# Role of Siglec-E in Regulating Alloimmunity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $434,120

## Abstract

Abstract
Despite the significant improvements in short-term survival of organ transplants, rejection remains a leading cause of
long-term transplant loss. Innate immune activation potentiates the adaptive immunity and is a crucial player in
precipitating acute rejection and preventing transplant tolerance. However, most immunosuppressive drugs used in
the clinic primarily target T cells and not innate immune cells. Therefore, there is an unmet need to develop effective
therapies to modulate innate immunity in transplantation. Siglec (sialic acid-binding immunoglobulin-like lectin)-E, or
SigE, is an innate receptor that down-modulates inflammation. SigE is expressed by dendritic cells (DCs) and inhibits
TLRs-triggered inflammatory responses. Engagement of SigE is a promising strategy to promote immune regulation.
However, the role of SigE in transplantation has not been investigated. We have found that allografts lacking SigE
have an accelerated rejection, and kidney transplant patients have decreased expression of human SigE counterpart
(Siglec-9) during rejection. Moreover, we have recently discovered that a mycobacterial protein DnaK can bind to
SigE with potent immunomodulatory effects in alloimmunity by decreasing DCs activation through downregulation of
MHC II and CD86. In situ targeting of donor DCs with DnaK is capable of prolonging skin allograft survival in the
absence of systemic immunosuppression and DnaK-effect was dependent on SigE. Thus, targeting SigE represents
a novel potential therapeutic target to enhance the modulation of the immune response in transplantation. Based on
our preliminary data, we hypothesize that SigE is a critical regulator of the immune response following
transplantation. To address this hypothesis, we propose three specific aims: 1) To define the role of SigE in
regulating DC maturation and antigen processing; 2) To determine the role of SigE in alloimmunity and in the
generation of antigen-specific T cells; and 3) To investigate a novel immunomodulatory molecule designed based on
the interaction between Siglec-9 and DnaK. To accomplish these aims, we will utilize heart and humanized mouse
transplantation models, a novel synthetic agonist peptide to SigE, SigE-deficient mice, tracking of antigen-specific T
cells using adoptive transferred cells and endogenous staining using tetramers. The proposed studies are innovative
and significant because we will explore the biology of an important regulatory innate immune receptor, SigE, in
transplantation and we will investigate a novel SigE targeting molecule to inhibit alloimmunity,

## Key facts

- **NIH application ID:** 10313448
- **Project number:** 7R01AI143887-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Leonardo V. Riella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,120
- **Award type:** 7
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313448

## Citation

> US National Institutes of Health, RePORTER application 10313448, Role of Siglec-E in Regulating Alloimmunity (7R01AI143887-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313448. Licensed CC0.

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