioning

confidence: 99%

Properties of bcr-abl-transformed mouse 12B1 cells secreting interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF): II. Adverse effects of GM-CSF

et al. 2012

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Abstract. Granulocyte-macrophage colony stimulating factor (GM-CSF) is considered to be the most effective immunostimulating factor for the construction of gene-engineered anti-cancer vaccines. In some tumour cells, this type of genetic modification has resulted in the loss of the oncogenic potential. This was not the case with bcr-abl-transformed mouse 12B1 cells. A cell line, designated 12B1/GM-CSF/cl-5 producing more than 100 ng/10 6 cells/24 h, displayed higher pathogenicity than the parental, non-transduced cells. Although the tumours induced by the parental 12B1 cells and 12B1/GM-CSF/ cl-5 cells appeared nearly at the same time and then grew at an approximately equal rate, the latter mice were in a much poorer clinical condition. In these animals the growth of the tumours was associated with gradually increasing blood levels of GM-CSF. In both groups of animals splenomegaly was observed; it was much more pronounced in the case of 12B1/ GM-CSF/cl-5-inoculated animals. While in the case of animals inoculated with the parental cells the splenomegaly was probably mainly due to infiltration with tumour cells, in the animals inoculated with the GM-CSF-secreting cells splenomegaly and derangement of parenchymal organs, such as lungs, liver and kidneys, were more complex, including congestion and infiltration with hemopoietic cells, predominantly immature cells of myeloid lineage. The most conspicuous of these changes was the hyperaemia of the lungs. No such alterations were seen in animals inoculated with the parental cells. On the other hand, the contents of T regulatory cells were comparable in both groups and they increased in parallel at the end of the observation period. When GM-CSF neutralizing antibody was administered to animals inoculated with the 12B1/GM-CSF/ cl-5 cells, the pathological changes observed within the organs were suppressed, this proving that the overproduced GM-CSF and not any other substance, played the key role in their induction.

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The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF

Cited by 18 publications

References 14 publications

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Safety of a GM-CSF adjuvant-plasmid DNA malaria vaccine

Properties of bcr-abl-transformed mouse 12B1 cells secreting interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF): II. Adverse effects of GM-CSF

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