# Effector-Regulator Immune Interactions During Autoimmune Demyelinating Disease

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) that
affects over 1 million people in the US. T-cell-driven immunopathology is a central feature of MS and other
immune-mediated diseases. As a consequence, the immune regulation of these pathogenic T-cell responses is
an important quest in the approach to autoimmunity. We have had a long-standing interest in the immune basis
of human multiple sclerosis (MS) and its animal model (EAE). While the pathogenic role of CD4 T-cells is well
established in these diseases, there is growing evidence from us and others for a role of CD8 T-cells in these
diseases. Through studies in MS and EAE, we have demonstrated the critical disease regulatory role of CD8
T-cells in disease. Similar appreciation for the role of these cells in downregulating other autoimmune
diseases has also emerged. We have also shown that the suppressor activity of MS relapse-associated CD8
T-cells can be restored by in vitro pre-treatment with specific cytokines, revealing functional plasticity of
these cells and providing a potential avenue for therapeutic intervention. At the same time, it is also
becoming clear that severe autoimmune disease is characterized by increased resistance of
effector/pathogenic CD4 T-cells to immune regulation. Collectively, these studies underscore the
importance of understanding both the biology of CD4 effector T-cell resistance to suppression as well
as the intricacies of CD8 suppression and its modulation. Our proposal addresses this poorly
understood but fundamental feature of the immune regulatory apparatus, in the context of MS. Our
recent studies demonstrate several novel aspects of the CD4-CD8 effector-regulator dynamics and based on
these findings, we hypothesize that CD4 T-cells from MS patients have an intrinsically enhanced tendency to
develop effector resistance to immune suppression in an inflammatory context, while CD8 T-cells from MS
patients have an intrinsically enhanced tendency to develop lower suppressive ability. We also hypothesize
that these phenotypes are plastic and can be modulated by appropriate stimuli. To address these hypotheses,
we will use a two-pronged approach: (1) We will address the biology and modulation of CD4 resistance in MS
to gain direct insights into these processes in the context of autoimmune disease. A part of this aim will also
focus on the novel CD4-intrinsic biology of IL-17 cytokines, as demonstrated in our recent publication; and (2)
We will also address the biology and modulation of CD8 suppression in MS. These studies will provide
important insights into the immune dysregulation that underlies MS pathogenesis, with implications for
treatment approaches in MS and multiple other disease settings.

## Key facts

- **NIH application ID:** 10359998
- **Project number:** 1I01CX002319-01A1
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** NITIN J KARANDIKAR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359998

## Citation

> US National Institutes of Health, RePORTER application 10359998, Effector-Regulator Immune Interactions During Autoimmune Demyelinating Disease (1I01CX002319-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10359998. Licensed CC0.

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