# Molecular and Cellular Mechanisms of Tolerance to Combined Organ and Hematopoietic Cell Transplantation after TLI and ATS/ATG Conditioning

> **NIH NIH P01** · STANFORD UNIVERSITY · 2020 · $425,843

## Abstract

Project Summary/Abstract
The goal of the proposed research is to determine how subsets of myeloid dendritic cells (DCs) in mice
conditioned with total lymphoid irradiation (TLI) and anti-T cell antibodies (anti-thymocyte serum; ATS) interact
with natural killer T (NKT) cells and Treg cells to promote tolerance to combined organ and bone marrow
transplants . Our previous studies showed that stable mixed chimerism and tolerance in this model system are
dependent on the presence of both type I invariant NKT cells and the CD8+ antigen cross priming subset of
DCs, since tolerance observed in wild type mice is abrogated in Jalpha18-/- and Batf3-/- recipients. In addition,
the conditioning regimen changes the balance of immune cells to favor the CD8+ DCs and NKT cells, and
results in their activation. Studies are designed to elucidate the changes in surface markers, cytokine secretion
patterns, gene expression and in vitro and in vivo functions of the DC subsets and NKT cells in recipients after
conditioning, and how these changes are required for the interactions between the DCs and NKT cells that
promote tolerance. We will test the hypothesis that the interactions require DC stress protein recognition by
NKG2D receptors on NKT cells that lead to NKT cell stimulation of Treg cells and myeloid derived suppressor
cells (MDSCs) in an IL-4 dependent manner. We will also test the mechanism by which myeloid DCs in TLI-
conditioned kidney transplant patients mediate suppression of T cell activation, including changes in gene
expression and cytokine secretion. Since we hypothesize that the activated immunosuppressive cells allow for
the acceptance of donor hematopoietic progenitors, chimerism, and associated clonal deletion, these studies
should provide important new information that impacts on current clinical trials of tolerance in HLA mismatched
kidney and hematopoietic cell transplant recipients using TLI based conditioning.

## Key facts

- **NIH application ID:** 9931287
- **Project number:** 5P01HL075462-15
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** EDGAR G. ENGLEMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,843
- **Award type:** 5
- **Project period:** — → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931287

## Citation

> US National Institutes of Health, RePORTER application 9931287, Molecular and Cellular Mechanisms of Tolerance to Combined Organ and Hematopoietic Cell Transplantation after TLI and ATS/ATG Conditioning (5P01HL075462-15). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/9931287. Licensed CC0.

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