Antibodies in Therapy & Pathology (INSERM UMR 1222): from Allergy & Autoimmunity to Cancer Immunotherapy

Antibodies are key effectors of the immune system. They are responsible for disease induction (autoimmunity, allergy) and can be protecting from or facilitating infections and tumors. Antibodies do not exert by themselves, however, biological functions: these are mainly mediated by antibody receptors (FcRs) and complement.

Aims:

1) Decipher the role of human antibodies, human antibody receptors (FcRs) and the cells expressing them, and human complement during therapy and in the induction of pathologies.

2) Establish high-throughput plasma cell screening, analysis and sorting using droplet microfluidics technologies to understand the antibody response, and demonstrate the pathogenic nature of antibodies in specific diseases (collaboration with ESPCI-ParisTech and HiFiBio)

3) Develop “humanized” mouse models and clinical studies (NASA; PlanA) to understand how antibodies and their effector functions induce/regulate autoimmune (rheumatoid arthritis, thrombocytopenia) and allergic diseases

4) Develop immunodeficient mice bearing human FcRs to study therapeutic antibodies against human tumors

To enhance the clinical relevance of our studies in mice, we have generated “humanized” mouse models expressing human FcRs in the presence of human antibodies, and soon human complement and targets. Our recent focus has been on FcR-expressing myeloid cells, in particular neutrophils and monocytes/macrophages that we extend now to platelets and their interaction with neutrophils, and to mast cells.

Altogether, our research integrating fundamental, clinical and industry-driven approaches, aims at elucidating the role of antibodies, their receptors and the cells expressing them in major disease and therapy models and, hopefully, propose novel therapeutic solutions in antibody-based therapies.

• RECENT HIGHLIGHTS

• Evidence that neutrophils do not promote Echis carinatus venom-induced tissue destruction. Stackowicz J, et al. Nat Commun. 2018

• Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis. Beutier H, et al. Sci Immunol. 2018

• Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring. Eyer K, et al. Nature Biotech 2017

• IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions. Lee CH et al, Nature Immunol 2017
• Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. Reber LL and Gillis CM et al, J Exp Med 2017

• IgG subclasses determine pathways of anaphylaxis in mice. Beutier H, et al. J Allergy Clin Immunol. 2017

• Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice. Gillis CM, et al. J Allergy Clin Immunol. 2017

• Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. Balbino B, et al. J Allergy Clin Immunol. 2017