Project Details
Description
Targeting human rhinoviruses and group 2 ILC in asthma exacerbations
Asthma constitutes a group of debilitating chronic diseases that affects millions of people worldwide, profoundly impacting patient quality of life and incurring large costs in terms of treatment and lost productivity. In particular so called asthma exacerbations induced by respiratory viruses such as human Rhinovirus and respiratory syncytial virus present significant unmet medical need. Successful discovery and development of more effective therapies to treat asthma exacerbations depends first on a better understanding of the underlying mechanisms, including how proinflammatory cells proliferate unchecked, and how the body’s own mechanisms might be enlisted to control inflammation and second on inhibition of exacerbating respiratory viruses. My group is addressing this challenge in two ways. First, we have discovered and characterized populations of innate lymphoid cells (ILCs) including ILCs that produce high amounts of Th2 cytokines (ILC2) and demonstrated amplified numbers of these cells in inflamed nose polyps in rhinosinusitis, a chronic type 2 inflammatory disease. Second, our group has developed a technological breakthrough that permits the establishment of clonal,
antigen-specific human B cell lines using a unique genetic reprogramming technology. Using this technology we have generated broadly reacting, highly neutralizing, human monoclonal antibodies against respiratory syncytial virus and influenza virus. We hypothesize that ILC2 activated by respiratory viruses are key players in asthma exacerbations induced by these viruses and are therefore compelling targets for effective therapies for asthma. Our objectives are to identify the key drivers of function of ILC2 and to develop broadly reacting highly neutralizing antibodies against human rhinovirus (HRV) which accounts for the majority of asthma exacerbations. In addressing these objectives, we make use of extensive expertise in fundamental human immunology with groundbreaking, translational approaches using human tissue biopsy samples, state-of-the-art in vitro techniques, and a human immune system mouse model developed by our laboratory that permits in vivo study of the human immune system.
ILC in the human Intestine
ILC play important roles in innate immunity, maintenance of tissue homeostasis and tissue repair after damage inflicted by pathogens. Our group investigates development and function of ILC populations present in different compartnments present in non-inflamed intestine and in intestines of patients suffering Inflammatory Bowel diseases, in particular Crohn's disease and Ulcerative Colitis. The ultimate goal is to determine whether these cells play a role in the pathology. If so the knowledge acquired in this project can result in new therapies targeting ILC.
Characterization of immortalized human B cells
We have developed a highly efficient platform to generate human monoclonal antibodies. The platform uses B cells immortalized by genetic modification. We also have set up a mouse model with a rudimentary human immune system; the so called human immune system (HIS) mouse. B cells develop in these mice but those cells do not mature. In this project we investigate how we can optimise B cell maturation in HIS. If successful this project will provide tools to optimally test the response of human immune cells against vaccines in vivo and to make fully human monoclonal antibodies against clinical targets following immunization.
Human monoclonal antibodies against tumor antigens
Immunotherapies such as treatment with checkpoint inhibitors such as antibodies against PD-1 and CTLA4 have a major impact on survival in a number of cancers, particular melanoma. Whereas the role of T cells in the immuneresponse against cancer cells following checkpoint inhibition is well established, the role of B cells and the antibodies they produce has not yet been systematically studied. We hypothesize that B cells of patients who successfully respond to immunotherapy produce antibodies that contribute to the tumor free status of these patients. Such antibodies may have therapeutic utility. In collaboration with Dr Mette Hazenberg of the department of Hematology, Dr Rosalie Luiten of the department of dermatology of the AMC and the AMC spin out company AIMM Therapeutics we establish B cell clones from patients with a durable remission following immunotherapy. We focus on Melanoma patients tretead with cellular therapies or with checkpoint inhibitors and on Acute Myeloid Leukemia patients treated with allogeneic stem cell transplatation. From peripheral blood B cells of these patients we establish immortalized B cell clones and screen these clones for production of
antibodies that specifically react with tumor cells. A number of tumor-specific antibodies have been generated which are now tested for their potential to reduce tumor growth
Asthma constitutes a group of debilitating chronic diseases that affects millions of people worldwide, profoundly impacting patient quality of life and incurring large costs in terms of treatment and lost productivity. In particular so called asthma exacerbations induced by respiratory viruses such as human Rhinovirus and respiratory syncytial virus present significant unmet medical need. Successful discovery and development of more effective therapies to treat asthma exacerbations depends first on a better understanding of the underlying mechanisms, including how proinflammatory cells proliferate unchecked, and how the body’s own mechanisms might be enlisted to control inflammation and second on inhibition of exacerbating respiratory viruses. My group is addressing this challenge in two ways. First, we have discovered and characterized populations of innate lymphoid cells (ILCs) including ILCs that produce high amounts of Th2 cytokines (ILC2) and demonstrated amplified numbers of these cells in inflamed nose polyps in rhinosinusitis, a chronic type 2 inflammatory disease. Second, our group has developed a technological breakthrough that permits the establishment of clonal,
antigen-specific human B cell lines using a unique genetic reprogramming technology. Using this technology we have generated broadly reacting, highly neutralizing, human monoclonal antibodies against respiratory syncytial virus and influenza virus. We hypothesize that ILC2 activated by respiratory viruses are key players in asthma exacerbations induced by these viruses and are therefore compelling targets for effective therapies for asthma. Our objectives are to identify the key drivers of function of ILC2 and to develop broadly reacting highly neutralizing antibodies against human rhinovirus (HRV) which accounts for the majority of asthma exacerbations. In addressing these objectives, we make use of extensive expertise in fundamental human immunology with groundbreaking, translational approaches using human tissue biopsy samples, state-of-the-art in vitro techniques, and a human immune system mouse model developed by our laboratory that permits in vivo study of the human immune system.
ILC in the human Intestine
ILC play important roles in innate immunity, maintenance of tissue homeostasis and tissue repair after damage inflicted by pathogens. Our group investigates development and function of ILC populations present in different compartnments present in non-inflamed intestine and in intestines of patients suffering Inflammatory Bowel diseases, in particular Crohn's disease and Ulcerative Colitis. The ultimate goal is to determine whether these cells play a role in the pathology. If so the knowledge acquired in this project can result in new therapies targeting ILC.
Characterization of immortalized human B cells
We have developed a highly efficient platform to generate human monoclonal antibodies. The platform uses B cells immortalized by genetic modification. We also have set up a mouse model with a rudimentary human immune system; the so called human immune system (HIS) mouse. B cells develop in these mice but those cells do not mature. In this project we investigate how we can optimise B cell maturation in HIS. If successful this project will provide tools to optimally test the response of human immune cells against vaccines in vivo and to make fully human monoclonal antibodies against clinical targets following immunization.
Human monoclonal antibodies against tumor antigens
Immunotherapies such as treatment with checkpoint inhibitors such as antibodies against PD-1 and CTLA4 have a major impact on survival in a number of cancers, particular melanoma. Whereas the role of T cells in the immuneresponse against cancer cells following checkpoint inhibition is well established, the role of B cells and the antibodies they produce has not yet been systematically studied. We hypothesize that B cells of patients who successfully respond to immunotherapy produce antibodies that contribute to the tumor free status of these patients. Such antibodies may have therapeutic utility. In collaboration with Dr Mette Hazenberg of the department of Hematology, Dr Rosalie Luiten of the department of dermatology of the AMC and the AMC spin out company AIMM Therapeutics we establish B cell clones from patients with a durable remission following immunotherapy. We focus on Melanoma patients tretead with cellular therapies or with checkpoint inhibitors and on Acute Myeloid Leukemia patients treated with allogeneic stem cell transplatation. From peripheral blood B cells of these patients we establish immortalized B cell clones and screen these clones for production of
antibodies that specifically react with tumor cells. A number of tumor-specific antibodies have been generated which are now tested for their potential to reduce tumor growth
| Status | Active |
|---|---|
| Effective start/end date | 1/01/2011 → … |