# Modulating pathogenic T cells in Type 1 diabetes

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $431,038

## Abstract

Summary:
Preclinical studies and clinical trials with agents such as anti-CD3 mAb, LFA3Ig, anti-thymocyte globulin,
CTLA4Ig, and cyclosporin A have shown that Type 1 diabetes (T1D) is caused by T cell killing of  cells, most
likely mediated by CD8+ T cells. In our previous clinical trials of anti-CD3 mAb (teplizumab) supported by this
grant and mechanisms that we studied in trial participants and others with T1D, we showed that a single
course of mAb attenuated the loss of C-peptide compared to control subjects over the first 2 years of disease,
even in patients who had T1D for more than 4 months. We also showed that CD8+ T cells were the cells most
affected by the drug and changes in these cells accounted for the clinical efficacy. There is, however, limited
information about how immunologics change the antigen specific CD8+ T cell responses that are thought to
cause the disease. The overall goal of this renewal proposal is to build on our previous clinical and laboratory
based studies to identify the role of CD8+ T cells in T1D and determine whether and how these cells are
affected by immune therapy. We have developed novel methods for identifying antigen specific CD8+ T cells in
HLA-A2+ subjects and tracking them over time in vivo based on creation of CD8+ T cell libraries. Also, under
this funding mechanism, we developed a novel assay to measure β cell death in vivo. Our preliminary data
shows that in individuals with T1D, there is an increased frequency of autoantigen reactive memory CD8+ T
cells compared to healthy control subjects. The antigen reactive cells are generally reactive to a single
diabetes peptide – most commonly ZnT8186-194, whereas non-diabetic and even non-diabetic identical twins of a
patient respond to other peptides. We will test the hypothesis that in those with diabetes and at-risk relatives
CD8+ T cells reactive to many antigens can be found but in those who progress to T1D, there is focusing of
the response to a limited repertoire of autoantigens. We have identified unique patient groups whose samples
will enable us to address this hypothesis: discordant and concordant twins and triplets and at-risk relatives of
patients. We will test the frequency, function, and phenotype of the antigen reactive T cells. Using autologous
iPS derived -like cells derived from patients, we will test whether autoantigen specific CD8+ T cells kill  cells.
We will use clinical samples from the anti-CD3 mAb prevention trial to determine whether anti-CD3 mAb
deletes autoreactive CD8+ T cells or renders them exhausted or anergic, and the relationship between the
changes in these cells, clinical responses, and β cell death. Finally, T1D has been shown to be more
aggressive in children than adults yet children show a more robust response to most immune therapies. We
will address this critical question using cellular studies of the autoantigen reactive cells and their responses to
teplizumab. The results of our studies will not only develop a...

## Key facts

- **NIH application ID:** 9972918
- **Project number:** 5R01DK057846-16
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kevan C Herold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,038
- **Award type:** 5
- **Project period:** 2000-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972918

## Citation

> US National Institutes of Health, RePORTER application 9972918, Modulating pathogenic T cells in Type 1 diabetes (5R01DK057846-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972918. Licensed CC0.

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