# Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $427,982

## Abstract

The primary objective of the proposed studies is to test a novel hypothetical model of optical neuritis with the
overall goal of pinpointing druggable therapeutic targets. Optic neuritis is a condition involving primary
inflammation of the optic nerve. Acutely it is associated with loss of vision or double vision and is often the first
presentation of multiple sclerosis. Several lines of evidence indicate that it is a multifactorial, autoimmune
condition involving T-cell mediated demyelination of the optic nerve, but it has proven difficult to distinguish
causative responses from bystander effects. To provide a framework for identification of causative responses in
the context of multifactorial interactions, we have developed mouse models of optic neuritis that combine
constitutive overexpression of interleukin-2 (IL-2) with HSV-1 infection through ocular infection with
recombinant HSV-IL-2 virus or delivery of IL-2 into the brains of mice using Alzet osmotic mini-pumps prior to
ocular infection with wild-type HSV-1. Both CD4+ and CD8+ T cells contribute to the HSV-1/IL-2-induced optic
nerve and CNS pathology and the pathology resembles that of the MOG35–55 EAE model. The current models
are distinct, however, in that they demonstrate that, in the context of viral infection, IL-2 can drive optic nerve
and CNS demyelination. Preliminary analysis of the interactions required for the IL-2-driven pathology using
knockout, depletion, adoptive transfer and/or blocking approaches have provided novel insights pinpointing a
potential requirement for interactions between IL-2 and the IL-2rγ (but not IL-2rα or IL-2rβ) subunit as well as
the association of a single amino acid mutation of IL-2 with blockade of pathogenesis; a potential requirement
for type 2 innate lymphoid (ILC2) cells, with ILC1 or ILC3 playing no role; and a potential requirement for
production of IL-17A by the ILC2 cells. Engagement of either the IL-17RA or IL-17RC receptor on TH17 cells
appears to drive CNS demyelination. Macrophages and IL-12p70 appear to play protective roles in this model.
Collectively, these data suggest a hypothetical model in which elevation of IL-2 in the context of viral infection
drives an autoaggressive TH17 response that causes optic neuritis and CNS pathology through generation of
IL-17-producing ILC2s. We will test this hypothesis by defining the cytokine/receptor interactions and
responses of ILC subtypes in these models to: (1) Determine whether the presence of ILC2 is required for optic
nerve/CNS pathology; (2) Determine whether ILC2-production of IL-17A contributes to optic nerve/CNS
pathology by promoting a TH17 response; and (3) Determine the interplay between ILC2 cell responses and
macrophage production of IL-12p70 in demyelination. CLINICAL RELEVANCE: Optic neuritis is a prototypic
inflammatory autoimmune disease that is closely associated with MS. Confirmation of the proposed
hypothetical model will have broad implications in terms of advancing the ...

## Key facts

- **NIH application ID:** 10357860
- **Project number:** 5R01EY029677-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** HOMAYON GHIASI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,982
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357860

## Citation

> US National Institutes of Health, RePORTER application 10357860, Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis (5R01EY029677-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10357860. Licensed CC0.

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