# An immunotherapeutic strategy for the induction and stabilization of remission in type 1 diabetes

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $501,000

## Abstract

PROJECT SUMMARY
 Type 1 diabetes (T1D) remains a clinical problem lacking a robust and specific therapy to address the
causative autoimmune attack on the insulin-producing pancreatic beta cells. Our overarching hypothesis is
that induction of remission at the hyperglycemic stage will be achieved by targeting key CD8+ T cell
specificities, while stabilization of remission, and the establishment of long-term tolerance to beta cells, will be
accomplished by fostering regulatory T cells (Treg). We will utilize a series of increasingly humanized murine
models, including ones incorporating human MHC molecules, antigens, and T cells, to test this hypothesis.
The project represents a collaboration between a T1D immunologist and an expert in T cell co-inhibitory
pathways and protein design and production. In Aim 1, induction of remission at the hyperglycemic stage will
be accomplished using innovative soluble precision biologics, termed synTacs (artificial immunological
synapse for T cell activation), that will enforce activity of the T cell co-inhibitory PD-1 pathway specifically in
beta cell-reactive CD8+ T cells, which are important beta cell executioners in both T1D patients and preclinical
models. Our uniquely designed synTac reagents covalently link non-exchangeable single-chain peptide-class I
MHC and PD-L1 in a manner that recapitulates the proximity, orientation, and overall organization
experienced at the immunological synapse. This strategy not only allows for the explicit targeting of disease-
relevant T cells, but also greatly reduces the devastating side effects associated with the global immune
modulation directed by all biologics currently in the clinic. While inhibition of beta cell-specific CD8+ T cells at
the hyperglycemic stage is a promising approach to induce disease remission, we hypothesize that stabilization
of remission will require conditions that foster an increased number of effective beta cell-specific Treg. To
achieve this goal, in Aim 2 we will take advantage of our experience in targeting antigens to classical dendritic
cells (cDC) in vivo using antigen-linked antibodies to cell surface receptors. As cDC1 may be more adept at
inducing Treg in the periphery, while cDC2 may be more specialized for the expansion and survival of Treg, we
will deliver the critical beta cell antigen proinsulin to cDC1 (via CD205), cDC2 (via DCIR2), or both, to identify
the best approach. In Aim 3, we will combine synTac immunotherapy with antigen delivery to cDC to both
induce and stabilize remission. Finally, in Aim 4, we will use in vitro and in vivo assays to further investigate
the translational potential of our tolerization strategies using human beta cell-specific T cells engineered by
lentiviral transduction or obtained from patients. The development of an improved immunodeficient mouse
host for the reception of human T cells will enable our combination therapy to be tested in in vivo models
incorporating human T cells.

## Key facts

- **NIH application ID:** 9991848
- **Project number:** 5R01DK120420-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** STEVEN C. ALMO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $501,000
- **Award type:** 5
- **Project period:** 2018-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991848

## Citation

> US National Institutes of Health, RePORTER application 9991848, An immunotherapeutic strategy for the induction and stabilization of remission in type 1 diabetes (5R01DK120420-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991848. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*