Antibodies in Therapy & Pathology (INSERM U.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).

Aims:

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

– Establish high-throughput plasma cell selection using droplet microfluidics to generate the “anatomical map” of antigen-specific plasma cells, and demonstrate the pathogenic nature of antibodies in specific diseases.

     How antibodies and their receptors induce/regulate autoimmune and allergic diseases is addressed using on one hand models of rheumatoid arthritis and anaphylaxis (allergic shock) in humanized mice and, on the other hand through a clinical study (NASA).

     How antibodies and their receptors participate in passive antibody therapy is addressed using human tumor xenografts in the mouse.

     How antigen-specific plasma cells disseminate in vivo and to identify antibodies at high-throughput is addressed using droplet-based microfluidic technologies developed at ESPCI-ParisTech

In most projects, we aim at identifying the cell population(s) responsible for antibody-mediated effects, and decipher the mechanism behind their contribution to therapy or pathology. 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. 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.

 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

• Identification of the differential pathways of anaphylaxis induced by the three main IgG subclasses in mice -IgG1, IgG2a and IgG2b – (Beutier et al, J Aller Clin Imm 2016)
• Identification of neutrophils as the cell population responsible for anti-tumor immunotherapy of solid tumors (Albanesi et al, Blood 2013).
• Demonstration that human IgG receptor (FcγRI,CD64) can trigger autoimmune and allergic diseases, and that it can mediate anti-tumor antibody therapy (Mancardi et al, Blood 2013).
• Demonstration that human IgG receptor (FcγRIIA,CD32A) can trigger anaphylaxis and airway inflammation (Jönsson et al, Blood 2012).
• Demonstration that neutrophils are the main inducers of active anaphylaxis in the mouse and that human neutrophils can induce anaphylaxis (Jönsson & Mancardi et al, J Clin Invest 2011).