We have a long-term program to profile the immune system and develop blood biomarkers in MS and to link them to disease stage and response to therapy. A major resource for our comprehensive program is the CLIMB observational study. The CLIMB study begun in 2000 and we currently follow over 2000 MS patients with yearly exams, MRI imaging, blood collection including immune peripheral cells, urine and microbiome samples. The CLIMB biorepository and cohort serves as an outstanding source to study and develop MS biomarkers including antigen arrays, microRNAs (serum and cells), and immune cell profiling that involves the characterization of TH17 cells, regulatory T cells, monocytes, B cells, and dendritic cells.
We investigate both, the classic relapsing and the progressive animal model of MS. There are many drugs for the treatment of inflammatory stages of MS but no treatment and a poor understanding of progressive MS and thus it represents our major challenge. Our studies in the progressive EAE model involve the role of microglial cells, astrocytes, endothelial cells and neurons. We hope that understanding the immune mechanisms in the mouse model will provide a basis for developing new targets of therapy.
AD is the most common form of dementia, affecting millions globally, and its risk increases with age. For decades, researchers have considered amyloid-beta plaques and neurofibrillary tau tangles to be the hallmarks of Alzheimer’s disease (AD). But a third culprit may play a critical role in AD, potentially linking these telltale signs of AD and leading to worsening symptoms, the neuroinflammation. We have been investigated the role of microbiome and nasal anti-CD3 in animals models of AD. Our goal is to stimulate the immune system to clear out the amyloid using this very novel approach.We have also created a nasal vaccine, called nasal protollin, to boost the immune system to fight AD. The vaccine prevents the catalyst of neuroinflammation and its harmful effects. A phase I study is now being conducted to test whether Protollin is safe and whether it stimulates the body’s white blood cells to remove toxic amyloid from the brain and ultimately improve cognition.
Although there are symptomatic treatments for PD there are no approved disease-modifying therapies. In PD, T cell infiltration and activated microglia are observed at sites of synaptic loss, likely contributing to neurodegeneration. We investigate the therapeutic potential of inducing T regulatory cells to restore microglia to a homeostatic state using anti-CD3 treatment, aiming to develop novel pharmacological strategies to slow disease progression.
One of the major problems associated with COVID is long COVID in which there is CNS dysfunction associated with microglial activation. We are studying a model of long COVID and found an immunomodulatory role of nasal administrated anti- CD3 which dampens microglial inflammation.
Our laboratory has a long-term interest in the induction of regulatory T cells and the modulation of autoimmune and inflammatory diseases by the mucosal (oral/nasal) route. The laboratory is currently focused on addressing a series of questions related to mucosal tolerance. These include mechanisms by which mucosally administrated anti-CD3 and other antibodies induce regulatory T cells, the role of the microbiota in mucosal tolerance, characterization of LAP+ Th3 type regulatory T cells, adjuvants and other molecules that can enhance mucosal tolerance
The gut microbiome modulates metabolic, cardiovascular, and neurologic function and may play a crucial role in the pathophysiology of neurological diseases. The gut-brain axis, a complex communication network between the gut microbiota and the central nervous system (CNS), and the gut microbiome can affect the brain by modulating immune responses and secreting bioactive metabolites. The gut microbiota can produce or consume neurotransmitters and other neuroactive metabolites that influence anxiety, depression, and other neuropsychiatric disorders such as gamma-aminobutyric acid (GABA) producing bacteria. At our center, we identified bacteria that correlate with anxiety, depression, and fatigue in subjects with MS and other neurological diseases including Alzheimer’s disease and Parkinson’s disease. Elucidating which microbes are linked to the development of or protection of morbidities could pave the way for innovative therapeutic strategies aimed at modulating the gut microbiota to improve outcomes in patients with neurological conditions.
We are investigating the role of the innate immune system in ALS in both animal models and patients with ALS. We have observed that the infiltration of monocytes from the periphery contribute to disease in the spinal cord and modulation of these cells ameliorates disease. In addition, we have observed a unique microRNA signature in the blood monocytes from ALS patients that is analogous to what is seen in the animal model. We have identified a prominent role for mir-155 in ALS and are currently investigating the possibility of developing a mir-155 antagomir for the treatment of patients with ALS. We are also testing nasal anti-CD3 in ALS models.
Infections in general are a known as a triggering agent for autoimmune diseases in which the body’s immune system attacks its own healthy tissue. Infections can trigger autoimmune diseases by activating autoreactive T and B cells and even by bystander T and B cell polyclonal activation. Wse are interested how malaria infections can have long term consequences on the CNS vasculature and more importantly try to understand the fundamental mechanism(s) by which infections like malaria predispose to auto-immune diseases like MS.
Diet-induced obesity can significantly impact the immune system, including the function of regulatory T cells (Tregs). Tregs play a crucial role in maintaining immune tolerance and modulating inflammatory responses, and their function can be altered in the context of obesity. We investigate T cell based immunotherapies that could contribute to a pro-inflammatory state and various metabolic disorders. Understanding these interactions can help in developing strategies to restore immune balance and improve health outcomes for individuals affected by obesity.
Microglia are key innate immune cells in the nervous system which play a crucial role in the maintenance of normal CNS homeostasis and in disease processes. We have identified unique microglial signatures in both mice and humans and have developed microglial specific monoclonal antibodies for the study of microglia. We are involved in an extensive investigation of the function of microglia in normal CNS function and during diseases of the nervous system such as in MS, Alzheimer’s disease, aging, brain injury, Parkinson’s Disease and more.
We have a program to understand microRNA and immune patterns in glioblastoma. We are investigating both mouse models and human glioblastoma. In addition, we are investigating the effect of modulation of glioblastoma by targeting regulatory T cells.
We have established several animal models in the laboratory for the study of immune based diseases. These animal models include acute and chronic EAE, type 1 and type 2 diabetes, arthritis, lupus, stroke, ALS and Alzheimer’s disease.
As people age, they become more susceptible to chronic diseases, including neurodegenerative disorders. There can be both qualitative and quantitative changes in their immune system including in the Treg populations. The functional decline with aging can contribute to a pro-inflammatory state, often referred to as “inflammaging.” Understanding the mechanisms of aged brain and using strategies to increase Treg numbers or enhance their function may help restore immune balance and prevent neurological conditions. We have initiated studies to investigate the role of Treg cells in aging with major focus on microglia modulation.
Brain injury includes the activation of microglia, the release of pro-inflammatory cytokines, and recruitment of various immune cells, including T cells affecting the health of the brain and other organ systems. This may trigger progressive degenerative processes and can be considered a risk factor for MS. Because Treg cells and microbiome products can control inflammation, we aim to use both to modulate brain injury and to help improve the outcomes of individuals with these conditions.
Epilepsy is a neurological disorder characterized by recurrent seizures due to abnormal electrical activity in the brain. The challenge in treating epilepsy is that one-third of patients may have drug-resistant epilepsy (also called refractory or intractable epilepsy). We are focused on better understanding the mechanisms of epilepsy with focus on the immune system. Our major goal is to improve treatment options and finding new including microglia and microbiome base therapies to treat disease.
