Michael J. Lenardo, M.D., NIAID, NIH, is the recipient of the 2020 AAI-Steinman Award for Human Immunology Research. He is recognized for his molecular characterization of primary immune disorders, resulting in new understanding of signaling pathways and novel successful treatments for patients.
Dr. Lenardo showed that activated T cells undergo programmed cell death upon T cell receptor restimulation and described the role of apoptosis in antigen-induced tolerance. He and his collaborators further demonstrated that dominant-negative mutations in the TNF-receptor Fas and resulting defects in lymphocyte apoptosis caused autoimmune lymphoproliferative syndrome.
This discovery provided confirmation of the role of Fas in peripheral tolerance and advanced understanding of the way Fas and TNF receptors signal. These studies broadened to describe other immune disorders caused by mutations of FasL, N-Ras, caspase-8, caspase-10, and others, and continued to provide mechanistic insight. His work defined a role for caspase-8 in lymphocyte activation via NF-κB activation and for CARD11 in B cell lymphocytosis.
Lenardo has not only described mutations in immunodeficiencies but has applied this knowledge to develop new therapeutic approaches. His laboratory demonstrated that mutations of the MAGT1 magnesium transporter were the cause of a novel primary immunodeficiency (XMEN) characterized by the inability to respond to Epstein-Barr virus. This discovery illuminated the role of magnesium flux in T cell activation and spurred the use of magnesium supplementation as a successful treatment for this disease. The description by Lenardo and his collaborators of activating mutations affecting PI3 kinase delta in an immunodeficiency (PASLI) associated with lymphoproliferation and T cell senescence led to promising clinical trials of PI3 kinase delta inhibitors for these patients. His discovery of CD55 deficiency as the cause for a lethal protein-losing enteropathy and thrombosis syndrome (CHAPLE) led to the successful use of a complement inhibitor as a long-term treatment.
Jean-Laurent Casanova, HHMI, investigator, professor, and head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, says, “A very specific feature of Dr. Lenardo’s work has been its direct therapeutic impact. Mike used his discoveries in pathogenesis to treat patients with new approaches based on a rational understanding of the disease mechanisms. His patient-based research is unique and has always been at the forefront of the field.”
Lenardo’s colleagues further laud his commitment to mentoring. Raif Geha, James L. Gamble Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, states, “His work is rigorous, substantive, creative, and well-respected in the field. Moreover, it is clear that he endeavors to pass along these qualities and his overall approach to science to those whom he mentors.”
Lenardo has trained more than 50 students and fellows, many of whom have gone on to leadership positions in academia, government, and industry. He also founded the NIH-Oxford-Cambridge Scholars Ph.D. program that has fostered international collaboration in student training through a dual-mentored Ph.D. with advisors at NIH and either Oxford or Cambridge in the United Kingdom.
Lenardo received his M.D. from Washington University School of Medicine, St. Louis. Following postdoctoral training at the University of Iowa and Massachusetts Institute of Technology, he joined the Laboratory of Immunology at NIAID as an investigator. He currently holds the positions of senior investigator and chief of the Molecular Development of the Immune System Section, chief of the Clinical and Molecular Genomics Unit, and director of the NIAID Clinical Genomics Program.
Lenardo is an elected member of the National Academy of Sciences and National Academy of Medicine, and a Fellow of the American Academy of Arts and Sciences. His honors include the NIH MERIT Award (awarded four times), NIH Director’s Award (awarded three times), and the NIH Clinical Center Director’s Award.
An AAI member since 1993, Lenardo has served as a lecturer at the AAI Introductory Course in Immunology and as a major symposium chair and speaker at the AAI annual meeting.