Professor, CMP Graduate Program Chair, Department of Pathology and Laboratory Medicine
Ph.D. University of Budapest, Hungary
Immune Reactivity in the CNS
As a neuroimmunologist, for the last several years, I have focused my research program on understanding immune privilege and immune surveillance in the central nervous system (CNS) and their contribution to CNS diseases such as multiple sclerosis, stroke and TB meningitis.
We are focusing on the following questions:
1. How the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? Clinical and preclinical studies suggest the importance of inflammation in acute and chronic neuronal tissue damage following ischemic stroke; however, the mechanisms and cells involved in neuroinflammation are not fully understood. We discovered that IL-21 is a major contributor to acute brain injury after ischemic stroke. This raises the possibility that IL-21–targeting therapies might be beneficial in stroke management.
2. What are the mechanisms for the bidirectional communication between the immune system and the central nervous systems? CNS immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions or in disease. We discovered that CNS or gut mucosal antigens are sampled similarly, but activated peripheral cells do not access the CNS in steady state condition. In contrast, neuroinflammation increased the level of antigen sampling and led to the accumulation of immune cells in the inflamed CNS. Using animal models such as experimental autoimmune encephalomyelitis (EAE) to model CNS autoimmunity, we demonstrated that CD11chigh dendritic cells (DC) accumulate with distinct distribution pattern within the brain and spinal cord during neuroinflammation. We also found that CCR7 mediates CD11chigh myeloid cell migration from the CNS parenchyma to the deep cervical lymph nodes (LN) during neuroinflammation. In the absence of CCR7, DC are retained in the CNS and exacerbate neuroinflammation. Regulating DC migration out from the inflamed CNS may be a therapeutic target for MS and other neuroinflammatory conditions. In order to achieve this, the exact route/s and mechanism of immune cell and antigen drainage from the CNS to the cervical LNs need to be understood. Lymphatic vessels surrounding the CNS have been described under steady-state conditions, yet it is still unclear how antigens or immune cells traffic from the CNS parenchyma to the cervical lymph nodes in disease. We discovered that in neuroinflammation, lymphatic vessels near the cribriform plate undergo extensive in situ neo-lymphangiogenesis. These studies will generate exciting novel mechanistic information on how lymphatic vessels develop in the CNS and could lead to novel therapies for controlling neuroinflammation.
3. How do brain cells respond to infection-induced inflammation in CNS Mycobacterium tuberculosis (Mtb) infection (CNSTB): The most dangerous form of Mycobacterium tuberculosis (Mtb) infection is central nervous system (CNS) tuberculosis (CNSTB). Despite its public health importance, current understanding about the pathogenesis of CNSTB is very limited, and prognosis for patients with CNSTB is bleak. We have generated novel recombinant mycobacterium strains that express green fluorescent protein (GFP) and express OVA257-264 and OVA323-339 antigenic epitopes. We found that mycobacterium induces strong cellular responses and immune cell infiltration in the murine brain. We found that mycobacterium induces strong cellular responses and immune cell infiltration in the murine brain.
4. Design new approaches for Multiple Sclerosis (MS) therapy: We are in a unique position to discover novel immunoregulatory mechanisms in MS using samples of serum, peripheral blood mononuclear cells (PBMCs), and DNA and RNA that were collected in the Helminth-Induced Immunomodulatory Therapy (HINT) clinical trial. Our studies led to novel findings and resulted in innovative alternative therapies for patients with RRMS.
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