36 results on '"Demaison, C"'
Search Results
2. TLR2/6 Agonist Treatment Enhances Antiviral Innate Immune Responses in a Novel Mouse Coronavirus Respiratory Infection Model
- Author
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Girkin, J., primary, Bryant, N.E., additional, Loo, S.-L., additional, Demaison, C., additional, Mercuri, F., additional, and Bartlett, N.W., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model
- Author
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Proud, PC, Tsitoura, D, Watson, RJ, Chua, BY, Aram, MJ, Bewley, KR, Cavell, BE, Cobb, R, Dowall, S, Fotheringham, SA, Ho, CMK, Lucas, V, Ngabo, D, Rayner, E, Ryan, KA, Slack, GS, Thomas, S, Wand, N, Yeates, P, Demaison, C, Zeng, W, Holmes, I, Jackson, DC, Bartlett, NW, Mercuri, F, Carroll, MW, Proud, PC, Tsitoura, D, Watson, RJ, Chua, BY, Aram, MJ, Bewley, KR, Cavell, BE, Cobb, R, Dowall, S, Fotheringham, SA, Ho, CMK, Lucas, V, Ngabo, D, Rayner, E, Ryan, KA, Slack, GS, Thomas, S, Wand, N, Yeates, P, Demaison, C, Zeng, W, Holmes, I, Jackson, DC, Bartlett, NW, Mercuri, F, and Carroll, MW
- Abstract
BACKGROUND: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. METHODS: SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). FINDINGS: We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. INTERPRETATION: The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. FUNDING: This work was funded by Ena Respiratory, Melbourne, Australia.
- Published
- 2021
4. TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs
- Author
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Deliyannis, G, Wong, CY, McQuilten, HA, Bachem, A, Clarke, M, Jia, X, Horrocks, K, Zeng, W, Girkin, J, Scott, NE, Londrigan, SL, Reading, PC, Bartlett, NW, Kedzierska, K, Brown, LE, Mercuri, F, Demaison, C, Jackson, DC, Chua, BY, Deliyannis, G, Wong, CY, McQuilten, HA, Bachem, A, Clarke, M, Jia, X, Horrocks, K, Zeng, W, Girkin, J, Scott, NE, Londrigan, SL, Reading, PC, Bartlett, NW, Kedzierska, K, Brown, LE, Mercuri, F, Demaison, C, Jackson, DC, and Chua, BY
- Abstract
The impact of respiratory virus infections on global health is felt not just during a pandemic, but endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen-independent innate immunity in the upper airways can prevent the spread of respiratory virus infection to the vulnerable lower airways. Activation of TLR2, when restricted to the nasal turbinates, resulted in prompt induction of innate immune-driven antiviral responses through action of cytokines, chemokines, and cellular activity in the upper but not the lower airways. We have defined how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to 7 days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.
- Published
- 2021
5. In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium
- Author
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Bainbridge, JWB, Stephens, C, Parsley, K, Demaison, C, Halfyard, A, Thrasher, AJ, and Ali, RR
- Published
- 2001
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6. Airway Epithelial Cells from Patients with Asthma and COPD Exhibit Improved Resistance to Rhinovirus Infection Following Treatment with TLR2 Immune Modulators
- Author
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Bartlett, N.W., primary, Loo, S.-L., additional, Girkin, J., additional, Jackson, D.C., additional, Mercuri, F., additional, and Demaison, C., additional
- Published
- 2019
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- View/download PDF
7. VH gene-family representation in peripheral activated B cells from systemic lupus erythematosus (SLE) patients
- Author
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Demaison, C., David, D., Fautrel, B., and Theze, J.
- Published
- 1996
8. ChemInform Abstract: Synthesis of Enantiomerically Pure Carbocyclic α-L-Isomeric Homonucleosides.
- Author
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GIRARD, F., primary, DEMAISON, C., additional, LEE, M.-G., additional, and AGROFOGLIO, L. A., additional
- Published
- 2010
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9. ChemInform Abstract: Stereoselective Synthesis of Carbocyclic α-L-Homonucleosides
- Author
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Agrofoglio, L. A., primary, Girard, F., additional, Demaison, C., additional, Lee, M.-G., additional, Roingeard, P., additional, and Fridland, A., additional
- Published
- 2010
- Full Text
- View/download PDF
10. Stereoselective Synthesis of Carbocyclic α-L-Homonucleosides
- Author
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Agrofoglio, L. A., primary, Girard, F., additional, Demaison, C., additional, Lee, M-G., additional, Roingeard, P., additional, and Fridland, A., additional
- Published
- 1999
- Full Text
- View/download PDF
11. Synthesis of enantiomerically pure carbocyclic α-l-isomeric homonucleosides
- Author
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Girard, F., primary, Demaison, C., additional, Lee, M.-G., additional, and Agrofoglio, L.A., additional
- Published
- 1998
- Full Text
- View/download PDF
12. Clonotypic Dominance and Variable Gene Elements of Pathogenic Anti‐DNA Autoantibodies from a Single Patient with Lupus
- Author
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CHASTAGNER, P., primary, DEMAISON, C., additional, THÈZE, J., additional, and ZOUALI, M., additional
- Published
- 1994
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13. Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype.
- Author
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Demaison, C, primary, Chastagner, P, additional, Thèze, J, additional, and Zouali, M, additional
- Published
- 1994
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14. VH gene-family representation in peripheral activated B cells from systemic lupus erythematosus (SLE) patients.
- Author
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Demaison, C., David, D., Fautrel, B., and Theze, J.
- Subjects
- *
B cells , *LYMPHOCYTES , *IMMUNOGLOBULIN G , *SKIN diseases , *VASCULAR diseases , *DNA polymerases , *POLYMERASE chain reaction - Abstract
A semiquantitative polymerase chain reaction (PCR) assay described in this study has been used lo analyse the VH1, VH3 and VH4 repertoire expressed by total IgM+ and IgG+ B cells from normal individuals and lupus patients. This approach consists of a combination of B cell selection, utilization of the anchored PCR technique to avoid technical bias in the amplification of different VH gene family cDNA templates, and screening of the amplified IgM or IgG cDNA rearrangements by family-specific oligonucleotide probes. In four lupus patients, VH family representation in IgM+ and IgG+ in vivo activated B cells, selected by anti-CD71 antibody, and in total CD19+ B cells were compared. In all patients VH4 gene family segments were preferentially underrepresented in IgM+ activated B cells. In IgG+ B cells the results suggest that VH4 expression is variable, depending on the phase of the disease. Polyclonal B cell activation, which is usually considered as being the first event in autoantibody production in SLE, cannot explain our results. The data evoke the possible involvement of a VH4-specific B cell superantigen in the onset or development of SLE. This hypothesis is also supported by the sequence conservation of the fourth β loop-a putative superantigen binding site-of functional VH4 gene segments which are preferentially used by anti-dsDNA lupus antibodies of established clones and hybridomas. [ABSTRACT FROM AUTHOR]
- Published
- 1996
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- View/download PDF
15. Analysis of variable region genes encoding anti-Sm and anti-cardiolipin antibodies from a systemic lupus erythematosus patient.
- Author
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Demaison, C., Ravirajan, C. T., Isenrerg, D. A., and Zouali, M.
- Subjects
- *
AUTOANTIBODIES , *GENES , *MONOCLONAL antibodies , *CARDIOLIPIN , *ANTIGENS , *SYSTEMIC lupus erythematosus , *PATIENTS - Abstract
We have analysed the heavy and light chain variable region genes of two monoclonal antibodies, specific for the Sm antigen (RSP1; IgGκ) and for cardiolipin (RSP4; IgMλ), derived from a patient with active systemic lupus erythematosus (SLE). We have established that the variable region genes of the RSPI autoantibody are somatic mutants of two germ line genes from the VH4 and VκI gene families. RSP4 antibody uses gene segments closely related to a VH3 gene member and to a Vλ1 gene. The presence and distribution of the somatic mutations on both monoclonal autoantibodies are compatible with an antigen-driven immune process. These data suggest that in SLE a common antigenic stimulus may govern the autoantibody response against a wide spectrum of unrelated antigens, including native DNA, cardiolipin or Sm antigens, and provide further evidence that disease-associated autoantibodies are generated through antigen-selected somatic mutations. [ABSTRACT FROM AUTHOR]
- Published
- 1995
16. Ligand-induced autoregulation of IL-2 receptor alpha chain expression in murine T cell lines.
- Author
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Demaison, C, Chastagner, P, Moreau, J L, and Thèze, J
- Abstract
The IL-2 receptor (IL-2R) is composed of three chains alpha, beta and gamma. In mice, contrary to the human system, we have previously demonstrated that the IL-2R beta gamma complex does not bind IL-2. Therefore, mouse IL-2 response is completely dependent on the expression of the IL-2R alpha gene product. T cell clones expressing mouse IL-2R beta gamma and the human IL-2R alpha transgene have been studied. When cells are grown in IL-4, mouse IL-2R alpha is not expressed. However, exposure to IL-2 leads to the expression of the endogenous murine IL-2R alpha subunit. The T cell line expressing mouse IL-2R gamma and human IL-2R beta can grow in IL-2 but does not express endogenous murine IL-2R alpha. Transfection of these cells with the human IL-2R alpha gene restores the capacity to induce murine IL-2R alpha. This result demonstrates that IL-2-IL-2R alpha interactions are required for induction of IL-2R alpha. The kinetics of induction and deinduction of murine IL-2R alpha have been studied using clone 18.III. From negative cells, expression of murine IL-2R alpha is a very slow phenomenon. From cells fully expressing IL-2R alpha, deinduction is a two-step process: after a rapid decrease of IL-2R alpha the cells continue to express, for a long period of time, basal levels of murine IL-2R alpha. When cells expressing basal levels of IL-2R alpha are exposed to IL-2, induction of IL-2R alpha is a very rapid phenomenon. The autoregulatory loop formed by IL-2-IL-2R alpha therefore displays different levels of functioning.
- Published
- 1996
- Full Text
- View/download PDF
17. Progressive decrease in VH3 gene family expression in plasma cells of HIV-infected patients.
- Author
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David, D, Demaison, C, Bani, L, and Thèze, J
- Abstract
We have analysed the expression of VH gene families in total peripheral plasma cells of mu and gamma isotypes from a group of HIV-infected patients. CD19- and CD20- cells were separated from B lymphocytes, and anchored RT-PCR products were hybridized with specific VH gene family probes and with a consensus JH region probe. The VH/JH hybridization intensity ratios were taken as a parameter to measure VH expression. In vivo VH3 gene family expression is reduced in plasma cells of all HIV-infected patients compared with adult healthy donors. This decrease is maximal in patients with AIDS: > 90%. This is true for both studied isotypes. Conversely, the two other main VH gene families, VH1 and VH4, show no significant variation in expression. We and others have previously shown that VH3 gene family expression is first expanded and then decreased in peripheral B lymphocytes of HIV-infected patients. The present results extend these observations and show that VH3 gene family expression is also affected in plasma cells. The existence of a B cell superantigen in HIV infection may explain these data. This pronounced reduction in VH3 family expression may participate in the impaired humoral responses against bacterial agents found in HIV-infected patients.
- Published
- 1996
- Full Text
- View/download PDF
18. Analysis of variable region genes encoding anti-Sm and anti-cardiolipin antibodies from a systemic lupus erythematosus patient
- Author
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Demaison, C., Ravirajan, C. T., David Isenberg, and Zouali, M.
19. Progressive decrease in V(H)3 gene family expression in plasma cells of HIV-infected patients
- Author
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David, D., Demaison, C., Bani, L., and Theze, J.
- Subjects
HIV infection -- Genetic aspects ,Plasma cells -- Research - Abstract
According to the authors' abstract of an article published in International Immunology, "We have analyzed the expression of V-H gene families in total peripheral plasma cells of mu and gamma [...]
- Published
- 1996
20. ChemInform Abstract: Stereoselective Synthesis of Carbocyclic α-L-Homonucleosides.
- Author
-
Agrofoglio, L. A., Girard, F., Demaison, C., Lee, M.-G., Roingeard, P., and Fridland, A.
- Published
- 1999
- Full Text
- View/download PDF
21. ChemInform Abstract: Synthesis of Enantiomerically Pure Carbocyclic α-L-Isomeric Homonucleosides.
- Author
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GIRARD, F., DEMAISON, C., LEE, M.-G., and AGROFOGLIO, L. A.
- Published
- 1998
- Full Text
- View/download PDF
22. Stereoselective synthesis of α--bicarbocyclic nucleosides as potential antiviral drugs
- Author
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DEMAISON, C
- Published
- 1998
23. Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology.
- Author
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Mercuri FA, White S, McQuilten HA, Lemech C, Mynhardt S, Hari R, Zhang P, Kruger N, McLachlan G, Miller BE, West NP, Tal-Singer R, and Demaison C
- Abstract
Background: Local priming of the innate immune system with a Toll-like receptor (TLR)2/6 agonist may reduce morbidity and mortality associated with viral respiratory tract infections, particularly for the elderly and those with chronic diseases. The objectives of the present study were to understand the potential of prophylactic treatment with a TLR2/6 agonist as an enhancer of innate immunity pathways leading to accelerated respiratory virus clearance from the upper airways., Methods: Two randomised, double-blind, placebo-controlled clinical trials were conducted in healthy adult participants. The first dose-escalation study assessed safety, tolerability and mechanistic biomarkers following single and repeated intranasal administrations of INNA-051. The second was an influenza A viral challenge study assessing the impact of treatment on host defence biomarkers and viral load., Results: INNA-051 was well tolerated in both studies, with no dose-limiting toxicities identified. Mechanistic biomarkers assessed in both studies demonstrated the expected engagement of pharmacology, including innate immune pathways. There were lower than anticipated rates of infection. Post hoc analysis conducted in laboratory-confirmed infected participants with low or no antibody titre against the challenge virus showed INNA-051 treatment led to a significantly shorter duration of infection and increased expression of genes and pathways associated with host defence responses against influenza., Conclusions: The safety and pharmacology profile of INNA-051 confirms preclinical studies. INNA-051 increased expression of genes and pathways associated with host defence responses against influenza and was associated with a shorter duration of infection. These studies support further clinical assessment in the context of natural viral respiratory tract infections in individuals at increased risk of severe illness., Competing Interests: Conflict of interest: F.A. Mercuri, C. Demaison and G. McLachlan are employees of ENA Respiratory Pty Ltd, and receive an annual salary and other benefits. In addition, they have shares and share options and are named inventors on numerous granted or pending patent applications controlled by ENA. Conflict of interest: H.A. McQuilten receives payments as a contract researcher from ENA Respiratory Pty Ltd. S. White, R. Tal-Singer, B.E. Miller and N. Kruger receive payments as paid consultants for ENA Respiratory Pty Ltd, and as part of their compensation have been awarded participation in the company share option plan. R. Tal-Singer is a retiree and shareholder of GSK, and reports personal fees from AstraZeneca, Roche, Vocalis Health, Teva, ImmunoMet, Renovion, Samay Health, GSK and ItayAndBeyond. Conflict of interest: S. Mynhardt, N.P. West, P. Zhang, C. Lemech and R. Hari receive payments to their institutions for carrying out research., (Copyright ©The authors 2024.)
- Published
- 2024
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- View/download PDF
24. The COPD Foundation's COPD360Net Initiative Approach to Patient-Centric Drug Development: A Case Study in Using Patient Surveys to Inform New Treatments for Viral Respiratory Infections.
- Author
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Tal-Singer R, Miller BE, Rommes JM, Luttmann MA, Demaison C, Bradley Drummond M, and Pasquale CB
- Abstract
Patient-centric drug development is crucial to creating treatments that address unmet patient needs but is often ignored. The COPD Foundation's COPD360Net
® includes a multistakeholder approach for operationalizing patient-centric development of treatments where patients, caregivers, scientists, and clinicians review opportunities based on scientific merit, potential to address an unmet need, and feasibility of adoption. COPD360Net deploys large-scale online community surveys to review profiles of potential therapies based on those criteria. This approach was implemented to inform the development of an intranasal spray to prevent viral respiratory infections (VRIs), a major cause of exacerbations in people with chronic lung diseases. Insights included: Of the 376 respondents with COPD surveyed, frequent exacerbators reported strong interest in a new type of antiviral nasal spray to prevent VRI.Patient survey and advisory committee insights demonstrated that a pan antiviral nasal spray has potential high value to both clinicians and patients and informed the COPD360Net decision to partner on its development.Including patient perspectives from the outset can be conducted efficiently by mobilizing an engaged online patient community., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs. Tal-Singer and Miller and Mr Luttmann are former employees and shareholders of GlaxoSmithKline. Dr Tal-Singer is a non-executive director of the ENA Respiratory Board on behalf of the COPD Foundation and holds share options. She also reports personal consulting fees prior to January 2021 from Teva, Immunomet, Vocalis Health, and ENA Respiratory. Dr Rommes is a patient advocate. Dr Demaison holds both shares and share options in ENA Respiratory. Dr Drummond reports research grants from the National Institutes of Health, Department of Defense, PCORI, American Lung Association, Boehringer-Ingelheim, Midmark and Teva unrelated to this work. He reports personal consulting fees from Boehringer-Ingelheim, GlaxoSmithKline, AstraZeneca, Teva, Midmark and Polarean unrelated to this work. Dr Drummond serves as Chair of the COPD360Net Pipeline Working Group., (© The Author(s) 2023.)- Published
- 2023
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25. TLR2-mediated innate immune priming boosts lung anti-viral immunity.
- Author
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Girkin J, Loo SL, Esneau C, Maltby S, Mercuri F, Chua B, Reid AT, Veerati PC, Grainge CL, Wark PAB, Knight D, Jackson D, Demaison C, and Bartlett NW
- Subjects
- Animals, Epithelial Cells, Humans, Immunity, Innate, Lung, Mice, Antiviral Agents, Toll-Like Receptor 2
- Abstract
Background: We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases., Methods: We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome., Results: We show, in vivo , that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro , INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response., Conclusion: Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation., Competing Interests: Conflict of interest: J. Girkin reports grants, personal fees for consultancy and non-financial support for travel to meetings from Ena Therapeutics Pty Ltd, during the conduct of the study; and has a patent PCT/AU2018/050295 issued. Conflict of interest: S-L. Loo reports grants from Ena Therapeutics, during the conduct of the study. Conflict of interest: C. Esneau has nothing to disclose. Conflict of interest: S. Maltby has nothing to disclose. Conflict of interest: F. Mercuri is an employee of Ena Therapeutics, and has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued. Conflict of interest: B. Chua is a co-founder and shareholder of Ena Therapeutics Pty Ltd. Conflict of interest: A.T. Reid has nothing to disclose. Conflict of interest: P.C. Veerati has nothing to disclose. Conflict of interest: C.L. Grainge has nothing to disclose. Conflict of interest: P.A.B. Wark has nothing to disclose. Conflict of interest: D. Knight reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Jackson is co-founder and shareholder of Ena Therapeutics Pty. Ltd, and has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued. Conflict of interest: C. Demaison is an employee of Ena Therapeutics, and has a patent PCT/AU2018/050295 pending, and a patent PCT/AU2011/001225 issued. Conflict of interest: N.W. Bartlett reports grants, personal fees for consultancy and other (stock options) from Ena Therapeutics, during the conduct of the study; has a patent PCT/AU2018/050295 issued., (Copyright ©ERS 2021. For reproduction rights and permissions contact permissions@ersnet.org.)
- Published
- 2021
- Full Text
- View/download PDF
26. TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs.
- Author
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Deliyannis G, Wong CY, McQuilten HA, Bachem A, Clarke M, Jia X, Horrocks K, Zeng W, Girkin J, Scott NE, Londrigan SL, Reading PC, Bartlett NW, Kedzierska K, Brown LE, Mercuri F, Demaison C, Jackson DC, and Chua BY
- Subjects
- Animals, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Disease Models, Animal, Female, Humans, Immunologic Factors therapeutic use, Influenza A virus, Lipopeptides therapeutic use, Male, Mice, Inbred C57BL, Orthomyxoviridae Infections drug therapy, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections metabolism, Orthomyxoviridae Infections virology, Respiratory System drug effects, Respiratory System immunology, Respiratory System metabolism, Respiratory System virology, Toll-Like Receptor 2 agonists, Mice, Immunity, Innate drug effects, Immunologic Factors pharmacology, Influenza, Human drug therapy, Influenza, Human immunology, Influenza, Human metabolism, Influenza, Human virology, Lipopeptides pharmacology, Lung drug effects, Lung immunology, Lung metabolism, Lung virology, Respiratory Tract Infections drug therapy, Respiratory Tract Infections immunology, Respiratory Tract Infections metabolism, Respiratory Tract Infections virology, Toll-Like Receptor 2 metabolism
- Abstract
The impact of respiratory virus infections on global health is felt not just during a pandemic, but endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen-independent innate immunity in the upper airways can prevent the spread of respiratory virus infection to the vulnerable lower airways. Activation of TLR2, when restricted to the nasal turbinates, resulted in prompt induction of innate immune-driven antiviral responses through action of cytokines, chemokines, and cellular activity in the upper but not the lower airways. We have defined how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to 7 days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.
- Published
- 2021
- Full Text
- View/download PDF
27. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model.
- Author
-
Proud PC, Tsitoura D, Watson RJ, Chua BY, Aram MJ, Bewley KR, Cavell BE, Cobb R, Dowall S, Fotheringham SA, Ho CMK, Lucas V, Ngabo D, Rayner E, Ryan KA, Slack GS, Thomas S, Wand NI, Yeates P, Demaison C, Zeng W, Holmes I, Jackson DC, Bartlett NW, Mercuri F, and Carroll MW
- Subjects
- Administration, Intranasal, Animals, COVID-19 pathology, Disease Models, Animal, Female, Ferrets, Immunity, Innate, Lipopeptides chemistry, Lipopeptides pharmacology, Nasal Cavity pathology, Nasal Cavity virology, Pharynx pathology, Pharynx virology, RNA, Viral metabolism, Real-Time Polymerase Chain Reaction, Respiratory System pathology, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, Viral Load drug effects, COVID-19 Drug Treatment, Lipopeptides administration & dosage, Respiratory System virology, SARS-CoV-2 pathogenicity, Toll-Like Receptor 2 agonists, Toll-Like Receptor 6 agonists, Virus Shedding
- Abstract
Background: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission., Methods: SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 10
6 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E)., Findings: We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals., Interpretation: The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19., Funding: This work was funded by Ena Respiratory, Melbourne, Australia., Competing Interests: Declaration of Competing Interests Authors report grants from Ena Respiratory, during the conduct of the study. W. Zeng and D.C. Jackson reports grants from Ena Therapeutics, during the conduct of the study. D. Tsitoura, C. Demaison, F. Mercuri, I. Holmes and N.W. Bartlett reports personal fees and other from Ena Therapeutics, outside the submitted work. D.C. Jackson, W. Zeng and B.Y. Chua reports other from Ena Therapeutics, outside the submitted work. Dr. Holmes reports personal fees from Ena Therapeutics, outside the submitted work. In addition, D. Tsitoura, C. Demaison and F. Mercuri have a patent AU 2020901709 pending to Ena Therapeutics. D.C Jackson, W. Zeng and C. Demaison have a patent PCT/AU2011/001225 issued to Ena Therapeutics. D.C Jackson, W. Zeng, I. Holmes and C. Demaison have a patent PCT/AU2020/050660 pending to Ena Therapeutics., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
28. High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter.
- Author
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Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, Kinnon C, Grez M, and Thrasher AJ
- Subjects
- Animals, Antigens, CD34 biosynthesis, Cells, Cultured, Cytokines biosynthesis, Fetal Blood metabolism, Flow Cytometry, Green Fluorescent Proteins, Hematopoietic Stem Cells metabolism, Hepatitis B Virus, Woodchuck genetics, Humans, Luminescent Proteins metabolism, Mice, Mice, SCID, Plasmids metabolism, Promoter Regions, Genetic, Purines chemistry, Spleen Focus-Forming Viruses genetics, Terminal Repeat Sequences, Transduction, Genetic, Viral Envelope Proteins genetics, Enhancer Elements, Genetic, Gene Transfer Techniques, Genetic Vectors, HIV-1 genetics, Lentivirus genetics, Membrane Glycoproteins
- Abstract
Prolonged exposure of human hematopoietic stem cells (HSC) to growth factors for efficient transduction by murine oncoretroviral vectors has major detrimental effects on repopulating activity. In this study, we have used a vesicular stomatitis virus G envelope protein (VSV-G)-pseudotyped human immunodeficiency virus type 1 (HIV-1) lentiviral-based vector system to transduce cord blood (CB) CD34+ cells over a limited time period (< or =24 hours). Under these conditions, significant gene marking was observed in engrafted human lymphoid, myeloid, and progenitor cells in all transplanted Severe Combined Immunodeficient (SCID) mice. To enhance the level of gene expression in hematopoietic cells, we also generated a series of lentiviral vectors incorporating the spleen focus forming virus (SFFV) long terminal repeat (LTR) sequences, and the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). By including the central polypurine tract (cPPT) sequence of HIV-1 we were then able to achieve high levels of transduction (over 80%) and gene expression in vivo after a single exposure to viral supernatant. These results demonstrate that lentiviral vectors are highly effective for gene transfer to human HSC, and that SFFV regulatory sequences can be successfully incorporated to enhance the long-term expression of a transgene in primary human hematopoietic cells in vivo.
- Published
- 2002
- Full Text
- View/download PDF
29. A defined window for efficient gene marking of severe combined immunodeficient-repopulating cells using a gibbon ape leukemia virus-pseudotyped retroviral vector.
- Author
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Demaison C, Brouns G, Blundell MP, Goldman JP, Levinsky RJ, Grez M, Kinnon C, and Thrasher AJ
- Subjects
- Animals, Antigens, CD34 genetics, Cytokines therapeutic use, Flow Cytometry, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy, Genetic Markers, Genetic Vectors, Leukemia Virus, Gibbon Ape genetics, Severe Combined Immunodeficiency immunology
- Abstract
We have investigated the minimal time required for efficient transduction of human hematopoietic repopulating cells using a surrogate nonobese diabetic (NOD)/severe combined immunodeficient (SCID) xenoengraftment assay. Cord blood CD34+ cells were transduced to high levels over 24-48 hr in the presence of Flt-3 ligand, stem cell factor, interleukin 3, and interleukin 6. Under these conditions, high levels of NOD/SCID repopulating activity were preserved, but the levels of gene marking in engrafting cell populations measured by expression of a reporter transgene were low. Extension of the transduction period by 24 hr (total culture period, 72 hr) under the same cytokine conditions resulted in high levels of gene marking, but on closer analysis expression was limited predominantly to the myeloid population. Efficient transduction of both lymphoid and myeloid lineages could be achieved only if the transduction protocol was extended by a further 24 hr (total culture period, 96 hr), suggesting that myeloid lineage-committed precursors are capable of repopulation, and that over shorter time periods transduction is largely restricted to this population. This adds to the emerging evidence of heterogeneity within the SRC compartment, and has important implications for the interpretation of this assay in stem cell transplantation and gene transfer studies.
- Published
- 2000
- Full Text
- View/download PDF
30. Quality of repopulation in nonobese diabetic severe combined immunodeficient mice engrafted with expanded cord blood CD34+ cells.
- Author
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Blundell MP, Demaison C, Brouns G, Goldman JP, Gaspar HB, Kinnon C, Thrasher AJ, Lazzari L, and Sirchia G
- Subjects
- Animals, Antigens, CD34, Diabetes Mellitus, Type 1, Hematopoietic System, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Fetal Blood, Graft Survival, Hematopoietic Stem Cell Transplantation
- Published
- 1999
31. IL-2-dependent expression of genes involved in cytoskeleton organization, oncogene regulation, and transcriptional control.
- Author
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Herblot S, Chastagner P, Samady L, Moreau JL, Demaison C, Froussard P, Liu X, Bonnet J, and Thèze J
- Subjects
- Animals, Base Sequence immunology, Cell Line, Heterozygote, Homozygote, Interleukin-2 genetics, Lymph Nodes metabolism, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, RNA, Messenger metabolism, Spleen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Thymus Gland metabolism, Cytoskeleton physiology, Gene Expression Regulation immunology, Interleukin-2 physiology, Oncogenes immunology, Transcription, Genetic immunology
- Abstract
IL-2 induces growth, differentiation, and/or apoptosis of lymphoid cells. To study further the molecular basis of IL-2 function, we used a cDNA subtraction approach involving a cell line grown in IL-2 or IL-4. From the corresponding library, 66 nonredundant sequences were characterized; 16 of them encode identified proteins. The kinetics of in vitro expression of 8 selected sequences, the functions of which could be associated with IL-2-induced T cell activation/differentiation, was investigated using an IL-2-dependent T cell line. IL-2 increased the expression of cytoskeleton proteins (alpha-tubulin), oncogene-regulating proteins (CCCTC-binding factor, Jun inhibitor factor-1), and transcription factors (E2F-4, cyclic AMP-responsive element-binding protein, zhx-1). IL-2 also regulated the expression of genes coding for multifunctional proteins, e.g., beta-catenin and nucleolin. These results were verified using Con A-induced T cell blasts stimulated or not by IL-2. The in vivo expression of four of these genes was also analyzed in spleen and lymph node cells of IL-2-deficient and MRL/lpr mice, which both have high numbers of activated cells, but the latter have intact IL-2 expression. The expression of beta-catenin, CCCTC-binding factor, Jun inhibitor factor-1, and nucleolin was significantly higher in MRL/lpr animals. A similar analysis of thymocytes from IL-2-/- and IL-2+/- mice demonstrated the same expression patterns of the 4 sequences in these strains. The expression of the IL-2-induced genes described herein is similar to the regulatory pattern of IL-2R alpha. Taken together, our data provide additional evidence for the pleiotropic action of IL-2 in the periphery and IL-2 independence of molecular processes involved in thymocyte differentiation.
- Published
- 1999
32. Dysregulation of interleukin-2 receptor beta and interleukin-2 receptor gamma expression during HIV infection.
- Author
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David D, Bani L, Moreau JL, Treilhou MP, Demaison C, Sun K, Février M, Salvucci O, Cayota A, Nakarai T, Chouaïb S, de Montalembert M, Joussemet M, Sugamura K, Ritz J, Dupont B, Pialoux G, and Thèze J
- Subjects
- Animals, HIV Infections metabolism, Humans, Receptors, Interleukin-2 physiology, HIV Infections immunology, Receptors, Interleukin-2 biosynthesis
- Published
- 1998
33. IL-2 receptor alpha-chain expression is independently regulated in primary and secondary lymphoid organs.
- Author
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Demaison C, Fiette L, Blanchetière V, Schimpl A, Thèze J, and Froussard P
- Subjects
- Animals, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Gene Expression Regulation immunology, Lymphocyte Activation genetics, Lymphoid Tissue cytology, Lymphoid Tissue immunology, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Inbred Strains, Mice, Knockout, Organ Specificity genetics, Organ Specificity immunology, Polymerase Chain Reaction, Receptors, Interleukin-2 deficiency, Receptors, Interleukin-2 genetics, Spleen cytology, Spleen immunology, Spleen metabolism, Thymus Gland cytology, Thymus Gland immunology, Thymus Gland metabolism, Lymphoid Tissue metabolism, Receptors, Interleukin-2 biosynthesis
- Abstract
The IL-2R is composed of three chains: IL-2R alpha, IL-2R beta, and IL-2R gamma. In mice, IL-2Ra is critical and determines IL-2 binding to the tripartite IL-2R complex. To extend our previous studies, which demonstrated that IL-2 regulates IL-2R alpha expression in vitro, we have analyzed expression in IL-2-deficient mice in vivo. As in control animals, CD4- CD8- thymocytes and bone marrow-derived B220+ pre-B cells were IL-2R alpha positive. In contrast, activated lymph node and splenic CD4 T cells (CD4+ CD69+) were found to be IL-2R alpha negative, whereas approximately 20% of the same cell populations from the MLR/lpr strain, which also accumulate large numbers of CD4-activated T cells in the presence of intact IL-2, retained expression. A similar pattern of IL-2R alpha expression was found among splenic CD8 cells from IL-2(-/-) and IL-2(+/-) animals. These findings demonstrate that in primary lymphoid organs, IL-2 is not directly involved in IL-2R alpha expression. However, at the level of mature lymphocytes, and more specifically CD4 T cells, IL-2 remains in vivo, as in vitro, the most critical cytokine controlling both IL-2R alpha expression and sensitivity to IL-2.
- Published
- 1998
34. Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets.
- Author
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David D, Bani L, Moreau JL, Demaison C, Sun K, Salvucci O, Nakarai T, de Montalembert M, Chouaïb S, Joussemet M, Ritz J, and Thèze J
- Subjects
- Anticoagulants pharmacology, Blood Specimen Collection, Calcium physiology, Cell Membrane metabolism, Chelating Agents pharmacology, Citrates pharmacology, Flow Cytometry, Gene Expression, Heparin pharmacology, Humans, Intracellular Fluid metabolism, Leukocytes, Mononuclear classification, Lymphocyte Subsets metabolism, Monocytes metabolism, Receptors, Interleukin-1 chemistry, Receptors, Interleukin-1 genetics, Leukocytes, Mononuclear metabolism, Receptors, Interleukin-1 biosynthesis
- Abstract
We have investigated the expression of the three components of the interleukin-2 receptor (IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma) on the surface of the various peripheral blood mononuclear cell (PBMC) subsets by flow cytometry analysis. The PBMC were immediately isolated (ficoll) from blood collected on heparin as anticoagulant. The three IL-2R components are absent or only marginally detectable on CD4 T lymphocytes. No expression of the IL-2R chains is found for the B lymphocytes. In most donors, the three chains are not detectable on CD8 T lymphocytes, but for a few of them, IL-2Rbeta or IL-2Rgamma are clearly expressed. CD56 high (IL-2Ralpha+) and CD56 low (IL-2Ralpha-) natural killer (NK) cells express IL-2Rbeta, but not IL-2Rgamma. IL-2Rgamma is expressed by monocytes of all donors although with variable intensity. When blood is collected on other anticoagulants or when cells are isolated 1 day after collection, IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma are largely expressed on the surface of most PBMC. This observation provides a possible explanation for divergent data previously reported on IL-2R expression. Finally, we show that IL-2Rgamma, which is not detectable on the cell surface of lymphocytes, is nevertheless expressed and stored as an intracellular component. This result is in agreement with the constitutive expression of the IL-2Rgamma gene and suggests a specific regulatory mechanism for IL-2Rgamma membrane translocation.
- Published
- 1998
35. Selective variations in vivo of VH3 and VH1 gene family expression in peripheral B cell IgM, IgD and IgG during HIV infection.
- Author
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David D, Demaison C, Bani L, Zouali M, and Thèze J
- Subjects
- Adult, B-Lymphocytes virology, Base Sequence, Gene Expression Regulation, HIV Infections genetics, Humans, Immunoglobulin D biosynthesis, Immunoglobulin G biosynthesis, Immunoglobulin M biosynthesis, Immunoglobulin Variable Region genetics, Molecular Sequence Data, RNA, Messenger analysis, B-Lymphocytes immunology, HIV Infections immunology, Immunoglobulin D genetics, Immunoglobulin G genetics, Immunoglobulin M genetics
- Abstract
We have analyzed the expression of VH gene families in IgM, IgD and IgG of peripheral blood B cells from a group of HIV-infected patients. CD19+CD20+ cells were purified and anchored reverse transcriptase-polymerase chain reaction products were hybridized with VH gene family probes. IgM, IgD and IgG that expressed a VH3 gene family segment, were decreased in patients with low CD4 counts and to a greater extend in patients with AIDS symptoms (up to 85% for IgG) compared to adult healthy donors. This was correlated with elevated levels of IgM and IgG encoded by a VH1 gene family segment (around 60% for IgG). These results confirm and extend previous work that has detected the VH3 gene family under-representation in HIV infection. Here, we show that, in vivo, this phenomenon actually affects the different B cell populations of the peripheral blood: IgM+ or IgG+ B cells and also IgM+IgD+ naive B cells. In the course of HIV infection, this results in their gradual depletion. Data presented here strengthen the hypothesis that a B-cell superantigen exists in HIV infection. These pronounced variations of the normally most-expressed VH gene family may be related to B cell abnormalities detected in HIV-infected patients.
- Published
- 1995
- Full Text
- View/download PDF
36. Analysis of human VH gene repertoire expression in peripheral CD19+ B cells.
- Author
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Demaison C, David D, Letourneur F, Thèze J, Saragosti S, and Zouali M
- Subjects
- Adult, Antigens, CD19 analysis, Base Sequence, DNA Primers chemistry, Female, Gene Expression, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Genes, Immunoglobulin, Humans, Male, Molecular Sequence Data, RNA, Messenger genetics, Sequence Alignment, Sequence Homology, Nucleic Acid, B-Lymphocyte Subsets immunology, Immunoglobulin Variable Region genetics
- Abstract
Using CD19 B-cell selection and polymerase chain reaction-amplified cDNA libraries, we analyzed the peripheral immunoglobulin heavy chain variable repertoire of three healthy adult donors. Here we report that most of the CD19+ circulating B cells expressed unmutated VH-D-JH rearrangements. By specific VH family hybridization, we show that VH gene family utilization in the periphery roughly corresponds to the complexity of these families in the germline and appears to be relatively constant among the analyzed subjects. However, sequence data of clones picked at random from one IgM cDNA library reveals that in spite of this "random" utilization, the VH gene expression in naive circulating B cells is highly biased towards the expression of a limited set of VH genes. As previously reported by others, this restricted mechanism is also found for the D and JH segments.
- Published
- 1995
- Full Text
- View/download PDF
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