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Identification of drug-specific public TCR driving severe cutaneous adverse reactions.
Pan RY, Chu MT, Wang CW, Lee YS, Lemonnier F, Michels AW, Schutte R, Ostrov DA, Chen CB, Phillips EJ, Mallal SA, Mockenhaupt M, Bellón T, Tassaneeyakul W, White KD, Roujeau JC, Chung WH, Hung SI
(2019) Nat Commun 10: 3569
MeSH Terms: Adoptive Transfer, Adult, Aged, Animals, Carbamazepine, Disease Models, Animal, Female, HLA-B15 Antigen, Humans, Male, Mice, Transgenic, Middle Aged, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Severity of Illness Index, Skin, Stevens-Johnson Syndrome, T-Lymphocytes, Cytotoxic
Show Abstract · Added March 30, 2020
Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
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MeSH Terms
High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.
Ferguson JF, Aden LA, Barbaro NR, Van Beusecum JP, Xiao L, Simmons AJ, Warden C, Pasic L, Himmel LE, Washington MK, Revetta FL, Zhao S, Kumaresan S, Scholz MB, Tang Z, Chen G, Reilly MP, Kirabo A
(2019) JCI Insight 5:
MeSH Terms: Adolescent, Adoptive Transfer, Adult, Angiotensin II, Animals, Aorta, Bacteria, Blood Pressure, CD11c Antigen, Colon, Cytokines, Dendritic Cells, Disease Models, Animal, Dysbiosis, Female, Gastrointestinal Microbiome, Humans, Hypertension, Inflammation, Lipids, Lymph Nodes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Myeloid Cells, Peyer's Patches, RNA, Ribosomal, 16S, Sodium Chloride, Sodium Chloride, Dietary, Young Adult
Show Abstract · Added March 3, 2020
Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen presenting cells including dendritic cells (DCs) play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG-adduct formation in myeloid antigen presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high salt diets. In humans and mice, high salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a sub-pressor dose of angiotensin II. Mice fed a high salt diet exhibited increased intestinal inflammation including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG-protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high salt-fed mice to germ-free mice predisposed them to increased intestinal inflammation and hypertension. These findings provide novel insight into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.
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31 MeSH Terms
Regulation of Diabetogenic Immunity by IL-15-Activated Regulatory CD8 T Cells in Type 1 Diabetes.
Stocks BT, Wilson CS, Marshall AF, Hoopes EM, Moore DJ
(2019) J Immunol 203: 158-166
MeSH Terms: Adoptive Transfer, Animals, B-Lymphocytes, CD8 Antigens, Cells, Cultured, Diabetes Mellitus, Type 1, Disease Models, Animal, Humans, Immunotherapy, Adoptive, Interleukin-15, Macrophages, Mice, Mice, Inbred NOD, NK Cell Lectin-Like Receptor Subfamily A, T-Lymphocytes, Regulatory
Show Abstract · Added May 28, 2019
Unchecked collaboration between islet-reactive T and B lymphocytes drives type 1 diabetes (T1D). In the healthy setting, CD8 T regulatory cells (Tregs) terminate ongoing T-B interactions. We determined that specific CD8 Tregs from NOD mice lack suppressive function, representing a previously unreported regulatory cell deficit in this T1D-prone strain. NOD mice possess 11-fold fewer Ly-49 CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and leaves them unable to regulate CD4 T follicular helper cells. As IL-15 is required for Ly-49 CD8 Treg development, we determined that NOD macrophages inadequately -present IL-15. Despite reduced IL-15 -presentation, NOD Ly-49 CD8 Tregs can effectively transduce IL-15-mediated survival signals when they are provided. Following stimulation with an IL-15/IL-15Ra superagonist complex, Ly-49 CD8 Tregs expanded robustly and became activated to suppress the Ag-specific Ab response. IL-15/IL-15Ra superagonist complex-activated CD8CD122 T cells also delayed diabetes transfer, indicating the presence of an underactivated CD8 T cell subset with regulatory capacity against late stage T1D. We identify a new cellular contribution to anti-islet autoimmunity and demonstrate the correction of this regulatory cell deficit. Infusion of IL-15-activated CD8 Tregs may serve as an innovative cellular therapy for the treatment of T1D.
Copyright © 2019 by The American Association of Immunologists, Inc.
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15 MeSH Terms
Transposon-modified antigen-specific T lymphocytes for sustained therapeutic protein delivery in vivo.
O'Neil RT, Saha S, Veach RA, Welch RC, Woodard LE, Rooney CM, Wilson MH
(2018) Nat Commun 9: 1325
MeSH Terms: Adoptive Transfer, Animals, Cell Engineering, Cell- and Tissue-Based Therapy, DNA Transposable Elements, Erythropoietin, Gene Expression, Genetic Vectors, Hematopoiesis, Herpesvirus 4, Human, Humans, Mice, Ovalbumin, Receptors, Antigen, T-Cell, T-Lymphocytes, Transgenes, Vaccination
Show Abstract · Added September 24, 2018
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein-Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
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17 MeSH Terms
Cardiovascular Toxicities Associated with Cancer Immunotherapies.
Wang DY, Okoye GD, Neilan TG, Johnson DB, Moslehi JJ
(2017) Curr Cardiol Rep 19: 21
MeSH Terms: Adoptive Transfer, Humans, Immunotherapy, Myocarditis, Neoplasms
Show Abstract · Added March 26, 2017
PURPOSE OF REVIEW - We review the cardiovascular toxicities associated with cancer immune therapies and discuss the cardiac manifestations, potential mechanisms, and management strategies.
RECENT FINDINGS - The recent advances in cancer immune therapy with immune checkpoint inhibitors and adoptive cell transfer have improved clinical outcomes in numerous cancers. The rising use of cancer immune therapy will lead to a higher incidence in immune-related adverse events. Recent studies have highlighted several reports of severe cases of acute cardiotoxic events with immune therapy including fulminant myocarditis. We believe that immune-mediated myocarditis is a driving mechanism behind these cardiovascular toxicities and requires vigilant screening and prompt management with corticosteroids and immune-modulating drugs, especially with combination immune therapies. While the incidence of serious cardiovascular toxicities with immune therapy appears low, these can be life-threatening especially when manifesting as acute immune-mediated myocarditis. Further collaborative studies are needed to effectively identify, characterize, and manage these events.
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5 MeSH Terms
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
Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality.
Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, Kim AS, Alford CE, Matta P, Weitkamp JH, Moore DJ
(2015) J Immunol 195: 1064-70
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Antigens, CD, Bone Marrow Cells, CD11b Antigen, Endotoxins, Erythroid Cells, Female, Fetal Blood, Humans, Male, Mice, Mice, Inbred C57BL, Receptors, Transferrin, Reticulocytes, Sepsis, Spleen
Show Abstract · Added June 24, 2015
Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization.
Copyright © 2015 by The American Association of Immunologists, Inc.
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18 MeSH Terms
Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis.
Punit S, Dubé PE, Liu CY, Girish N, Washington MK, Polk DB
(2015) Gastroenterology 149: 993-1005.e2
MeSH Terms: Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes, Cell Proliferation, Colitis, Colon, DNA-Binding Proteins, Disease Models, Animal, Gene Expression Regulation, Immunity, Cellular, Interleukin-10, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Time Factors
Show Abstract · Added April 12, 2016
BACKGROUND & AIMS - Tumor necrosis factor receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function, but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice.
METHODS - Tnfr2(-/-) mice were crossed with interleukin (Il) 10(-/-) mice, which spontaneously develop colitis, to generate Il10(-/-)Tnfr2(-/-) mice. Colonic tissues were collected from Il10(-/-)Tnfr2(-/-) mice along with Il10(-/-) mice (controls) and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10(-/-) and Il10(-/-)Tnfr2(-/-) mice from Il10(-/-) or Il10(-/-)Tnfr2(-/-) donors by intravenous injection. CD8(+) T cells were neutralized in Il10(-/-)Tnfr2(-/-) mice by intraperitoneal injection of anti-CD8 or isotype control antibodies. Colitis was induced in Rag2(-/-) mice by intravenous injections of naïve CD8(+) T cells isolated from C57BL/6 or Tnfr2(-/-) mice.
RESULTS - Il10(-/-)Tnfr2(-/-) mice spontaneously developed more severe colitis compared with Il10(-/-) controls, characterized by selective expansion of colonic CD8(+) T cells. Transplantation of TNFR2-deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8(+) T cells and included genes associated with risk for IBD. Depletion of CD8(+) T cells from Il10(-/-)Tnfr2(-/-) mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8(+) T cells compared with CD8(+) T cells from control mice increased the severity of colitis that developed in Rag2(-/-) mice.
CONCLUSIONS - TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8(+) T cells. TNFR2 regulates expression of genes that regulate CD8(+) T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated with pathogenesis. Strategies to increase levels or activity of TNFR2 and thereby reduce the activity of CD8(+) T cells might be developed to treat IBD patients with CD8(+) T cell dysfunction.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase.
Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG
(2014) Circ Res 114: 616-25
MeSH Terms: Adoptive Transfer, Angiotensin II, Animals, Aortic Diseases, CD4 Antigens, CD8 Antigens, Cells, Cultured, Collagen, Disease Models, Animal, Elastin, Fibroblasts, Homeodomain Proteins, Hypertension, Inflammation, Interleukin-17, Male, Mice, Mice, Knockout, Stress, Mechanical, T-Lymphocytes, Vascular Stiffness, Vasculitis, Vasoconstrictor Agents, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 21, 2014
RATIONALE - Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.
OBJECTIVE - Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.
METHODS AND RESULTS - Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.
CONCLUSIONS - Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.
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24 MeSH Terms
Requirement for Rictor in homeostasis and function of mature B lymphoid cells.
Lee K, Heffington L, Jellusova J, Nam KT, Raybuck A, Cho SH, Thomas JW, Rickert RC, Boothby M
(2013) Blood 122: 2369-79
MeSH Terms: Adoptive Transfer, Animals, B-Lymphocytes, Blotting, Western, Carrier Proteins, Cell Differentiation, Cell Proliferation, Cell Survival, Electrophoretic Mobility Shift Assay, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Homeostasis, Immunohistochemistry, Mice, Mice, Inbred C57BL, Rapamycin-Insensitive Companion of mTOR Protein, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added November 6, 2013
The mammalian target of rapamycin (mTOR), an essential serine/threonine kinase, functions in biochemically distinct multiprotein complexes, but little is known about roles of the complexes in B cells. The acutely rapamycin-sensitive mTOR complex 1 (mTORC1) is defined by a core subunit Raptor, whereas mTORC2 lacks Raptor and, instead, has Rictor and SIN1 as distinct essential components. We now show that homeostasis and function of B cells require Rictor. Conditional deletion of Rictor before lymphoid specification impaired generation of mature follicular, marginal zone, and B1a B lymphocytes. Induced inactivation in adult mice caused cell-autonomous defects in B lymphoid homeostasis and antibody responses in vivo, along with affecting plasma cells in bone marrow. Survival of B lymphocytes depended on Rictor, which was vital for normal induction of prosurvival genes, suppression of proapoptotic genes, nuclear factor κB induction after B-cell receptor stimulation, and B-cell activating factor-induced nuclear factor κB2/p52 generation. Collectively, the findings provide evidence that mTOR signaling affects survival and proliferation of mature B lymphocytes, and establish Rictor as an important signal relay in B-cell homeostasis, fate, and functions.
2 Communities
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18 MeSH Terms