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

Bernard Ng¹, Andrew C Harris², Sayeh Abdossamadi³, Madeline P Lauener³, Geraldine Aubert⁴, Rajinder Bajwa⁵, Monica Bhatia⁶, Henrique Bittencourt⁷, Nataliya P Buxbaum⁸, Emi H Caywood⁹, Sonali Chaudhury¹⁰, Joseph H Chewning¹¹, Sung Won Choi¹², Ashley Chopek¹³, Julia Chu¹⁴, Donald Coulter¹⁵, Shahinaz M Gadalla¹⁶, Richard T Hogg³, David A Jacobsohn¹⁷, Amanda K Johnson¹⁸, Michael Joyce¹⁹, Kimberly A Kasow²⁰, Michael Kent²¹, Carrie L Kitko²², Donna Lau³, Anita Lawitschka²³, Victor A Lewis²⁴, Amanda M Li³, Laura McLaughlin²⁵, David Mitchell²⁶, Eneida R Nemecek²⁷, Vaishnavi Parthasarathy²⁸, Anna B Pawlowska²⁹, Filip Pirsl¹⁷, Michael A Pulsipher¹⁸, Muna Qayed³⁰, Jacob Rozmus³, Süreyya Savaşan³¹, Tal Schechter³², Shalini Shenoy³³, Alima Suleimenova³, Dong Jun Zheng³, Elena Ostroumov³, Ramon I Klein Geltink³⁴, Andrew Gilman³⁵, Daniel Wolff³⁶, Geoffrey D E Cuvelier²⁴, Kirk R Schultz³⁷

Affiliations

¹ Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
² MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
⁴ Repeat Diagnostics Inc, North Vancouver, BC Canada.
⁵ Nationwide Children's Hospital Columbus, OH, USA.
⁶ Pediatric Stem Cell Transplant Program, Morgan Stanley Children's Hospital, Columbia University, New York, NY, USA.
⁷ Pediatric Hematology-Oncology Division, Saint-Justine University Hospital Centre, Montreal, QC, Canada.
⁸ Roswell Park Comprehensive CancerCancer Center, Buffalo, NY, USA.
⁹ Nemours Children's Health, Thomas Jefferson University, Wilmington, DE, USA; Thomas Jefferson University, Philadelphia, PA.
¹⁰ Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL, USA.
¹¹ Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹² University of Michigan, Blood and Marrow Transplantation Program, Ann Arbor, MI USA.
¹³ Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁴ Pediatric Blood and Marrow Transplant Program, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
¹⁷ Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
¹⁸ Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant. University of Utah/Primary Children's Hospital, Salt Lake City, UT, USA.
¹⁹ Nemours Children's Health, Jacksonville, FL, USA.
²⁰ Pediatric Bone Marrow Transplant, University of North Carolina, Chapel Hill, NC, USA.
²¹ Atrium Health/Levine Children's Charlotte, NC, USA.
²² Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN, USA.
²³ Stem Cell Transplant Unit, St. Anna Children's Hospital, Medical University, Vienna, Austria.
²⁴ Pediatric Oncology and Transplant, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
²⁵ Children's Hospital Colorado Denver, CO, USA.
²⁶ Division of Pediatric Hematology-Oncology, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
²⁷ Pediatric Blood and Marrow Transplantation, Doernbecher Children's Hospital, Oregon Health and Sciences University, Portland, OR, USA.
²⁸ 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.
²⁹ Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplant. City of Hope, Duarte, CA, USA.
³⁰ Emory University School of Medicine, Atlanta, GA, USA.
³¹ Pediatric Hematology & Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
³² Pediatric Hematology-Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
³³ Washington University School of Medicine, St. Louis, MO, USA.
³⁴ Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC.
³⁵ ICON Biotech, Center for Cell and Gene Therapy, Charlotte, NC USA.
³⁶ Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
³⁷ Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada. Electronic address: kschultz@mail.ubc.ca.

PMID: 41033605
DOI: 10.1016/j.jtct.2025.09.034

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

Bernard Ng et al. Transplant Cell Ther. 2025.

. 2025 Sep 29:S2666-6367(25)01458-7.

doi: 10.1016/j.jtct.2025.09.034. Online ahead of print.

Authors

Affiliations

¹ Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
² MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
⁴ Repeat Diagnostics Inc, North Vancouver, BC Canada.
⁵ Nationwide Children's Hospital Columbus, OH, USA.
⁶ Pediatric Stem Cell Transplant Program, Morgan Stanley Children's Hospital, Columbia University, New York, NY, USA.
⁷ Pediatric Hematology-Oncology Division, Saint-Justine University Hospital Centre, Montreal, QC, Canada.
⁸ Roswell Park Comprehensive CancerCancer Center, Buffalo, NY, USA.
⁹ Nemours Children's Health, Thomas Jefferson University, Wilmington, DE, USA; Thomas Jefferson University, Philadelphia, PA.
¹⁰ Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL, USA.
¹¹ Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹² University of Michigan, Blood and Marrow Transplantation Program, Ann Arbor, MI USA.
¹³ Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁴ Pediatric Blood and Marrow Transplant Program, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Division of Pediatric Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
¹⁷ Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
¹⁸ Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant. University of Utah/Primary Children's Hospital, Salt Lake City, UT, USA.
¹⁹ Nemours Children's Health, Jacksonville, FL, USA.
²⁰ Pediatric Bone Marrow Transplant, University of North Carolina, Chapel Hill, NC, USA.
²¹ Atrium Health/Levine Children's Charlotte, NC, USA.
²² Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN, USA.
²³ Stem Cell Transplant Unit, St. Anna Children's Hospital, Medical University, Vienna, Austria.
²⁴ Pediatric Oncology and Transplant, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada.
²⁵ Children's Hospital Colorado Denver, CO, USA.
²⁶ Division of Pediatric Hematology-Oncology, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
²⁷ Pediatric Blood and Marrow Transplantation, Doernbecher Children's Hospital, Oregon Health and Sciences University, Portland, OR, USA.
²⁸ 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.
²⁹ Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplant. City of Hope, Duarte, CA, USA.
³⁰ Emory University School of Medicine, Atlanta, GA, USA.
³¹ Pediatric Hematology & Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
³² Pediatric Hematology-Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
³³ Washington University School of Medicine, St. Louis, MO, USA.
³⁴ Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Children's Hospital, Vancouver, BC.
³⁵ ICON Biotech, Center for Cell and Gene Therapy, Charlotte, NC USA.
³⁶ Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
³⁷ Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada. Electronic address: kschultz@mail.ubc.ca.

PMID: 41033605
DOI: 10.1016/j.jtct.2025.09.034

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_reg 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.

Keywords: Chronic GvHD; Hematopoietic cell transplantation; Immune tolerance; Modeling immune patterns.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest None of the authors have any significant conflict of interest in the results of these studies.

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources