# ST8Sia6 protects against the immune response

> **NIH NIH R21** · MAYO CLINIC ROCHESTER · 2020 · $198,750

## Abstract

Abstract
 1.25 million Americans have type 1 diabetes (T1D), where the immune system destroys insulin-
producing beta cells. Transplantation of islets into patients with type 1 diabetes as a curative measure has
yet to overcome the barrier of immune-mediated destruction of the transplanted cells. Islet transplantation
requires a drug regiment to suppress the immune response from allorejection, resulting in chronic
immunosuppression with its own severe complications. Thus, targeted immunotherapy to prevent immune-
mediated attack on transplanted islets without systemic immunosuppression would be ideal.
Immunotherapies to date have targeted the adaptive immune response (T and B cells), ignoring the innate
immune system (neutrophils, monocytes and macrophages). Siglecs are a family of sialic acid binding
proteins, each with a preference for a particular type of sialic acid moiety on the cell surface. Siglec-E is an
inhibitory receptor expressed on neutrophils, monocytes and macrophages that functions to block
inflammation. Therefore, engagement of Siglec-E by innate immune cells could promote immune tolerance
rather than inflammation and immune activation, which may be a novel approach to treat T1D. We have
demonstrated that the sialyltransferase ST8Sia6 generates α2,8 linked disialic acids on O-linked
glycoproteins which are recognized specifically by Siglec-E. ST8Sia6 knockout mice have decreased
recombinant Siglec-E binding to T cells. We hypothesized that expression of ST8Sia6 could inhibit the
immune response by generating ligands for Siglec-E on the cell surface. To test this, we generated a novel
line of mice in our laboratory where ST8Sia6 is constitutively overexpressed only in pancreatic β cells (“RIP-
cre LNL-tTA ST8Sia6”). RIP-cre LNL-tTA ST8Sia6 mice are healthy, have resting blood glucose levels
indistinguishable from littermate controls, and respond normally to a glucose tolerance test. Therefore,
constitutive expression of ST8Sia6 in pancreatic β cells does not interfere with β cell function or survival. To
test whether constitutive ST8Sia6 expression could be protective, we utilized the multiple low dose
streptozocin (STZ) model to induce diabetes, which has a strong pro-inflammatory component. We
demonstrated that targeted expression of ST8Sia6 in pancreatic β cells provided protection from diabetes
induced using MLD-STZ. The median onset to diabetes was 28 days for ST8Sia6-expressing mice as
compared to 18.5 days for littermate controls. In addition, the hyperglycemia was less severe in ST8Sia6-
expressing mice. Thus, ST8Sia6 expression provides protection in the MLD-STZ model of diabetes. The
focus of this proposal is to target ST8Sia6 expression in β cells in autoimmune models to show protection
from immune-mediated attack.

## Key facts

- **NIH application ID:** 9859338
- **Project number:** 5R21AI135858-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Virginia Smith Shapiro
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2019-02-04 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859338

## Citation

> US National Institutes of Health, RePORTER application 9859338, ST8Sia6 protects against the immune response (5R21AI135858-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859338. Licensed CC0.

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