Clinical research program

Clinical Research programs driven by CIRI teams

Monitoring NK cell activity in humans

More and more data show that the human immune system differs greatly from the mouse immune system. It is therefore essential to validate the findings obtained in the mouse models in human. To this aim, we collaborated with the service de biologie at the Lyon-Sud hospital headed by Pr Jacques Bienvenu to set up a platform of human NK cell monitoring that complements our activity at the CIRI. We measure the following parameters in a blood sample:

  • Frequency and number of NK cells
  • Maturation and activation status
  • Expression of activating and inhibitory NK cell receptors
  • Expression of intracellular cytotoxic mediators
  • Expression of transcription factors important for NK cell function

We also perform functional tests that allow the measurement of the natural killing activity of NK cells and their antibody-induced cell cytotoxicity (ADCC) as well as their secretion of several cytokines in response to stimulation with tumor cells coated or not with antibodies.

Personnel involved:

  • Pr Jacques Bienvenu (head of service)
  • Emily Charrier, research engineer
  • Sébastien Viel, PhD student
  • Thierry Walzer

Research projects:

  • NK cell activity in patients with multiple myeloma (Collaboration Gilles Salles, LBMC Lyon; funding: Celgene)
    Multiple myeloma (MM) is a deadly B cell malignancy. MM cells have been shown to be recognized and killed by NK cells in a NKG2D and NCR-dependent manner. Yet, the activity of NK cells has been reported to be lower in the blood of MM patients suggesting that MM evades NK cell surveillance. This study aims at better characterizing NK cell activity in MM patients at early stages (MGUS) of the disease, at diagnosis and over time after treatment with lenalidomide, an immunomodulatory drug that is though to stimulate NK cell activity.
  • NK cell activity in patients with chronic infections (Collaboration Tristan Ferry – François Vandenesch HCL Lyon)
    Chronic infections often impact on the function of immune effectors, as exemplified by HIV infections. This study aims at better understanding the effect of different chronic infections (osteoarticular infections with S. Aureus, HIV, HCV, HIV+HCV) on the phenotype and functions of NK cells. In particular, we address the changes in the transcriptional networks that govern NK cell function.
  • NK cell activity in paediatric patients with primary immune deficiencies or autoimmune diseases (Collaboration Alexandre Belot, HFME Lyon, Yves Bertrand CLB)
    In collaboration with different hospitals, we explore NK cell function in different paediatric patients that suffer from recurrent infections, inflammation or autoimmunity that indicate genetic alterations of the immune function. Our NK cell monitoring platform helps characterizing the immune status of these patients and also to diagnose certain rare genetic syndromes (such as familial hemophagocytic lymphoproliferations)

Immunothérapie par vaccination anti-rougeoleuse chez l’adulte atteint de la dermatite atopique

Participants: Geraldine Gourru-Lesimple1, Thomas Thevenet1, Cindy B. Boer1, Marie Chalons1, Cyrille Mathieu1, Celine Giraud2, Sophie Grande3, Catherine Goujon3, Catherine Cornu2 and Branka Horvat1
1CIRI, INSERM U1111; CNRS UMR5308; University Lyon 1; ENS-Lyon ; 69365 Lyon, France
2 CIC201, CHU Lyon, Service de Pharmacologie Clinique, Lyon, F-69000 France
3Hospital Lyon-Sud, Unité de Recherche Clinique en Immunologie (URCI-LS), Lyon, France

The objective of this project is to investigate the immunomodulatory effect of anti-measles vaccine in the treatment of atopic dermatitis (AD). The clinical study has been carried out in Hospital Lyon Sud, Clinical Research Unit in Immunology, with a participation of Center for Clinical Investigation-Lyon. This study aims to analyze the modulation of pathophysiological parameters and therapeutic efficacy of vaccination ROUVAX, live attenuated measles virus in patients with atopic dermatitis (AD). The effectiveness of treatment is objectified by: 1. the evolution of biological and immunological parameters associated with the disease 2. the immunomodulatory effect on subpopulations of CD4+ T cells 3. improvement of clinical signs of disease (SCORAD) 4. modulation of the production of chemokines in skin of patients, analyzed by RT-qPCR of biopsies. In light of our previous results, our working hypothesis is that the measles vaccination could have a therapeutic effect particularly suitable for the treatment of inflammatory disorders mediated by T lymphocytes. This study, by providing a proof of concept of the vaccinotherapy in AD, should allow progress in the development of innovative immunotherapeutic strategies for inflammatory diseases.

Inflammasome dysregulation and autoinflammatory syndromes

People involved: Bénédicte Py, Thomas Henry
In collaboration with Bicêtre Hospital, the laboratory investigates biochemical signatures associated with inflammasome dysregulation in patients suffering autoinflammatory diseases. In collaboration with Cochin and Montpellier Hospitals, our team aims at facilitating autoinflammatory syndrome diagnosis by investigating putative polymorphisms in genes regulating inflammasome. These projects are funded by the ANR.

Staphylococcus aureus Necrotizing pneumonia:

People involved: Coordinator: F. Vandenesch. Researchers and National Reference Centre for Staphylococci: F.Vandenesch, Thomas Henry, Gerard Lina, Anne Tristan, Mitra Saadatian, M. Bes. Clinicians: Y.Gillet (pediatrician coordinator), L. Argaud (ICU coordinator). Genetics: C. Picard, L. Abel, J.L. Casanova (INSERM-U980, Faculté Necker Paris)

Community-acquired necrotizing pneumonia due to Panton-Valentine Leukocidin (PVL) producing strains of S. aureus , first described in 2002 by our team, is a severe infection leading to hospitalization in Intensive Care Units.

Overall, 3% of S. aureus strains express PVL. This corresponds to approximately 0.6 million strains circulating in France. However, PVL associated community-acquired necrotizing pneumonia remains a rare disease with an annual number of 30-50 cases reported in France. These data suggest that individuals developing the disease would have a genetic predisposition that facilitate the occurrence of the infection .

Even if several clinical studies report on the severity of necrotizing pneumonia, the role of PVL as an independent factor of severity remains controversial. Our earlier investigations provided evidence of a significant increase in the rate of methicillin resistant strains (MRSA) of PVL between 2002 and 2007. However, in the absence of mandatory declaration, the exact prevalence of resistance to antibiotics is unknown. Furthermore, to our knowledge, the hypothesis of genetic susceptibility has not yet been investigated. To address the aforementioned points, we set-up a prospective cohort study at national level. The study has been funded by the ministry of health (PHRC interrégional 2010) and will include all new cases of S. aureus pneumonia admitted to adult and pediatric ICU during a three years period.

Objectives: (i) Confirm the role of PVL as an independent factor of severity in community- acquired S. aureus pneumonia – Identify clinical and/or biological factors associated with the disease prognostic – Assess the level of antibiotic sensitivity of S. aureus strains carrying PVL. (ii) Investigate the genetic susceptibility of the host that could explain the atypical characteristics (rare and severe) of the disease

Study design and population: Prospective cohort study including two components: (i) Observational study: 97 PVL-positive and 97 PVL-negative cases of community-acquired S. aureus pneumonia leading to hospitalization in ICU. (ii) Genetic study: 40 PVL-positive patients and 90 family members

This cohort and its afferent biotheque will form the basis of a collaborative fundamental project financed by ANR Blanc, which will focus on staphylococcal pore-forming toxins receptor and the genetic susceptibility of the human host to these toxins.

“Immunology of skin allergy and vaccination”

People involved: Jean-François NICOLAS, Aurore ROZIERES, Marc VOCANSON, Coline DELATTRE, Gaelle POYET, Karen RODET, Catherine GOUJON-HENRY, Sophie GRANDE, David BOTTIGIOLI

Three research programs accredited by Lyon BioPôle has been accepted by the Ministry of Industry under the FUI programs.

Lyon BioPôle is a world competitive cluster, labeled the 12.07.2005, which aim of research is human and animal infectious diseases, their diagnosis and prevention by vaccines.

Intradermal injectThe first program, “Microvax” was accepted in 2006 and was completed in 2009. It was a new system of vaccination by intradermal microinjection, developed by Becton Dickinson in partnership with Sanofi Pasteur and Inserm. This project aims to make available to health professionals a vaccination system by microinjection to deliver precisely micro-volumes of vaccine, while improving the effectiveness of vaccination. All Microvax clinical studies in humans were carried out under the responsibility of URCI-LS.

The second program, “Expand ID” was accepted in 2009 and is ongoing. The overall objective of the Expand ID program is the extension of the application scope of ID vaccination to new vaccine targets (non-responders to IM vaccination), a greater diversity of types of vaccine antigens (live attenuated vaccines, subunit vaccines, polysaccharide conjugate vaccine) and a technological diversification by applying the technology of Becton Dickinson micro-needles to area of lyophilized vaccines. All Expand ID clinical studies in humans was carried out under the responsibility of URCI-LS.

The third program, TB-Dermatest project brought together industrial partners (BD-France, PX’Therapeutics [PXT]) and academics (Inserm U629, Institut Pasteur de Lille [IPL]; Inserm U851-URCI-LS-HCL, CEA-LETI)

A clinical study has validated the BD microinjection system compared to the classic ID tuberculin injection on 30 patients between January and March 2012. Preliminary analysis of the results showed that it does not seem to be any major difference between the two injection methods (BD micro needle and technical Mantoux).

Probe spectrometry with white light allowed characterizing the inflammatory response to the injection of tuberculin separating the phenomena of scattering and absorption and quantifying control chromophores. Thus, this easy handling probe allows an objective and quantitative reading of a dermal inflammatory reaction.

Phenotypic and functional study of the anti-infectious immune reconstitution in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) (Moëlle et Partage, Guillaume Espoir, HCL, Inserm, CNRS, UCBL)

People involved : Coordinator: MC Michallet. Clinicians: Pr M. Michallet, Dr H. Labussière-Wallet, Pr Y. Bertrand, Dr Aurélien Marabelle, Pr J. Bienvenu, Pr D. Guyotat, Dr J. Cornillon, Pr J.O. Bay, Dr E. Hermet. Research Scientists: Dr C. Caux, Dr C. Menestrier-Caux, Dr J. Marvel, Dr M.C. Michallet, Dr T. Walzer

This project is a prospective longitudinal study of 100 patients undergoing allogeneic HSCT. The main objective of the project is to conduct a comprehensive immunological phenotypic and functional monitoringof the immune reconstitution after allogeneic HSCT depending on the source of HSCs (Bone Marrow, Stem Cells or Cord Blood). Immuno-monitoring will be performed by flow cytometry, and all data will be calibrated and standardized for longitudinal monitoring of patients to ensure the high sensitivity of each marking and data mining posteriori hierarchically or without supervision. The secondary objective of this project is to understand the role of different immune sub-populations in the control of viral infections. The number of patients included in the study should allow to establish correlations between the frequencies of immune sub-populations and the emergence of viral complications.
This project is based on the synergy of expertise of clinical HSCT departments (Lyon: adults and children, Saint-Etienne, Clermont-Ferrand) and two immunomonitoring plateforms (Cancer Research LYON (LYRIC)) with the active participation of research units working on antiviral immunity, cytotoxic lymphocytes, NK cells and dendritic cells (DC) (CIRI, CRCL). This project is funded by the partners and patient organizations, and grant applications are in progress (PHRC, ARC).

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