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Anti-Tumor Effects after Adoptive Transfer of IL-12 Transposon-Modified Murine Splenocytes in the OT-I-Melanoma Mouse Model.
Galvan DL, O'Neil RT, Foster AE, Huye L, Bear A, Rooney CM, Wilson MH
(2015) PLoS One 10: e0140744
MeSH Terms: Adoptive Transfer, Animals, DNA Transposable Elements, HeLa Cells, Humans, Interleukin-12, Melanoma, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasms, Experimental, Spleen, T-Lymphocytes
Show Abstract · Added March 7, 2016
Adoptive transfer of gene modified T cells provides possible immunotherapy for patients with cancers refractory to other treatments. We have previously used the non-viral piggyBac transposon system to gene modify human T cells for potential immunotherapy. However, these previous studies utilized adoptive transfer of modified human T cells to target cancer xenografts in highly immunodeficient (NOD-SCID) mice that do not recapitulate an intact immune system. Currently, only viral vectors have shown efficacy in permanently gene-modifying mouse T cells for immunotherapy applications. Therefore, we sought to determine if piggyBac could effectively gene modify mouse T cells to target cancer cells in a mouse cancer model. We first demonstrated that we could gene modify cells to express murine interleukin-12 (p35/p40 mIL-12), a transgene with proven efficacy in melanoma immunotherapy. The OT-I melanoma mouse model provides a well-established T cell mediated immune response to ovalbumin (OVA) positive B16 melanoma cells. B16/OVA melanoma cells were implanted in wild type C57Bl6 mice. Mouse splenocytes were isolated from C57Bl6 OT-I mice and were gene modified using piggyBac to express luciferase. Adoptive transfer of luciferase-modified OT-I splenocytes demonstrated homing to B16/OVA melanoma tumors in vivo. We next gene-modified OT-I cells to express mIL-12. Adoptive transfer of mIL-12-modified mouse OT-I splenocytes delayed B16/OVA melanoma tumor growth in vivo compared to control OT-I splenocytes and improved mouse survival. Our results demonstrate that the piggyBac transposon system can be used to gene modify splenocytes and mouse T cells for evaluating adoptive immunotherapy strategies in immunocompetent mouse tumor models that may more directly mimic immunotherapy applications in humans.
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13 MeSH Terms
Mycobacterium tuberculosis TlyA Protein Negatively Regulates T Helper (Th) 1 and Th17 Differentiation and Promotes Tuberculosis Pathogenesis.
Rahman MA, Sobia P, Dwivedi VP, Bhawsar A, Singh DK, Sharma P, Moodley P, Van Kaer L, Bishai WR, Das G
(2015) J Biol Chem 290: 14407-17
MeSH Terms: Animals, Bacterial Proteins, Host-Pathogen Interactions, Interleukin-10, Interleukin-12, Lung, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Th1 Cells, Th17 Cells, Tuberculosis, Virulence Factors
Show Abstract · Added September 28, 2015
Mycobacterium tuberculosis, the causative agent of tuberculosis, is an ancient pathogen and a major cause of death worldwide. Although various virulence factors of M. tuberculosis have been identified, its pathogenesis remains incompletely understood. TlyA is a virulence factor in several bacterial infections and is evolutionarily conserved in many Gram-positive bacteria, but its function in M. tuberculosis pathogenesis has not been elucidated. Here, we report that TlyA significantly contributes to the pathogenesis of M. tuberculosis. We show that a TlyA mutant M. tuberculosis strain induces increased IL-12 and reduced IL-1β and IL-10 cytokine responses, which sharply contrasts with the immune responses induced by wild type M. tuberculosis. Furthermore, compared with wild type M. tuberculosis, TlyA-deficient M. tuberculosis bacteria are more susceptible to autophagy in macrophages. Consequently, animals infected with the TlyA mutant M. tuberculosis organisms exhibited increased host-protective immune responses, reduced bacillary load, and increased survival compared with animals infected with wild type M. tuberculosis. Thus, M. tuberculosis employs TlyA as a host evasion factor, thereby contributing to its virulence.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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15 MeSH Terms
Increased serum tumor necrosis factor α levels in patients with lenalidomide-induced hypothyroidism.
Iams WT, Hames ML, Tsai JP, Dahlman KB, Talbott MS, Richards KL, Reddy NM
(2015) Exp Hematol 43: 74-8
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Hypothyroidism, Immunologic Factors, Interferon-gamma, Interleukin-12, Interleukin-15, Interleukin-6, Lenalidomide, Lymphoma, Large B-Cell, Diffuse, Male, Middle Aged, Rituximab, Severity of Illness Index, Thalidomide, Tumor Necrosis Factor-alpha
Show Abstract · Added February 13, 2015
As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study, we compared rates of therapy-induced hypothyroidism in 329 patients with diffuse large B-cell lymphoma (DLBCL) treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor α, interferon gamma, interleukin 6, interleukin 12, and interleukin 15 before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs. 1.3%), and we found a statistically significant increase in serum tumor necrosis factor α in patients with lenalidomide-induced hypothyroidism.
Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Deficiency of gp91phox inhibits allergic airway inflammation.
Sevin CM, Newcomb DC, Toki S, Han W, Sherrill TP, Boswell MG, Zhu Z, Collins RD, Boyd KL, Goleniewska K, Huckabee MM, Blackwell TS, Peebles RS
(2013) Am J Respir Cell Mol Biol 49: 396-402
MeSH Terms: Animals, Asthma, Bronchoalveolar Lavage Fluid, Cells, Cultured, Dendritic Cells, Female, Gene Deletion, Interleukin-12, Interleukin-13, Lipopolysaccharides, Lung, Membrane Glycoproteins, Mice, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidases, Ovalbumin, Reactive Oxygen Species, Th1 Cells, Th1-Th2 Balance, Th17 Cells, Th2 Cells
Show Abstract · Added March 7, 2014
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox(-/-) mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrow-derived dendritic cells from WT and gp91phox(-/-) mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox(-/-) bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox(-/-) animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox(-/-) mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.
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22 MeSH Terms
Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis.
Zhou W, Dowell DR, Huckabee MM, Newcomb DC, Boswell MG, Goleniewska K, Lotz MT, Toki S, Yin H, Yao S, Natarajan C, Wu P, Sriram S, Breyer RM, Fitzgerald GA, Peebles RS
(2012) PLoS One 7: e33518
MeSH Terms: Animals, Antineoplastic Agents, Cell Differentiation, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental, Epoprostenol, Female, Humans, Iloprost, Interleukin-12, Interleukin-17, Interleukin-23, Mice, Mice, Inbred BALB C, Mice, Knockout, Platelet Aggregation Inhibitors, Receptors, Epoprostenol, Spinal Cord, Th17 Cells
Show Abstract · Added December 21, 2013
BACKGROUND - Prostaglandin I(2) (PGI(2)), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI(2) signaling suppressed Th1 and Th2 immune responses, the role of PGI(2) in Th17 differentiation is not known.
METHODOLOGY/PRINCIPAL FINDINGS - In mouse CD4(+)CD62L(+) naïve T cell culture, the PGI(2) analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI(2) receptor IP signaling. In mouse bone marrow-derived CD11c(+) dendritic cells (BMDCs), PGI(2) analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI(2) promotes in vivo Th17 responses.
CONCLUSION - The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI(2) and its analogs are commonly used to treat human pulmonary hypertension.
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19 MeSH Terms
MCP1 SNPs and pulmonary tuberculosis in cohorts from West Africa, the USA and Argentina: lack of association or epistasis with IL12B polymorphisms.
Velez Edwards DR, Tacconelli A, Wejse C, Hill PC, Morris GA, Edwards TL, Gilbert JR, Myers JL, Park YS, Stryjewski ME, Abbate E, Estevan R, Rabna P, Novelli G, Hamilton CD, Adegbola R, Østergaar L, Williams SM, Scott WK, Sirugo G
(2012) PLoS One 7: e32275
MeSH Terms: Adolescent, Adult, African Americans, African Continental Ancestry Group, Aged, Argentina, Case-Control Studies, Chemokine CCL2, Epistasis, Genetic, Ethnic Groups, European Continental Ancestry Group, Female, Gambia, Genetic Predisposition to Disease, Genetic Variation, Guinea-Bissau, Humans, Interleukin-12 Subunit p40, Male, Middle Aged, Polymorphism, Genetic, Tuberculosis, Pulmonary, United States
Show Abstract · Added April 1, 2014
The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (-2581A/G), rs2857656 (-362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility.
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23 MeSH Terms
Cationic amino acid transporter 2 enhances innate immunity during Helicobacter pylori infection.
Barry DP, Asim M, Scull BP, Piazuelo MB, de Sablet T, Lewis ND, Coburn LA, Singh K, Ellies LG, Gobert AP, Chaturvedi R, Wilson KT
(2011) PLoS One 6: e29046
MeSH Terms: Acute Disease, Amino Acid Transport Systems, Basic, Animals, Cell Count, Chronic Disease, Colony Count, Microbial, Dendritic Cells, Gastritis, Helicobacter Infections, Helicobacter pylori, Immunity, Innate, Interleukin-12, Macrophages, Mice, Nitric Oxide Synthase Type II, Stomach, Th1 Cells, Th2 Cells
Show Abstract · Added March 5, 2014
Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of L-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2(-/-) mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2(-/-) mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2(-/-) mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection.
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18 MeSH Terms
CD4+ T cell-derived novel peptide Thp5 induces interleukin-4 production in CD4+ T cells to direct T helper 2 cell differentiation.
Khan MM, Chatterjee S, Dwivedi VP, Pandey NK, Singh Y, Tousif S, Bhavesh NS, Van Kaer L, Das J, Das G
(2012) J Biol Chem 287: 2830-5
MeSH Terms: Animals, Cell Differentiation, Interleukin-12, Interleukin-4, Mice, Mice, Inbred BALB C, Mice, Knockout, Peptides, STAT6 Transcription Factor, Th1 Cells, Th17 Cells, Th2 Cells, Transforming Growth Factor beta, Vasoactive Intestinal Peptide
Show Abstract · Added March 20, 2014
The differentiation of naïve CD4(+) T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4(+) T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4(+) T cells. Induction of IL-4 in CD4(+) T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4(+) T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype.
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14 MeSH Terms
Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.
Morris GA, Edwards DR, Hill PC, Wejse C, Bisseye C, Olesen R, Edwards TL, Gilbert JR, Myers JL, Stryjewski ME, Abbate E, Estevan R, Hamilton CD, Tacconelli A, Novelli G, Brunetti E, Aaby P, Sodemann M, Østergaard L, Adegbola R, Williams SM, Scott WK, Sirugo G
(2011) PLoS One 6: e16656
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Argentina, Case-Control Studies, Cohort Studies, Female, Gambia, Gene Frequency, Genetic Association Studies, Genetic Variation, Genetics, Population, Guinea-Bissau, Humans, Interleukin-12 Subunit p40, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Tuberculosis, Pulmonary, United States, Young Adult
Show Abstract · Added April 1, 2014
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 3' UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it.
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24 MeSH Terms
Genetic deletion of mPGES-1 abolishes PGE2 production in murine dendritic cells and alters the cytokine profile, but does not affect maturation or migration.
Monrad SU, Kojima F, Kapoor M, Kuan EL, Sarkar S, Randolph GJ, Crofford LJ
(2011) Prostaglandins Leukot Essent Fatty Acids 84: 113-21
MeSH Terms: Animals, Cell Movement, Cricetinae, Cytokines, Dendritic Cells, Dinoprostone, Gene Deletion, Interleukin-12, Intramolecular Oxidoreductases, Lipopolysaccharides, Mice, Mice, Knockout, Prostaglandin-E Synthases, Rats
Show Abstract · Added September 18, 2013
We undertook this study to determine the role of Microsomal PGE Synthase-1 (mPGES-1), and mPGES-1-generated Prostaglandin (PG) E2 on Dendritic Cell (DC) phenotype and function. Using mPGES-1 KnockOut (KO) mice, we generated bone marrow derived DCs and determined their eicosanoid production profile, cell surface marker expression, and cytokine production. We also assessed DC migratory and functional capacity in vivo. Compared to wild-type, mPGES-1 deficient DCs exhibited a markedly attenuated increase in PGE2 production upon LPS stimulation, and displayed preferential shunting towards PGD2 production. mPGES-1 KO DCs did not display deficiencies in maturation, migration or ability to sensitize T cells. However, mPGES-1 deficient DCs generated reduced amounts of the Th1 cytokine IL-12, which may in part be due to increased PGD2 rather than decreased PGE2. These findings provide useful information on the effects of inducible PGE2 on the innate immune system, and have important implications regarding potential consequences of pharmacologic mPGES-1 inhibition.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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14 MeSH Terms