# Cadaveric Donor Lung and Bone Marrow Transplantation in Immunodeficiency Diseases

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $863,011

## Abstract

Abstract: Bone marrow transplant (BMT) can be a curative therapy for patients with primary immunodeficiency
(PID) syndromes, however those with end-stage lung disease are ineligible for either BMT or bilateral
orthotopic lung transplantation (BOLT). Thus, definitive treatment for patients with PID/end-stage lung disease
represents an unmet clinical need. This U01 project proposes a single center clinical trial to evaluate the safety
and efficacy of performing BOLT followed by CD3+/CD19+-depleted BMT from the same cadaveric, partially
HLA-matched donor, in patients with PID/end-stage lung disease. We hypothesize that tandem BOLT/BMT in
patients with PID/end-stage lung disease will result in correction of the underlying PID, normalization of lung
function, restoration/preservation of pathogen-specific immunity and the establishment of immune tolerance
that will allow withdrawal of immunosuppression therapy (IST). To test our hypothesis, we propose 3 aims. In
Aim 1, we will conduct a phase I/II tandem BOLT/BMT clinical trial in 8 patients with PID/end-stage lung
disease. This trial will be conducted under the direction of two Co-PIs with complementary expertise: Dr. Paul
Szabolcs (contact PI; BMT) and Dr. John McDyer (Co-PI; lung transplant). Key oversight bodies will include the
NIAID DSMB, a NIAID-appointed monitor, and the University of Pittsburgh Education and Compliance Office
for Human Research. This trial incorporates intensive safety monitoring, a milestone-driven protocol, and
rigorous data collection and management for safety reporting and endpoint analyses. Scheduled collection of
blood, bronchoalveolar lavage (BAL) and bronchial brush samples for basic studies in each study patient will
coincide with routine clinical monitoring. In Aim 2, we will test the hypothesis that tandem BOLT/BMT restores
and/or preserves pathogen-specific T cell mucosal/systemic host immunity in study patients. We will perform
flow cytometry-based assays to interrogate pathogen-specific systemic/lung mucosal T cell responses to key
opportunistic pathogens such as CMV, EBV, Aspergillus, Pseudomonas, Staph, RSV, flu and use RNA
sequence analysis to assess the airway transcriptome. In Aim 3, we will test the hypothesis that tandem
BOLT/BMT will result in a level of chimerism sufficient to establish long-term lung allograft/BMT tolerance,
thereby facilitating withdrawal of IST. We will assess chimerism using an ultra-sensitive technique and perform
comprehensive mixed lymphocyte reaction studies to test alloreactivity and evaluate differential mechanisms of
anticipated immune tolerance throughout the study toward the goal of complete withdrawal of IST. The PIs
have assembled an outstanding, multidisciplinary team with broad expertise, and will use the multiple PI format
for this U01 project. Drs. Szabolcs, McDyer and their teams are highly dedicated to advancing the currently
limited treatment options for patients with PID/end-stage lung disease. Success in this nove...

## Key facts

- **NIH application ID:** 9977086
- **Project number:** 5U01AI125050-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JOHN F MCDYER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $863,011
- **Award type:** 5
- **Project period:** 2016-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977086

## Citation

> US National Institutes of Health, RePORTER application 9977086, Cadaveric Donor Lung and Bone Marrow Transplantation in Immunodeficiency Diseases (5U01AI125050-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977086. Licensed CC0.

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