{"doi":"10.1016/j.jtct.2025.09.034","title":"Identification of Distinct Subtypes in Immune Tolerance after Hematopoietic Cell Transplantation Using the Prospective ABLE1.0 Pediatric Study Cohort","abstract":"• There appears to be more than one distinct biologic subtype or pathway to achieve primary and secondary immune tolerance after HCT. • Acute GvHD induces some changes in immune tolerance development after HCT, especially in the timing of reconstitution of some immune cell populations. • Pubertal impact on thymic function, MMP3, Phosphatidylcholine metabolism, and NK and NKT cells appear to impact on different distinctive patterns of tolerance. 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. 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. 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. 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. 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.","journal":"Transplantation and Cellular Therapy","year":2025,"id":576739,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":312103,"name":"Andrew C. 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