Research

Antibodies in Therapy & Pathology (INSERM U.760)

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 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 mouse FcγRIII (CD16) and mouse FcγRI (CD64) are responsible for anti-melanoma antibody therapy in a syngeneic mouse metastatic melanoma model (Albanesi et al., J Immunol Cutting Edge 2012)

- 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).

 

ONGOING PROJECTS

 

PROJECT 1: Developing novel models of disease and vaccination in Ab- and FcR-humanized mice: establishment in these mice of clinically pertinent models of allergic and autoimmune (inflammatory) diseases. Refer to ERC MyeloSHOCK for research on Anaphylaxis.

  

PROJECT 2: Clinical and pathological consequences of human anti-drug antibodies (NASA study) that aims at demonstrating in the clinic that neutrophils are activated by antibody-curare complexes and involved in curare-induced anaphylaxis (allergic shock) in humans, and at establishing in parallel a mouse model of curare-induced anaphylaxis.

http://clinicaltrials.gov/ct2/show/NCT01637220

 

PROJECT 3: Deep-mining of antibody repertoires using droplet-based microfluidics combined with barcoded deep sequencing for diagnostics and therapeutic antibody discovery. Aim: establish the proof of concept for high-throughput antibody selection, generate the “anatomical map” of Ag-specific plasma cells, and demonstrate the pathogenic nature of antibodies in two pathological conditions (rheumatoid arthritis and anaphylaxis). Refer to ANR DROPmAbs for research novel technologies for antibody and plasma cell identification.

 

PROJECT 4: Role of platelets and their interactions in allergic diseases that aims at understanding how platelets induce/promote/regulate antibody-induced allergic diseases, their interaction partners (myeloid cells, endothelium) and their dynamics.


PROJECT 5: Antibody-based anti-tumor immunotherapy that aims at identifying the human FcγRs involved in melanoma and/or breast cancer immunotherapy, and at identifying the effector population(s) responsible for tumor destruction.

Updated on 10/10/2014

Contact

Laboratory of Antibodies in Therapy and Pathology

INSERM U.760

Département d’Immunologie

Institut Pasteur

25, rue du Docteur Roux

75015 Paris

France

General enquiries: Ms Danièle SINNAYA

daniele.sinnaya@pasteur.fr

 

Head and Principal Investigator

Dr. Pierre Bruhns, PhD

bruhns@pasteur.fr

 

Investigator

Dr. Friederike Jönsson, PhD

joensson@pasteur.fr

INTERNSHIP REQUESTS

- CV + publication list

 

- Motivation letter detailing why you are interested by our recent research and investigation areas (standard motivation letters will not be considered).

 

Send requests to bruhns@pasteur.fr

Organizer

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