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1.
J Virol ; 86(7): 3422-35, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22258241

ABSTRACT

The success of helper-dependent adenoviral (HD-Ad) vector-mediated lung gene therapy is hampered by the host immune response, which limits pulmonary transgene expression following multiple rounds of vector readminstration. Here, we show that HD-Ad-mediated pulmonary gene expression is sustained even upon three rounds of readministration to immunodeficient mice, highlighting the need to suppress the adaptive immune response for sustained gene expression following vector readministration. Therefore, we devised a dendritic cell (DC)-based strategy for induction of immunological tolerance toward HD-Ad vectors. DCs derived in the presence of interleukin-10 (IL-10) are refractory to HD-Ad-induced maturation and instead facilitate generation of IL-10-producing Tr1 regulatory T cells which suppress HD-Ad-induced T cell proliferation. Delivery of HD-Ad-pulsed, IL-10-modified DCs to mice induces long-lasting immunological tolerance to HD-Ad vectors, whereby pulmonary DC maturation, the T cell response, and antibody response to HD-Ad vectors are suppressed even after three rounds of pulmonary HD-Ad readministration. Moreover, sustained transgene expression is also observed in the lungs of mice immunized with HD-Ad-pulsed, IL-10-modified DCs even after three rounds of pulmonary HD-Ad delivery. Taken together, these studies identify the use of DCs generated in the presence of IL-10 as a novel strategy to induce long-lasting immune tolerance to HD-Ad vectors.


Subject(s)
Adenoviridae Infections/immunology , Adenoviridae/immunology , Dendritic Cells/immunology , Genetic Vectors/immunology , Immune Tolerance , Immunologic Techniques/methods , Adenoviridae/genetics , Adenoviridae Infections/virology , Animals , Cells, Cultured , Genetic Therapy/instrumentation , Genetic Vectors/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/immunology , Humans , Interleukin-10/immunology , Lung/immunology , Lung/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal
2.
Lab Invest ; 92(3): 320-30, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22157719

ABSTRACT

The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epithelium-specific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases.


Subject(s)
DNA-Binding Proteins/physiology , Epithelium/physiopathology , Proto-Oncogene Proteins/physiology , Transcription Factors/physiology , Adenocarcinoma/metabolism , Animals , Breast Neoplasms/metabolism , Carcinoma, Large Cell/metabolism , Cell Differentiation , Embryonic Development , Female , Humans , Intestines/cytology , Intestines/embryology , Lung/immunology , Lung Neoplasms/metabolism , Mammary Glands, Human/growth & development , Mammary Glands, Human/metabolism , Mice , Proto-Oncogene Proteins c-ets , Regeneration
3.
J Immunol ; 187(9): 4639-53, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21948981

ABSTRACT

Elf3 belongs to the Ets family of transcription factors and has been implicated in inflammation. Elf3 is highly expressed in the lungs, and Elf3(-/-) mice are impaired in IL-6 production after intranasal LPS exposure. To identify the role of Elf3 in Th17-driven pulmonary inflammation, we have performed epicutaneous sensitization of Elf3(-/-) mice with OVA followed by airway OVA challenge and have identified Elf3(-/-) mice to be impaired in induction of Th17 response, attributable to impairment of IL-6 production by dendritic cells (DCs). However, increased serum levels of OVA-specific IgG1 and IgE were observed, pointing toward an exaggerated Th2 response. To study Th2 response, we performed i.p. sensitization of Elf3(-/-) mice with OVA and confirmed loss of Elf3 to result in an aggravated Th2 response, characterized by increased generation of IL-4-producing T cells, increased levels of OVA-specific IgE and IgG1 Ab titers, and increased serum levels of Th2 cytokines, together with extensive inflammation and mucus production in airways. Elf3(-/-) DCs were impaired in priming Th1 differentiation, which, in turn, promoted Th2 differentiation. This was mediated by the ability of Elf3(-/-) DCs to undergo hypermaturation but secrete significantly lower levels of IL-12 in response to inflammatory stimuli. The impairment of IL-12 production was due to impairment of IL-12p40 gene induction in Elf3(-/-) DCs in response to inflammatory stimuli. Taken together, our study identifies a novel function of Elf3 in regulating allergic airway inflammation by regulating DC-driven Th1, Th2, and Th17 differentiation.


Subject(s)
Cell Differentiation/immunology , DNA-Binding Proteins/physiology , Dendritic Cells/immunology , Dendritic Cells/pathology , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Transcription Factors/physiology , Administration, Intranasal , Animals , Cell Differentiation/genetics , Cells, Cultured , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Dendritic Cells/metabolism , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-12/antagonists & inhibitors , Interleukin-12/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/administration & dosage , Ovalbumin/immunology , Respiratory Hypersensitivity/genetics , T-Lymphocyte Subsets/metabolism , Th1 Cells/immunology , Th1 Cells/pathology , Th2 Cells/immunology , Th2 Cells/pathology , Transcription Factors/deficiency , Transcription Factors/genetics
4.
Lab Invest ; 91(10): 1514-29, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21709667

ABSTRACT

E74-like transcription factor-3 (Elf3), a member of the E26 transformation-specific transcription factor family, is strongly expressed in epithelial-rich tissues, such as small intestine, fetal lung, and various lung cancers. Although previous studies have shown a defect in terminal differentiation of the small intestinal epithelium of Elf3-deficient (Elf3-/-) mice during embryonic development, very little is known about the role Elf3 may play in repair of the airway epithelium after injury. In order to investigate whether Elf3 is involved in regeneration of the bronchiolar epithelium after Clara cell-specific injury, we administered naphthalene to both wild-type (Elf3+/+) and Elf3-/- mice. Histopathological analysis revealed no significant difference in the extent of naphthalene-induced Clara cell necrosis between Elf3+/+ mice and Elf3-/- mice. In the bronchiolar epithelium of Elf3-/- mice, there was a substantial delay in the kinetics of cell proliferation and mitosis along with Clara cell renewal, whereas in the peribronchiolar interstitium, there was a significantly greater level of cell proliferation and mitosis in Elf3-/- mice than in Elf3+/+ mice. Last, the intensity of immunopositive signal for transforming growth factor-ß type II receptor, which is a well-known transcriptional target gene of Elf3 and involved in the induction of epithelial cell differentiation, was significantly lower in the bronchiolar epithelium of Elf3-/- mice when compared with Elf3+/+ mice. Taken together, our results suggest that Elf3 plays an important role in the regulation of lung cell proliferation and differentiation during repair of the injured bronchiolar airway epithelium.


Subject(s)
Bronchioles/physiopathology , DNA-Binding Proteins/metabolism , Respiratory Mucosa/physiopathology , Respiratory Tract Diseases/physiopathology , Transcription Factors/metabolism , Wound Healing , Animals , Bronchioles/pathology , Cell Differentiation , Cell Proliferation , DNA-Binding Proteins/deficiency , Epithelial Cells , Female , Fluorescent Antibody Technique , Kinetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitosis , Naphthalenes , Necrosis , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Regeneration , Respiratory Mucosa/pathology , Respiratory Tract Diseases/chemically induced , Transcription Factors/deficiency
5.
Eur J Immunol ; 40(4): 1022-35, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20101618

ABSTRACT

DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-beta1, which induced differentiation of naïve T cells into Foxp3(+) Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3(+) Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.


Subject(s)
Apoptosis , Dendritic Cells/immunology , Forkhead Transcription Factors/analysis , Immune Tolerance/immunology , Phagocytosis/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , B7-2 Antigen/biosynthesis , B7-2 Antigen/genetics , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Dendritic Cells/radiation effects , Interleukin-12/biosynthesis , Interleukin-12/genetics , Intracellular Signaling Peptides and Proteins/physiology , Lipopolysaccharides/pharmacology , Lymphopoiesis , Mice , Mice, Inbred C57BL , Necrosis , Protein Biosynthesis , Protein Serine-Threonine Kinases/physiology , Spleen/cytology , Spleen/immunology , T-Lymphocytes, Regulatory/cytology , TOR Serine-Threonine Kinases , Transforming Growth Factor beta1/metabolism
6.
J Immunol ; 183(11): 7104-18, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19917707

ABSTRACT

Dendritic cell (DC) apoptosis has been shown to play a role in maintaining a balance between tolerance and immunity. However, the mechanisms of how DC apoptosis affects the immune response are unclear. We have shown that in vitro culture of apoptotic DCs with immature DCs, results in their uptake by immature DCs, which subsequently turn into tolerogenic DCs, which then secrete TGF-beta1 and induce Foxp3(+) regulatory T cells (T(regs)). In this study we looked at the effects of apoptotic DCs in vivo. Here we show that apoptotic DCs are taken up by viable DCs in vivo, which suppresses the ability of viable DCs to undergo maturation and subsequent migration to the lymph nodes in response to LPS. Additionally, delivery of apoptotic DCs to LPS inflamed lungs results in resolution of inflammation, which is mediated by the ability of apoptotic DCs to suppress response of viable DCs to LPS. Additionally, apoptotic DCs also induce TGF-beta1 secretion in the mediastinal lymph nodes, which results in expansion of Foxp3(+) T(regs). Most importantly, we show that delivery of apoptotic DCs followed by OVA in CFA to mice suppresses T cell response to OVA and instead induces de novo generation of OVA-specific T(regs). Furthermore, delivery of apoptotic DCs followed by OVA in CFA results in expansion of T(regs) in TCR transgenic (OT-II) mice. These findings demonstrate that apoptotic DCs are taken up by viable DCs in vivo, which promotes tolerance through suppression of DC maturation and induction of T(regs).


Subject(s)
Apoptosis/immunology , Dendritic Cells/immunology , Immune Tolerance/immunology , Lymphocyte Activation/immunology , T-Lymphocytes, Regulatory/immunology , Adjuvants, Immunologic/pharmacology , Animals , Cell Differentiation/immunology , Dendritic Cells/cytology , Enzyme-Linked Immunosorbent Assay , Mice , Mice, Inbred C57BL , Mice, Transgenic , Ovalbumin/immunology , Ovalbumin/pharmacology , Transforming Growth Factor beta1/biosynthesis , Transforming Growth Factor beta1/immunology
7.
Toxicol Appl Pharmacol ; 210(3): 190-9, 2006 Feb 01.
Article in English | MEDLINE | ID: mdl-15979673

ABSTRACT

A previous study (Oliver, J.R., Mara, T.W., Cherian, M.G. 2005. Impaired hepatic regeneration in metallothionein-I/II knockout mice after partial hepatectomy. Exp. Biol. Med. 230, 61-67) has shown an impairment of liver regeneration following partial hepatectomy (PH) in metallothionein (MT)-I and MT-II gene knockout (MT-null) mice, thus suggesting a requirement for MT in cellular growth. The present study was undertaken to investigate whether MT may play a similar role in hepatic injury and regeneration after acute treatment with thioacetamide (TAA). Hepatotoxicity of TAA is caused by the generation of oxidative stress. TAA was injected ip to both wild-type (WT) and MT-null mice. Mice were killed at 6, 12, 24, 48, 60, and 72 h after injection of TAA (125 mg/kg) or 48 h after injection of saline (vehicle control), and different parameters of hepatic injury were measured. The levels of hepatic lipid peroxidation were increased at 12 h in both types of mice; however, lipid peroxidation was significantly less in WT mice than MT-null mice at 48 h after injection of TAA. Analysis of hepatic glutathione (GSH) levels after TAA injection showed depletion of GSH at 12 h in WT mice and at 6 h in MT-null mice; however, significantly more GSH was depleted early (6-24 h) in MT-null mice than WT mice. An increase in hepatic iron (Fe) levels was observed in both types of mice after injection of TAA, but Fe levels were significantly higher in MT-null mice than WT mice at 6-60 h. The levels of hepatic copper (Cu) and zinc (Zn) were significantly higher in WT mice than MT-null mice at 6-60 h for Cu, and at 24 h and 60 h for Zn, respectively. Histopathological examination showed hemorrhagic necrosis in the liver of both types of mice at 12-72 h, with hepatic injury being more prominent in MT-null mice than WT mice. The hepatic MT levels were increased in WT mice after injection of TAA, and were highest at 24-72 h. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24-72 h after TAA injection. Cell proliferation, as assessed by immunohistochemical staining for proliferating cell nuclear antigen, was detected mainly in the livers of WT mice at 48-72 h after TAA treatment. Hepatic proliferation index in MT-null mice was very low as compared to WT mice during liver regeneration after injection of TAA. These results show that the liver cells of MT-null mice with no functional MT are unable to regenerate after TAA-induced hepatic injury, demonstrating an important role for MT in cellular regeneration.


Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Liver Regeneration , Metallothionein/metabolism , Thioacetamide/toxicity , Acute Disease , Animals , Cell Proliferation , Glutathione/metabolism , Iron/metabolism , Lipid Peroxidation , Liver/metabolism , Liver/pathology , Metallothionein/genetics , Mice , Mice, Knockout , Necrosis
8.
Exp Biol Med (Maywood) ; 230(1): 61-7, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15618127

ABSTRACT

Although the translocation of metallothionein (MT) from cytoplasm to nucleus has been demonstrated in liver during times of high requirement for zinc (fetal development and the neonatal period), the role of MT in cellular growth is not well understood. In this study, a potential role of MT in liver regeneration was investigated in wild type (WT) and MT-I and MT-II gene knockout (MT-null) mice after 35% partial hepatectomy (PH) or sham laparotomy. Hepatic MT levels and proliferation index were measured at 0, 5, 15, 24, 36, 48, and 60 hrs after PH and 48 hrs after sham laparotomy (control). MT levels were increased in WT mice (peak at 24 hrs after PH) and declined to normal levels by 60 hrs after PH. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24 hrs after PH, whereas MT was present mainly in the cytoplasm at 36-60 hrs after PH and 48 hrs after sham laparotomy. Hepatic proliferation index in both WT and MT-null mice, as determined by argyrophilic nucleolar organizing region staining and proliferating cell nuclear antigen immunohistochemical staining, reached a peak at 48 hrs and declined by 60 hrs after PH. Cell proliferation was significantly less in MT-null mice as compared to WT mice during liver regeneration after PH. These results suggest that MT may play a positive role in hepatic regeneration after PH.


Subject(s)
Hepatectomy , Liver Regeneration , Metallothionein/physiology , Animals , Immunohistochemistry , Metallothionein/genetics , Mice , Mice, Knockout , Proliferating Cell Nuclear Antigen/metabolism
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