Jorfi Lab

Research Overview

The interplay between the brain and the immune system plays a critical role in the neuropathology of neurological diseases. However, precise mechanistic underpinnings still need to be discovered. Interactions between the nervous and immune systems are complex and can have beneficial or detrimental impacts on brain function, depending on the context. Thus, it is crucial to understand the biological mechanisms that give rise to these divergent outcomes.

The Jorfi Lab develops multicellular engineered living systems as human surrogates to model components of the human immune system and delve into the mechanisms underlying neural-immune crosstalk in neurological diseases, primarily focusing on Alzheimer’s disease and multiple sclerosis. Leveraging a multidisciplinary approach, the lab combines molecular and cellular biology, neuroimmunology, multicellular engineered living systems, transcriptomic and functional profiling to discover fundamental neuroimmune interactions and inspire new therapeutics for patients with neurological conditions.

Projects in the lab fall into three major categories:

Modeling neurodegeneration using multicellular engineered systems

The current understanding of neurological disorders primarily derives from studying patients and animal models. However, patient examinations often miss the early stages of disease progression and provide limited opportunities for intervention. Animal models also fall short in fully replicating human pathophysiology. To address these gaps, the Jorfi Lab is creating tissue chip platforms that use microfluidic technologies and 3D-cultured human pluripotent stem cells. These models include neurons, astrocytes, microglia, vascular networks, and peripheral immune cells, providing a holistic representation of the complex interplay between the nervous and immune systems and their interactions in neurological diseases. The lab aims to unravel the molecular intricacies of central-peripheral immune interactions and their role in neurodegeneration.

Neuroimmune mechanisms in Alzheimer’s disease

Alzheimer’s disease is linked with significant alterations in the innate immune system (both in terms of microglia and peripheral immune cells) and the adaptive immune system. The Jorfi Lab employs multicellular engineered living systems to elucidate important signaling between brain cells and the immune system and how these are perturbed in Alzheimer’s disease. Recent findings highlight the infiltration of CD8+ T cells into the brain model of Alzheimer’s, triggering glial activation and exacerbating neuroinflammation and neurodegeneration. An antibody therapeutic is utilized to ameliorate this damage by preventing these cells from entering the brain and causing damage to neural cells. The lab also seeks to understand the role of brain barrier breakdown and immune signaling across brain barriers in Alzheimer’s disease. The studies aim to uncover the underlying mechanisms of brain-immune crosstalk and inform new therapies.

Neuroimmune mechanisms in multiple sclerosis

The interaction between the immune and nervous systems plays an important role in various neurological disorders. Multiple sclerosis is a chronic inflammatory disease involving a complex interplay between brain resident cells and peripheral immune cells. Immunotherapeutic drugs for relapsing-remitting have shown limited effectiveness in treating the progressive form of the disease. Expanding on its long-standing interest in neuroimmune interactions, the Jorfi Lab's research aims to delve into the role of innate immunity in progressive multiple sclerosis, both in terms of monocytes in the periphery and their communication with glial cells in the brain. These studies are designed to lay the groundwork for a more comprehensive understanding of immune mechanisms and immunotherapy in multiple sclerosis, specifically focusing on the mechanisms by which progressive multiple sclerosis develops.

Lab Members

Mehdi Jorfi, PhD
Principal Investigator

Dr. Jorfi is an Assistant Professor of Neurology at Harvard Medical School and Massachusetts General Hospital. He obtained his Ph.D. from the University of Fribourg in 2014, then completed his postdoctoral work at MIT and Mass General. As a postdoc and later an instructor at Mass General, Dr. Jorfi studied neuroimmune interactions in Alzheimer’s disease.

Currently, Dr. Jorfi holds a faculty position at the Genetics and Aging Research Unit, where his work focuses on the interplay between peripheral immune cells and neurodegeneration. His lab employs multicellular engineered systems as human surrogates to model components of the human immune system and gain insights into the fundamental neuroimmune mechanisms in Alzheimer’s disease and multiple sclerosis. Dr. Jorfi’s research aims to elucidate important signaling between brain cells and the immune system and how these are perturbed in chronic neurological diseases. Dr. Jorfi is the recipient of several grants, including NIH R01 grants and Cure Alzheimer’s Fund, as well as multiple awards, such as the honorary Faculty Science Prize.

View Dr. Jorfi's Harvard Catalyst profile

Mahsa Khayat-Khoei, MD
Research Fellow

Mahsa Khayat-Khoei, MD, MBA, is a fellowship-trained neuroimmunologist, currently a research fellow at Dr. Howard Weiner’s lab. Mahsa finished medical school in Tehran, Iran, followed by neurology residency training at the University of Texas Health Science Center and a three-year clinical research fellowship in multiple sclerosis and neuroimmunology at Brigham and Women’s Hospital and Harvard Medical School. Mahsa has received several awards, including the National Multiple Sclerosis Society Postdoctoral Fellowship, Best Poster and Presentation Award in the Massachusetts Neurological Association 2023 Annual Meeting, and Educational Travel Grant from the Americas Committee for Treatment and Research in Multiple Sclerosis and American Academy of Neurology. Mahsa is interested in stem-cell biology and regenerative medicine, particularly in exploring the role of innate immunity in neuroinflammation and neurodegeneration. Currently, she is involved in a collaborative project between Dr. Jorfi and Dr. Weiner to investigate the roles of monocytes in progressive multiple sclerosis.

Yuyao Tian, PhD
Research Fellow

Dr. Yuyao Tian joined Dr. Jorfi’s lab as a Research Fellow in 2024, where she focuses on studying neuroimmune interactions in neurological conditions, including Alzheimer's disease and multiple sclerosis, using organ-on-chips, stem cells, and patient-derived immune cells. Before joining Dr. Jorfi's lab, Yuyao worked as a Postdoctoral Fellow in the Department of Biomedical Engineering at the Chinese University of Hong Kong, where she used brain-on-chips to study the molecular mechanisms of neurodegeneration. Yuyao holds a Ph.D. in biomedical sciences from the Chinese University of Hong Kong. Her doctoral work explored the molecular mechanisms of the developmental defects in Werner Syndrome, which was supported by the Hong Kong Ph.D. Fellowship. Outside the lab, she enjoys playing with her cat, drawing, and reading books.

Brent Li
Research Technician

Alice Tsai
Research Technician

Cameron Miller
Undergraduate Student

Recent Publications

1. Jorfi M, Kim DY, Tanzi RE. T cell-microglia signaling exacerbates neuropathology in an Alzheimer's disease model. Nat Neurosci. 2023 Sep;26(9):1487-1488. doi: 10.1038/s41593-023-01417-1. PMID: 37620444.
2. Jorfi M, Park J, Hall CK, Lin CJ, Chen M, von Maydell D, Kruskop JM, Kang B, Choi Y, Prokopenko D, Irimia D, Kim DY, Tanzi RE. Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model. Nat Neurosci. 2023 Sep;26(9):1489-1504. doi: 10.1038/s41593-023-01415-3. Epub 2023 Aug 24. PMID: 37620442.
3. Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer's disease. Genome Med. 2023 Jan 26;15(1):6. doi: 10.1186/s13073-023-01155-w. PMID: 36703235; PMCID: PMC9878767.
4. Jorfi M, D'Avanzo C, Tanzi RE, Kim DY, Irimia D. Human Neurospheroid Arrays for In Vitro Studies of Alzheimer's Disease. Sci Rep. 2018 Feb 5;8(1):2450. doi: 10.1038/s41598-018-20436-8. PMID: 29402979; PMCID: PMC5799361.

View all publications

Featured News

In 3D Cell Model of AD, Microglia and CD8+ T Cells Gang Up on Neurons – Alz Forum

New Human Cell-based 3D Model Reveals Insights into How Immune Cells Contribute to Alzheimer’s Disease – Mass General News

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