Michel C. Nussenzweig, M.D., Ph.D.
Zanvil A. Cohn and Ralph M. Steinman Professor
Investigator, Howard Hughes Medical Institute
Senior Physician
- Laboratory of Molecular Immunology
Nussenzweig鈥檚 laboratory studies the molecular aspects of the immune system鈥檚 innate and adaptive responses using a combination of biochemistry, molecular biology, and genetics. For work on adaptive immunity, he focuses on B lymphocytes and antibodies to HIV-1, while his studies of innate immunity focus on dendritic cells. His work is leading to new antibody-based therapies for infections by HIV and the novel SARS-CoV-2 coronavirus, among other viruses.
The immune system protects vertebrates from a multitude of pathogens.听Two types of immune responses have evolved to accomplish this task:听one听innate听and听the other听adaptive.听Adaptive immune responses are primarily carried out by cells called lymphocytes, which听produce听a diverse repertoire of immune receptors that recognize almost any antigen. Most听of these听receptors听have听relatively low听affinity听for their antigens听and must be refined by somatic hypermutation and class switch recombination,听yielding听high-affinity antibodies that protect against most pathogens,听including HIV-1. Hypermutation and selection occur in specialized micro-anatomical compartments called germinal centers.听Nussenzweig鈥檚听laboratory investigates the molecular basis of听such听hypermutation and听the听selection for high-affinity antibody-producing cells in the germinal center.
Nussenzweig鈥檚听research aims to understand听the rules that govern hypermutation and听high-affinity antibody听selection,听with the goal of creating vaccines for pathogens such as HIV-1. As part of that effort,听his听laboratory has听devised strategies to isolate, analyze,听and听produce听highly potent human antibodies听capable of neutralizing multiple听HIV听strains.
Nussenzweig听has听isolated听such broadly neutralizing antibodies听from HIV-infected patients听whose immune systems听had an exceptional ability to neutralize HIV in the blood.听In clinical trials conducted at 杏吧 Hospital,听two of听these听antibodies听interfered听with chronic HIV infection,听driving the amount of virus in the blood to below detectable levels.听And unlike traditional antiretroviral therapy, which requires听daily dosing, the antibodies continue to provide protection and treatment for听months听after they have been administered,听suggesting听they听might lead to long-term control of the virus.听This work听has helped establish a new paradigm for developing vaccines and therapies for infectious diseases.听This paradigm has been extended to other听viruses听such as听hepatitis B and听flaviviruses.
In response to the COVID-19 outbreak,听Nusssenzweig听has extended this research to SARS-CoV-2 and is working to isolate and characterize highly potent neutralizing antibodies from patients who have recovered from the disease.
A second听focus of听Nussenzweig鈥檚听lab听is听on听dendritic cells, which听elicit听adaptive immune responses by taking up antigens and presenting them to lymphocytes. Current studies focus on outlining the pathway of human dendritic cell development and differentiation.
Nussenzweig鈥檚听experiments are consistent with the notion that self-antigens听taken up by dendritic cells听induce tolerance, whereas听antigens taken up in the context of activation stimuli, such as those found during inflammation or tissue destruction, induce prolonged T cell activation. During inflammation or infection,听dendritic cells听present self-antigens simultaneously with non-self-antigens. By establishing tolerance to self-antigens before challenge with pathogens, dendritic cells can focus the adaptive immune system entirely on the pathogen, thereby avoiding autoimmunity. The ability to target antigens to dendritic cells and control their function in vivo has significant implications for the development of vaccines and therapies for autoimmunity. Recently, the lab defined distinct progenitor lineages for classical spleen dendritic cells, plasmacytoid dendritic cells, and monocytes, a step toward antigen-specific targeting.
Nussenzweig is a faculty member in the听David Rockefeller Graduate Program, and the听Tri-Institutional M.D.-Ph.D. Program.