# Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques -- (KEAN)

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $672,809

## Abstract

ABSTRACT:
Hematopoietic stem cell transplantation (HCT) is a life-saving therapy, but one that is still plagued with
complications, the most deadly of which is graft-versus-host disease (GVHD). Acute GVHD (AGVHD) occurs in
as many as 70% of transplant recipients, despite their treatment with multiple immunosuppressive drugs.
Moreover, Grade III-IV GVHD, especially involving the GI system, is often untreatable, leading to high rates of
post-HCT morbidity and mortality. These issues give rise to three central challenges in the field. They are: (1)
What are the mechanisms that drive breakthrough T cell allo-immunity and tissue damage despite current
immune suppression strategies? (2) Can we design treatment strategies to directly target these mechanisms?
and (3) What are the necessary components of a GVHD-prevention strategy that will safely produce long-term
immune tolerance? To address these questions, we have developed and refined the only non-human primate
(NHP) model of GVHD, and have used this model to discover a series of new insights into the immunology of
this disease. These include: (1) That a systems biology approach can be applied to GVHD to uncover central
mechanisms and targetable pathways. (2) That AGVHD can be divided into “primary” and “breakthrough”
mechanisms: with primary GVHD driven by Th/Tc1 pathways, while breakthrough GVHD is driven by IL17-
predominant pathways. (3) That primary AGVHD can be successfully controlled by calcineurin Inhibitor-free
CD28:CD80/86 blockade + rapamycin. These discoveries form the core of our new understanding of AGVHD
and inform the next phase of our work. This work is based on the overarching hypothesis that the tissue-
specific molecular mechanisms controlling GVHD can be identified, and that by targeting these mechanisms,
an evidence-based approach to the prevention and treatment of this disease can be achieved. We will test this
hypothesis through the following Specific Aims: Aim 1: Evidence-based GVHD Prevention: This Aim will
determine strategies by which immune escape pathways, identified through transcriptome analysis, can be
targeted to prevent GVHD. Aim 2: Tissue-Specific GVHD Diagnostics: In this Aim, we will establish a
transcriptomic map comparing blood- liver, and GI-specific immune activation during NHP GVHD, using both
population- and single-cell techniques. Aim 3: Evidence-based GVHD Treatment: In this Aim we will
determine the mechanisms controlling breakthrough GVHD in both NHP and patients and test novel
treatment strategies in our newly-developed NHP GVHD Treatment Model.

## Key facts

- **NIH application ID:** 9982123
- **Project number:** 5R01HL095791-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Leslie S Kean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $672,809
- **Award type:** 5
- **Project period:** 2010-02-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982123

## Citation

> US National Institutes of Health, RePORTER application 9982123, Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques -- (KEAN) (5R01HL095791-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982123. Licensed CC0.

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