# Role of the brain-immune axis in neuropsychiatric disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $419,390

## Abstract

The study of brain-immune interactions has contributed to a paradigm shift in the understanding of the
pathophysiology of mental disorders and has provided new insights into their prevention and treatment. Notably,
the blood-brain barrier (BBB) functions to restrict interactions between the brain and periphery, limiting the
influence of peripheral inflammation on the brain. However, increasing evidence indicates impairment of the BBB
in conditions like autism and schizophrenia, which combined with the consistently elevated levels of the cytokines
IL-6 and IL-1β, could potentially affect the ontology and outcome of neuropsychiatric disease. Thus, this proposal
addresses the connectivity of peripheral-neuroinflammation through brain vasculature, its impact on behavior,
and how they interact in response to an environmental “second hit”. We will study this interplay within the brain-
immune axis in the context of genetic susceptibility to neuropsychiatric disease. Besides providing a compelling
rationale to devise immune therapeutic strategies, the demonstration of a brain-immune link will be crucial for
understanding the mechanisms driving disease processes in mental illness.
Our proposal makes use of a model of human genetic susceptibility to neuropsychiatric disease conferred by the
22q11.2 deletion syndrome (22qDS). Based on the inclusion of genes that could affect BBB function, our
previous work demonstrated BBB compromise in 22qDS, a phenotype recapitulated in the mouse model of the
disease. Furthermore, our preliminary data indicate that adult 22qDS model mice have elevated levels of IL-6
and IL-1β, cytokines that promote T cell responses characterized by the expression of the pro-inflammatory
cytokine IL-17. We find enhanced IL-17-mediated inflammatory activation in the brain, modeling the exaggerated
IL-17 responses seen in 22qDS and neuropsychiatric patients. Notably, 22qDS mice also exhibit behavioral
deficits reminiscent of those seen in human patients. Therefore, we will test the hypothesis that inflammation
across the brain-immune axis exacerbates a deficient BBB to promote neuroinflammation and
neuropsychiatric disease in 22qDS. To address this, we will: (Aim 1) Define the links between these different
phenotypes throughout development. (Aim 2) Determine how the BBB impacts brain-immune axis responses to
environmental “second hits” known to trigger symptom onset and the potential of restoring BBB properties
therapeutically. (Aim 3) Identify potential immune therapeutic strategies aiming at brain-immune axis dysfunction
to treat behavioral deficits. As CHOP houses the world's largest 22qDS clinic and Penn is a leader in
neuropsychiatric research, our environment is ideal for translating these studies into actionable science.

## Key facts

- **NIH application ID:** 10766613
- **Project number:** 1R01MH134797-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jorge Ivan Alvarez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,390
- **Award type:** 1
- **Project period:** 2023-11-15 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766613

## Citation

> US National Institutes of Health, RePORTER application 10766613, Role of the brain-immune axis in neuropsychiatric disease (1R01MH134797-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10766613. Licensed CC0.

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