Identification of Distinct Subtypes in Immune Tolerance after Hematopoietic Cell Transplantation Using the Prospective ABLE1.0 Pediatric Study Cohort

Bernard Ng, Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Andrew C. Harris, MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sayeh Abdossamadi, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Madeline P. Lauener, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Geraldine Aubert, Repeat Diagnostics Inc, North Vancouver, BC Canada.
Rajinder Bajwa, Nationwide Children's Hospital Columbus, OH, USA.
Monica Bhatia, Pediatric Stem Cell Transplant Program, Morgan Stanley Children's Hospital, Columbia University, New York, NY, USA.
Henrique Bittencourt, Pediatric Hematology-Oncology Division, Saint-Justine University Hospital Centre, Montreal, QC, Canada.
Nataliya P. Buxbaum, Roswell Park Comprehensive CancerCancer Center, Buffalo, NY, USA.
Emi H. Caywood, Nemours Children's Health, Thomas Jefferson University, Wilmington, DE, USA; Thomas Jefferson University, Philadelphia, PA.
Sonali Chaudhury, Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL, USA.
Joseph H. Chewning, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
Sung Won Choi, University of Michigan, Blood and Marrow Transplantation Program, Ann Arbor, MI USA.
Ashley Chopek, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
Julia Chu, Pediatric Blood and Marrow Transplant Program, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
Donald Coulter, Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
Shahinaz M. Gadalla, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
Richard T. Hogg, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
David A. Jacobsohn, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Amanda K. Johnson, Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant. University of Utah/Primary Children's Hospital, Salt Lake City, UT, USA.
Michael Joyce, Nemours Children's Health, Jacksonville, FL, USA.
Kimberly A. Kasow, Pediatric Bone Marrow Transplant, University of North Carolina, Chapel Hill, NC, USA.
Michael Kent, Atrium Health/Levine Children's Charlotte, NC, USA.
Carrie L. Kitko, Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN, USA.
Donna Lau, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Anita Lawitschka, Stem Cell Transplant Unit, St. Anna Children's Hospital, Medical University, Vienna, Austria.
Victor A. Lewis, Pediatric Oncology and Transplant, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
Amanda M. Li, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Laura McLaughlin, Children's Hospital Colorado Denver, CO, USA.
David Mitchell, Division of Pediatric Hematology-Oncology, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
Eneida R. Nemecek, Pediatric Blood and Marrow Transplantation, Doernbecher Children's Hospital, Oregon Health and Sciences University, Portland, OR, USA.
Vaishnavi Parthasarathy, Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada; Allen Institute for Immunology, Seattle, WA, USA.

Document Type

Journal Article

Publication Date

9-29-2025

Journal

Transplantation and cellular therapy

DOI

10.1016/j.jtct.2025.09.034

Keywords

Chronic GvHD; Hematopoietic cell transplantation; Immune tolerance; Modeling immune patterns

Abstract

BACKGROUND: The lack of immune tolerance after hematopoietic cell transplantation (HCT) can result in chronic graft-versus-host-disease (cGvHD), which is the primary non-relapse limitation on a successful HCT. OBJECTIVES: To date, immune tolerance has been considered as a single biologic entity, but we hypothesized that post-HCT immune tolerance could develop through multiple pathways. STUDY DESIGN: Using the ABLE network database, which comprises measurements of 75 cell populations, 10 cytokines and chemokines, lymphocyte population telomere length, KREC and TREC, and 132 metabolites from the largest pediatric cGvHD cohort (N = 241), we applied clustering analysis to the primary immune tolerance (PIT; no acute GvHD or cGvHD) and secondary immune tolerance (SIT; previous acute GvHD and no cGvHD) patients to test whether subtypes could be identified. RESULTS: Evaluation of PIT found three subtypes. PIT-1, associated with post-pubertal age and lower thymic output, and increased ST2 compared to PIT-2 and PIT-3, was effector memory T cell-predominant. PIT-2, associated with prepubertal age, normal thymic output, increased B cell development, longer lymphocyte telomeres, had a naïve T cell-predominant pattern. PIT-3, associated with post-puberty, higher thymic output, and malignancy, was dominated by increased PD1 T and helper T cells and decreased long chain acylcarnitine. We partially replicated these PIT subtypes using metabolomic data from a separate pediatric cohort of the COG trial ASCT0031 (24 PIT patients). Previously resolved acute GvHD had minimal impact on the overall patterns of SIT-1 and SIT-2 compared to PIT-1 and PIT-2, except for time delays in expansion of some immune cells. PIT-3 and SIT-3 were dominated by a late increase in phosphatidylcholines (lysophosphatidylcholines precursors) and long chain lysophosphatidylcholines (LYSOC20:4 and LYSOC16:2), respectively. CONCLUSIONS: This is the first time that distinct biologic patterns of immune reconstitution after HCT are identified, which upon validation, could potentially aid future strategies for tolerance induction.

Department

Pediatrics

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