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Differing Gene Expression Profiles and Signaling Pathways Observed Between Alloreactive and Tolerant T Cells in a Recipient Following Bilateral Orthotopic Lung Transplant (BOLT) and Bone Marrow Transplant (BMT) from the Same Cadaveric UNOS Donor

P. Szabolcs, E. Garchar, D. Rajasundaram, X. Chen

UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA

Meeting: 2022 American Transplant Congress

Abstract number: 1278

Keywords: Bone marrow transplantation, Gene expression, Lung transplantation, Tolerance

Topic: Basic Science » Basic Science » 12 - Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Information

Session Name: Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Type: Poster Abstract

Date: Monday, June 6, 2022

Session Time: 7:00pm-8:00pm

 Presentation Time: 7:00pm-8:00pm

Location: Hynes Halls C & D

*Purpose: Primary immunodeficiency (PID) patients may develop pulmonary complications, and most are ineligible for either BOLT or BMT due to futility. A prospective trial in PID with end-stage lung disease (NCT01852370) tests our hypothesis that persistent engraftment of cadaveric lung donor vertebral body (VB) marrow stem cells could restore immunity and result in lifelong tolerance.

*Methods: A 14 year old female (IL7R– SCID) underwent BMT 4m after BOLT from a 1/8 HLA-allele matched donor. Marrow suspension from VB was CD3+/CD19+depleted and cryopreserved. We have previously shown reduced proliferative, cytotoxic and cytokine responses 2yrs post-BMT (1yr off ISD). Peripheral regulatory mechanism(s) were examined by depletion of Tregs, blocking the IL10R or adding low dose IL2 to break anergy. T-cell receptor (TCR)β repertoires of alloreactive T-cell clones were assessed for clonal deletion using ImmunoSEQ™. Gene expression profiling and signaling pathway analysis on alloreactive or tolerant T cells were performed using RNA-sequencing and software of CLC Genomic Workbench®v21, GSEA®v4.1.0 and IPA®.

*Results: Initially, she engrafted with 100% donor cells. Declining donor chimerism (CD33+ myeloid 60-70% or CD3+T-cell ~27% donor) prompted donor leukocyte infusion ~10w post-BMT. Myeloid chimerism settled between 7-14% during years 2-5 while T-cells remained >95% donor. T/B cells, TCR/BCR repertoires, and sjTREC exceeded pre-BMT values by 3-6m. She was off ISD by 1yr post-BMT and serial lung biopsies detected no rejection. Circulating donor T-cells 2yrs post-BMT were hyporesponsive to host DCs while vigorously responding to 3rd party APCs. Treg depletion or IL10R blocking did not lead to rebound alloreactivity. TCRβ ImmunoSEQ® revealed the gradual disappearance of host reactive clones that remained undetectable even following exogenous IL2. Unlike T-cells from the marrow graft, tolerant T-cells in circulation presented distinct patterns of gene expressions, with downregulation of allograft rejection and T-helper response, co-stimulation, cell proliferation pathways paired with upregulation of co-inhibition and PTEN pathways (Fig1).

*Conclusions: This is the first case to demonstrate successful engraftment, immune competence, and acquisition of long-term tolerance from deceased organ donor VB marrow. Tolerance was characterized by clonal deletion of alloreactive T cells, along with altered signaling pathways in tolerant T-cells.

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To cite this abstract in AMA style:

Szabolcs P, Garchar E, Rajasundaram D, Chen X. Differing Gene Expression Profiles and Signaling Pathways Observed Between Alloreactive and Tolerant T Cells in a Recipient Following Bilateral Orthotopic Lung Transplant (BOLT) and Bone Marrow Transplant (BMT) from the Same Cadaveric UNOS Donor [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/differing-gene-expression-profiles-and-signaling-pathways-observed-between-alloreactive-and-tolerant-t-cells-in-a-recipient-following-bilateral-orthotopic-lung-transplant-bolt-and-bone-marrow-transp/. Accessed May 30, 2025.

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