AccueilAccueil>Research>Teams>Sébastien LACROIX-DESMAZES

Immunopathology and Therapeutic
Immuno-intervention

Our research focuses on some molecules derived from human plasma that are used for therapy, namely immunoglobulin G (IgG) and pro-coagulant factor VIII (FVIII). We scrutinize their interactions with the immune system (i.e., their capacity to regulate or to be the target of immune responses), and with molecules in the microenvironment (co-factors, molecules of the complement system), investigating the putative consequences on their structure, function and immunogenicity. We aim at translating our basic findings to the clinic, by developing new therapeutic molecules, or altering the existing protein therapeutics to reduce their immunogenicity
Our work focuses on:
1. Regulatory functions of normal IgG in physiopathology. Therapeutic normal immunoglobulin G (IVIG) is one of the most highly used therapies for autoimmune and inflammatory diseases and is a safe and effective therapy for the patients. However, some patients are refractory to IVIG treatment. We wish to identify the molecular targets and pathways through which IVIG inhibits inflammation and autoimmunity while enhancing immune tolerance, unravel new therapeutic targets for IVIG in autoimmune and inflammatory diseases, and identify biomarkers to predict patient responsiveness to treatment.
2. Cofactor-binding antibodies. The immune repertoire of healthy individuals contains antibodies (Abs) that bind diverse low molecular compounds, including essential cofactor molecules – heme, ATP, FAD. Our working hypothesis is that the binding of cofactors to circulating Abs is part of a physiological process: it can impact the functional properties of Abs and regulate the availability of the cofactors, modulating their catabolism and their signaling properties. A corollary is that the capacity of some monoclonal Abs to bind various cofactors may be used in different therapeutic strategies, for example for the selective and targeted delivery of compounds or catalytic activities at particular sites in infectious or inflammatory conditions, or for neutralizing the pathogenic potential of some cofactors (ATP, heme).
3. Immunogenicity of protein therapeutics. Using therapeutic pro-coagulant factor VIII (FVIII) as a model, we aim at understanding the immunogenicity of protein therapeutics. About 30% of patients with hemophilia A develop neutralizing Abs against therapeutic FVIII. We wish to dissect the interactions of FVIII with the immune system, and to decipher the state of central and peripheral tolerance to FVIII in health and disease together with the mechanisms underlying immune tolerance induction. We also develop novel strategies to prevent the onset of the anti-FVIII immune response, for instance by inducting materno-fetal tolerance using Fc-fused FVIII constructs, controlling memory B cells using immuno-suppressive drugs, or optimizing FVIII-derived molecules for induction of oral tolerance.


Materno-fetal transfer of fluorescent FVIII C2 domain fused to the Fc fragment of IgG. The fluorescent FVIII C2 domain was injected to pregnant mice and was found to accumulate in the placenta of fetuses from neonatal Fc receptor-deficient (left panel) mice, while it was transferred to fetuses of wild-type (right panel).

 
Team Leader :  Sébastien LACROIX-DESMAZES (DR; CNRS)

 

Team members:

Researchers:  Jagadeesh BAYRY (DR; Inserm), Paul COPPO (PU-PH; Sorbonne Univ), Jordan DIMITROV (CR; Inserm), Athina KALOPISSIS (DR em; Inserm), Srini V KAVERI (DR; CNRS), 

Technical Staff: Victoria DAVENTURE (IE; CDD), Sandrine DELIGNAT (IR; Inserm), Maxime LECERF (AI; Inserm), Justa LUENGO (Adj Tec; Inserm).

Young Researchers: Aurélien AZAM (Post-Doc), Melissa BENJAHOUDE (PhD Student), Nina BOZINOVIC (Post-Doc), Alexia KANAYUZ TAVARES (PhD Student), Anupama KARNAM (PhD Student), Angelina MIMOUN (PhD Student). Rémi NOE (PhD Student), Naresh RAMBABU (PhD Student), Rohini SEKAR (PhD Student).

 

Administration:  Véronique BARRAUD

Contact : Téléphone 33 1 44 27 81 93

 

Publications

  • Galeotti, C., E. Stephen-Victor, A. Karnam, M. Das, L. Gilardin, M.S. Maddur, S. Wymann, C. Vonarburg, A. Chevailler, J.D. Dimitrov, O. Benveniste, P. Bruhns, S.V. Kaveri and J. Bayry. 2019. Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE. J Allergy Clin Immunol. (in press)
  • Sharma, M., M. Das, E. Stephen-Victor, C. Galeotti, A. Karnam, M. S. Maddur, P. Bruneval, S. V. Kaveri, and J. Bayry. 2018. Regulatory T cells induce activation rather than suppression of human basophils. Sci Immunol 3.
  • Prigent, J., A. Jarossay, C. Planchais, C. Eden, J. Dufloo, A. Kok, V. Lorin, O. Vratskikh, T. Couderc, T. Bruel, O. Schwartz, M. S. Seaman, O. Ohlenschlager, J. D. Dimitrov, and H. Mouquet. 2018. Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity. Cell Rep 23: 2568-2581.
  • Rayes, J., M. Ing, S. Delignat, I. Peyron, L. Gilardin, C. W. Vogel, D. C. Fritzinger, V. Fremeaux-Bacchi, S. V. Kaveri, L. T. Roumenina, and S. Lacroix-Desmazes. 2018. Complement C3 is a novel modulator of the anti-factor VIII immune response. Haematologica 103: 351-360.
  • Das, M., C. Galeotti, E. Stephen-Victor, A. Karnam, S. V. Kaveri, and J. Bayry. 2017. Human basophils may not undergo modulation by DC-SIGN and mannose receptor-targeting immunotherapies due to absence of receptors. J Allergy Clin Immunol 139: 1403-1404 e1401.
  • Gupta, N., S. Culina, Y. Meslier, J. Dimitrov, C. Arnoult, S. Delignat, B. Gangadharan, M. Lecerf, S. Justesen, V. Gouilleux-Gruart, B. L. Salomon, D. W. Scott, S. V. Kaveri, R. Mallone, and S. Lacroix-Desmazes. 2015. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Sci Transl Med 7: 275ra221.
  • Lecerf, M., T. Scheel, A. D. Pashov, A. Jarossay, D. Ohayon, C. Planchais, S. Mesnage, C. Berek, S. V. Kaveri, S. Lacroix-Desmazes, and J. D. Dimitrov. 2015. Prevalence and gene characteristics of antibodies with cofactor-induced HIV-1 specificity. J Biol Chem 290: 5203-5213.

 

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