Three Department of Medicine faculty were recently elected to the Association of American Physicians (AAP): Marisa Alegre, MD, PhD, Gokhan Mutlu, MD and Thomas Gajewski,MD,PhD. The AAP is an honorific, elected society of America’s leading physician-scientists who exemplify the pinnacle of pioneering and enduring, impactful contributions to improve health.

Dr. Alegre, Professor of Medicine in the Section of Rheumatology, is a leader in the field of transplantation immunology. Stemming from her clinical training as an intensivist and her basic immunology training, she addresses critical clinical questions with new mouse models of solid organ transplantation. This has led to several paradigm-shifting discoveries. In collaboration with Anita Chong’s group, her work has focused on the mechanisms necessary to achieve the goal of one transplant for life. Their group has identified several novel mechanisms that additively contribute to long-term graft stability and has modeled in mice the erosion, and breaking of tolerance that can be brought about by infections. In the process, they uncovered the intriguing phenomenon of memory of tolerance, where tolerance mechanisms are restored post-infection. Their work on the consequences of infections in transplanted hosts led Dr. Alegre to study the impact of commensals on transplant outcome. Her group was the first to demonstrate the causal modulation of anti-transplant immune responses by the microbiota and the distinct impact of gut versus skin microbiota on skin allografts, with important clinical implications for transplanted colonized organs.

Dr. Alegre has been recognized with many national and international awards during her career including American Transplantation Society’s Basic Science Investigator Award in 2019, and is an elected member of the ASCI and the Henry Kunkel Society.

Dr. Mutlu, Professor of Medicine and Chief, Section of Pulmonary and Critical Care, has made significant contributions to pulmonary and critical care and environmental health sciences research. His seminal contribution is the discovery of the mechanistic link between particulate matter air pollution and acute thrombotic events via the development of a prothrombotic state and activation of sympathetic nervous system and release of catecholamines. This paradigm shifting discovery not only provided new research avenues for environmental health research community but also has given hope to over 4 million people who die annually from air pollution, the greatest environmental health risk in the world. For his work, Dr. Mutlu received the prestigious Outstanding New Environmental Scientist (ONES) Award from NIEHS in 2006. Since then, he has expanded this work into understanding the role of lung macrophage metabolism and epigenetics through additional funding from NIEHS.

In addition to his contributions to environmental health research, Dr. Mutlu has made significant contributions to our understanding about the mechanisms of acute lung injury/ARDS, and pulmonary fibrosis. Some of his discoveries include the role of β2-adrenergic receptors and leptin signaling in acute lung injury and fibrosis. Increasingly, his research has focused on understanding how cellular metabolism in lung cells (macrophages, epithelial cells and fibroblasts) is altered during acute lung injury and fibrosis. His research team has recently discovered that serine glycine synthesis pathway is upregulated in pulmonary fibrosis and importantly is required for collagen protein synthesis. These recent studies provide promising therapeutic targets for a lethal disease that lack effective therapies.

Dr. Mutlu has served as a standing member of NIH Environmental Health Sciences (EHS) Review Committee and continues to participate as an ad hoc reviewer in numerous NIH Study sections. He is an elected member of the ASCI.

Dr. Gajewski, the AbbVie Foundation Professor of Cancer Immunotherapy  in the Ben May Department for Cancer Research and Professor of Pathology and Medicine (Hematology/Oncology) , is an internationally recognized physician scientist who has made seminal contributions to cancer immunotherapy. Beginning with therapeutic cancer vaccines in melanoma, he utilized patient material for reverse-translation discoveries around fundamental mechanisms in anti-tumor immunity, enabling translation of new therapeutic strategies back to the clinic in cancer patients. His current work focuses on identifying how tumors actively evade immunity, is transforming the cancer field.  Dr. Gajewski is responsible for several landmark discoveries, including: a) the observation that a major subset of patients have a T cell-inflamed tumor microenvironment, suggesting that their immune system was capable of recruiting T cells but that inhibitory pathways (including PD-1, IDO, and Tregs) restrained their function; b) that spontaneous immune priming can be driven by tumor-derived DNA , which is sensed by innate immune cells through activation of the STING pathway; c) that non-T cell-inflamed tumors can show activation of specific oncogene pathways that cause immune evasion, the first of which was the Wnt/ b-catenin pathway that leads to T cell exclusion and immunotherapy resistance; and d) the commensal microbiota can profoundly impact on anti-tumor immune responses, such that specific bacteria as a probiotic can improve tumor control and synergize with immunotherapies.   His discoveries have contributed to a) FDA approval of anti-PD1 antibodies for melanoma, and combination studies with IDO inhibitors that are in phase 3 clinical trials; b) development of new drugs that can stimulate the STING pathway, now in phase I studies; c) prioritization of Wnt/b-catenin pathway inhibitors as a therapeutic approach to expand immunotherapy efficacy; and d) identification of a role for the gut microbiota in regulating anti-tumor immunity.  Each of these discoveries has led to new therapeutic strategies being explored in the clinic.

Dr. Gajewski is the first recipient of the American Cancer Society Plangere Immunotherapy Professorship and has received numerous recognition, most recently the European Society for Medical Oncology Immuno-Oncology Award. He is an elected member of the ASCI and served as President of the Society for the Immunotherapy of Cancer.