# NOVEL INNATE MECHANISMS OF IMMUNE TOLERANCE INDUCTION IN ALLOGENEIC HCT FOR HEMOGLOBINOPATHIES

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $441,168

## Abstract

PROGRAM DESCRIPTION/ SUMMARY:
 Development and maintenance of immune tolerance is critical to minimizing complications of allogeneic
hematopoietic cell transplantation (HCT) for non-malignant hematologic disorders, allowing donor cell
engraftment while minimizing graft-versus-host disease (GVHD). Harnessing innate immune mechanisms has
great potential to maintain immune tolerance across histocompatibility barriers. However, the mechanisms
through which innate immune regulation of the adaptive immune system can be achieved after allogeneic HCT
are poorly understood. Understanding these mechanisms will allow us to better apply them to generate
immune tolerance between transplant donor and recipient, thus expanding alternative donor HCT to cure non-
malignant blood disorders. We recently described novel innate mechanisms through which recipient regulatory
myeloid dendritic cells (MDC) spared by non-marrow ablative total lymphoid irradiation (TLI) and T cell-
depletive anti-thymocyte serum (ATS) can induce the proliferation of Foxp3+ regulatory T cells in the donor
graft across major histocompatibility complex (MHC) barriers. We have since determined a modified pre-
transplant preparative regimen which augments the recovery of these regulatory myeloid cells and key
signaling mechanisms required for regulatory function, and which results in durable donor-recipient immune
tolerance after MHC-mismatched HCT in β-thalassemic mice. Our central hypotheses are that a group of
recipient myeloid precursor cells spared by non-myeloablative conditioning develop into regulatory MDC
through direct interactions with another recipient innate immune cell population, and that these myeloid
precursors thus play a central role in regulating donor immune responses after MHC-mismatched HCT. We will
test these hypotheses through 4 specific questions: 1. Can these cells regulate graft-versus-host immune
responses after HCT? 2. How are these myeloid cells formed under the influence of other specific innate
immune cells of the recipient? 3. Can similar immune tolerance induction be achieved when other alkylators
are added to TLI/ATS conditioning, in a high-fidelity murine model of human sickle-cell disease (SCD)? 4. Do
similar immune tolerance mechanisms operate when these TLI/ATS/alkylator therapy is applied in SCD? Our
studies should provide critical insights into specific immune mechanisms of regulation of MHC-mismatched
transplantation tolerance and new therapeutic options in HCT for hemoglobinopathies, health conditions with
high global prevalence and relevance.

## Key facts

- **NIH application ID:** 10067378
- **Project number:** 5R01HL133462-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Asha Bhaskaran Pillai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,168
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067378

## Citation

> US National Institutes of Health, RePORTER application 10067378, NOVEL INNATE MECHANISMS OF IMMUNE TOLERANCE INDUCTION IN ALLOGENEIC HCT FOR HEMOGLOBINOPATHIES (5R01HL133462-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067378. Licensed CC0.

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