# Impact of pathogenic MS patient-derived IgG on oligodendrocytes: bystanders or participants in remyelination failure?

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2022 · $67,482

## Abstract

Project Summary/Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that is
most commonly characterized by discreet periods of measurable and sustained reduction in neurologic
function followed by remission. Available interventions target inflammatory injury by interfering with
inflammatory immune functions but typically do not stimulate myelin repair or restore neurologic function.
Targeted approaches that promote remyelination in MS would have a substantial impact on its management:
demyelination interrupts metabolic support to axons normally provided by oligodendrocytes (OGs). As a result,
denuded axons often degenerate, thereby worsening disability in MS patients. Although recent studies into the
diverse role of glia in CNS pathologies have identified unique transcriptomes expressed during injury and
recovery, OG responses to antibody-mediated demyelination/remyelination remain unclear. This proposal
incorporates an innovative and cross-disciplinary approach to dissect OG responses during failed myelin
repair. We have developed unique ex vivo and in vitro assays using disease-specific myelin binding
recombinant antibodies (rAbs) first cloned from MS patient cerebrospinal fluid that recapitulate some of the
barriers to remyelination in MS. In contrast to other demyelination/remyelination models, our patient-based
remyelination model blocks remyelination during the transition of OGs from the early myelinating to actively
myelinating stage, not during OPC differentiation. Experiments described in this application are designed to
disentangle factors intrinsic & extrinsic to OGs that contribute to rAb-induced remyelination failure by
thoroughly delineating OG-rAb responses using live cell imaging, immunohistochemistry, transgenic mice,
innovative myelination assays, and next generation RNA sequencing modalities. To maximize the translational
relevance of results generated in this model, biomarkers of remyelination blockade will be identified and
interrogated in MS lesions. Thus, by utilizing sequential experimental and translational approaches, this
proposal will identify how specific interactions between B cell humoral autoimmunity and OGs contribute to
remyelination failure in human disease. Initially, we will test how MS rAbs affect oligodendrocytes directly by
observing their effect on OG differentiation, ability to elaborate new myelin, and signaling pathways transduced
by rAbs. We will then identify how oligodendroglial gene expression is influenced by rAbs during differentiation
and myelinogenesis experimentally and evaluate candidate biomarkers for remyelination blockade in human
MS plaques. These studies will not only expand scientific understanding of MS neuroimmunology, they will
also illuminate factors contributing to remyelination that may be harnessed for the treatment of MS and other
CNS demyelinating diseases.

## Key facts

- **NIH application ID:** 10533728
- **Project number:** 5F32NS122997-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andrew S Lapato
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,482
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533728

## Citation

> US National Institutes of Health, RePORTER application 10533728, Impact of pathogenic MS patient-derived IgG on oligodendrocytes: bystanders or participants in remyelination failure? (5F32NS122997-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10533728. Licensed CC0.

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