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).
Our aim is to decipher the role of human antibodies, human antibody receptors (FcRs) and the cells expressing them during therapy and in the induction of pathologies. 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. In all these 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.
- Identification of the ligands of all human IgG receptors, thereby describing new receptors for IgG2 and IgG4 (Bruhns et al, Blood 2009).
- Identification of unexpected mouse IgG and IgE receptors and of cells involved in autoimmune and allergic diseases (Mancardi et al, J Clin Invest 2008) (Mancardi & Jönsson et al, J Immunol 2011).
- 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).
- Demonstration that human IgG receptor (FcgRIIA,CD32A) can trigger anaphylaxis and airway inflammation (Jönsson et al, Blood 2012).
- Demonstration that mouse FcgRIII (CD16) and mouse FcgRI (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 (FcgRI,CD64) can trigger autoimmune and allergic diseases, and that it can mediate anti-tumor antibody therapy (Mancardi et al, Blood 2013).
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 and of vaccination.
PROJECT 2: Antibody-based anti-tumor immunotherapy that aims at identifying the human FcgRs involved in melanoma and/or breast cancer immunotherapy, and at identifying the effector population(s) responsible for tumor destruction.
PROJECT 3: 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.
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 dynamic.