Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice.

Huffman, J A; Hull, William M.; Dranoff, Glenn; Mulligan, Richard C.; Whitsett, JA

doi:10.1172/jci118461

Cited by 235 publications

(192 citation statements)

References 26 publications

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“…delivery of a rBCG strain secreting detectable levels of GM-CSF in situ augments local immunogenicity and demonstrates significant protection against M. tuberculosis infection. GM-CSF is critical to the differentiation of myeloid cells such as DC and macrophages from haematopoietic stem cell precursors, yet in the lung it has been shown to possess unique functions in the regulation of inflammation and host defense against infectious pathogens, as well as pulmonary surfactant and alveolar cell homeostasis [23][24][25][26]. The pattern of GM-CSF production within the lung, with GM-CSF concentrations diminishing over time (Fig.…”

Section: Discussionmentioning

confidence: 99%

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

et al. 2009

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The rational design of new vaccines engineered to target key components of the host immune response is crucial to aid control of important infectious diseases such as tuberculosis. In this report, we determined whether modifying the function of pulmonary APC could improve protection against infection with Mycobacterium tuberculosis. Targeted delivery to the lung of the cytokine GM‐CSF, expressed by the Mycobacterium bovis BCG vaccine strain, increased pulmonary DC numbers and secretion of the immunoregulatory cytokine IL‐12, compared with parental BCG immunization. This impact on APC number by BCG:GM‐CSF resulted in accelerated priming of antigen‐specific CD4+ T cells in the mediastinal lymph nodes and increased migration of activated CD4+ T cells into the lung. i.n. administration of BCG:GM‐CSF resulted in significantly increased protection against M. tuberculosis infection compared with mice vaccinated with BCG alone. BCG:GM‐CSF exhibited an improved safety profile, as immunodeficient RAG1−/− mice vaccinated i.n. with BCG:GM‐CSF survived significantly longer than control BCG‐vaccinated mice. These data demonstrate that manipulating immune cells in the lung by BCG‐based delivery of GM‐CSF can assist the development of protective mucosal immunity against pulmonary bacterial infection.

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Section: Discussionmentioning

confidence: 99%

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

et al. 2009

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“…11,16,17 The lesions in GM-CSF −/− mice can in fact be corrected by local lung epithelial expression of transgenic GM-CSF. 26 The presence of excess levels of GM-CSF in GM-CSF transgenic ␤c −/− mice had no impact on the occurrence or severity of the lung pathology.…”

Section: Figurementioning

confidence: 95%

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

et al. 1998

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GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common ␤ chain (␤c) of the GM-CSF receptor to produce mice with constitutively elevated GM-CSF levels but no high-affinity GM-CSF receptors. GM-CSF transgenic ␤c ؊/؊ mice had exceptionally elevated serum GM-CSF levels but failed to develop the abnormal peritoneal cell population, eye destruction or tissue lesions characteristic of GM-CSF transgenic ␤c ؉/؉ mice. The alveolar proteinosis of ␤c ؊/؊ mice was not altered in GM-CSF transgenic ␤c ؊/؊ mice. Levels of GM-CSF mRNA in transgenic GM-CSF ␤c ؊/؊ were elevated but lower than in transgenic ␤ ؉/؉ mice and the higher serum GM-CSF levels were traced in part to the longer serum half-life of GM-CSF in ␤c ؊/؊ than in ␤c ؉/؉ mice although urinary loss of GM-CSF was higher in ␤c ؊/؊ than in ؉/؉ mice. The data indicate that the transgenic phenotype was due to stimulation by GM-CSF and not an insertional effect, that low-affinity receptors are not capable of initiating tissue pathology even in the presence of excess GM-CSF levels and that autocrine production of GM-CSF by GM-CSFresponsive cells also fails to induce changes in these cells. The results support current dogma that the action of polypeptide regulators is mediated exclusively by activation of high-affinity membrane receptors.

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“…GM-CSF 2/2 mice were provided by Prof. Jeff Whitsett (Division of Pulmonary Biology, Cincinnati Children's Hospital, Cincinnati, OH) (32). Mice included in experiments were from the offspring of all the strains.…”

Section: Micementioning

confidence: 99%

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Samavedam

Iwata

Müller

et al. 2014

The Journal of Immunology

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GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease.

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Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice.

Cited by 235 publications

References 26 publications

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

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

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

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