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INFORMATION FOR

Neuroimmunology

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The Iwasaki Lab is interested in the interactions between our body's nervous and immune systems when we grapple with infection and disease — as well as how researchers can harness or suppress natural immune responses to fight the cognitive impairment characteristic of some conditions. Below are descriptions of several neuroimmunology projects that we are working on.

Leveraging the immune system to transiently open blood-brain barrier (BBB):

The blood brain barrier, or BBB, has been a historic roadblock in medicine when it comes to treating brain metastases and other diseases where the CNS requires drugs. This same highly semipermeable membrane that allows the brain to exchange materials with the blood while protecting it from deleterious microorganisms can be a hindrance when therapies and antibiotics fail to achieve adequate concentrations in the microtumor environment, if at all.

By studying how the body’s immune system reacts to pathogens that infects the neurons, specifically in the context of the herpes simplex virus, the Iwasaki lab has discovered that CD4 T cells specific to the viral peptide enter the neural tissues, secrete IFN-y and mediate transient opening of the BBB, to enable access of antiviral antibodies. Without this process, lethal disease is caused by uncontrolled viral replication in the neurons. Based on this discovery, we are developing a new approach that leverages our natural immune response to open the BBB. Here’s how it works: an intranasal spray containing patient-specific, MHC Class II peptides is administered; the peptide then follows olfactory nerves to enter the CNS, stimulating CD4+ T-cells that in turn secrete interferon gamma and enable temporary permeability of the BBB for several days. In the case of glioblastoma, T-cell stimulation through peptides allows checkpoint inhibitor biologics to access brain tissue and treat the tumors.

This work forms the scientific basis for the creation of CynAxis technology.

VEGF-C meningeal lymphatic therapy:

In addition to the BBB, there is yet another challenge confronting the immune system when it is trying to monitor tumors and pathogens buried away in CNS: limited lymphatic drainage. This can be lethal when disease-fighting lymphocytes and immune cells cannot reach the antigen in time or in adequate concentrations, permitting uncontrollable pathogenic spread or tumor growth.

Iwasaki Lab is developing meningeal lymphatic therapy as a means of manipulating lymphatic vasculature and promoting heightened immune surveillance of the CNS. In a recent study, we ectopically expressed a growth factor called VEGF-C in mice with glioblastoma, a brain cancer deprived of lymphangiogenic signals. This particular growth factor is known for promoting lymphangiogenesis, a process by which new lymphatic vessels form and grow.

What the team then found was that greater VEGF-C expression allowed for increased priming, recruitment, and migration of CD8 T-cells to the CNS. The result? Rapid tumor clearance and recovery. But there’s more — versions of this strategy can also be used in tandem with checkpoint blockade therapy, which prevents the inhibition of T-cells in their killing of cancer cells, to further the removal of existing glioblastoma in patients.

Neuro-long COVID:

While cognitive dysfunction appears to be most severe in patients with long COVID, individuals exhibiting even mild symptoms in the acute phase report impaired attention, concentration, mental processing, memory, and overall bodily function. Neurological symptoms may result from direct infection in the brain, autoimmunity or distal inflammation.

We demonstrated early in the pandemic that SARS-CoV-2 is neuroinvasive, and that it is able to infect neurons in mouse models, human brain organoid, and in autopsy study. While this may occur in some patients with severe COVID, the neurological impact of mild COVID is likely not due to direct brain infection.

In collaboration with Prof. Michelle Monje’s laboratory and others, we used a mouse model to determine whether a mild respiratory-only infection with SARS-CoV-2 can lead to impact within the brain. We found that mild respiratory SARS-CoV-2 infection — and the increased inflammation that follows — results in a number of neuroimmunological changes that damaged or activated various brain cells. Among these changes include increased reactivity of white matter-selective microglial cells and other macrophages found in the Central Nervous System (CNS); increased cytokine and chemokine signaling that is potentially characteristic of aging; impaired hippocampal neurogenesis; decreased oligodendrocytes and the concordant loss of the fatty myelin coat that promotes proper action potential conductance.

Many of the aforementioned cells and molecules are critical to body homeostasis when in moderation; it is only when they are overactive or over-expressed that they can induce inflammation and damage brain cells. Moreover, the cellular dysregulation is oftentimes multi-lineage, with pathways and feedbacks intersecting with and regulating one another. Microglia cells, for example, help remove damaged neurons and particles, but can initiate neurotoxic activity through cytokine and chemokine signaling when a patient is infected with COVID. One of the notable chemokines is CCL11 — which can activate hippocampal microglia and inhibit neurogenesis — has been found in higher levels in people with cognitive symptoms in long COVID patients and in infected mice. A similar overreaction of microglia in white matter has been observed in cancer patients who are undergoing chemotherapy and cranial radiation — as well as in influenza patients, though the cognitive and cellular dysregulation of the latter is not as persistent. The transcriptional changes within the microglia clusters of individuals with mild respiratory COVID also show certain patterns that resonate in victims of Alzheimer’s, a neurodegenerative disease that progressively destroys brain cells and causes weaker neuronal connections.

Having identified this cognitive relationship across COVID and other conditions, we are continuing to explore the underlying mechanism of pathogenesis, intersectionality of therapies, working towards a future where the treatment for one disease can be used, recycled or modified to treat another.

Transposable elements and neurodegenerative diseases

Retrotransposons including endogenous retroviruses (ERV) and long interspersed nuclear element 1 (LINE-1) occupy almost half of our genomic real estate. While many such elements are fossil records of truncated, or mutated genetic elements, a handful of LINE-1 elements are still active in retrotransposition. Our recent work demonstrated that deliberate expression of LINE-1 in the cerebellum of mice induces DNA damage response and unfolded protein response in the Purkinje neurons, followed by their dysfunction and neurodegeneration. This leads to the onset of severe cerebellar ataxia. Notably, cerebellum of patients with ataxia- telangiectasia, a rare inherited neurodegenerative disease marked by a lack of coordination and deficits in immune and other body systems, also have elevated LINE-1 expression and neuroinflammation. Treatment of LINE-1 overexpression mice with reverse transcriptase inhibitor (used for HIV treatment) prevented neurodegeneration and ataxia disease caused by LINE-1. These studies highlight the role of LINE-1 in neurodegenerative diseases and suggest possible interventions using antiretroviral drugs.