Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:149

Article

Delmonte, Ottavia M.¹  Castagnoli, Riccardo¹  Yu, Jason^2,3,4  Dvorak, Christopher C.^2,4  Cowan, Morton J.^2,3,4  Saldana, Blachy J. Davila⁵  De Ravin, Suk See¹  Mamcarz, Ewelina⁶  Chang, Catherine K.^2,4  Daley, Stephen R.⁷  Griffith, Linda M.⁸  Notarangelo, Luigi D.¹  Puck, Jennifer M.^2,3,4 

[1] NIAID, Lab Clin Immunol & Microbiol, NIH, Bethesda, MD 20892 USA

[2] Univ Calif San Francisco, Sch Med, Dept Pediat, Div Allergy Immunol & Blood & Marrow Transplantat, San Francisco, CA USA

[3] Smith Cardiovasc Res Inst, San Francisco, CA USA

[4] UCSF Benioff Childrens Hosp, San Francisco, CA USA

[5] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC USA

[6] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, Memphis, TN USA

[7] Queensland Univ Technol, Sch Biomed Sci, Ctr Immunol & Infect Control, Brisbane, Qld, Australia

[8] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA

关键词: Complementarity determining region 3 (CDR3);    hematopoietic cell transplantation;    high-throughput sequencing;    immune reconstitution;    severe combined immunodeficiency (SCID);    T-cell receptor (TCR);    T-cell receptor beta (TRB) diversity;    T-cell receptor beta (TRB) repertoire;   

DOI  :  10.1016/j.jaci.2021.07.029

来源: Elsevier

【 摘 要 】

Background: Development of a diverse T-cell receptor beta (TRB) repertoire is associated with immune recovery following hematopoietic cell transplantation (HCT) for severe combined immunodeficiency (SCID). High-throughput sequencing of the TRB repertoire allows evaluation of clonotype dynamics during immune reconstitution. Objectives: We investigated whether longitudinal analysis of the TRB repertoire would accurately describe T-cell receptor diversity and illustrate the quality of T-cell reconstitution following HCT or gene therapy for SCID. Methods: We used high-throughput sequencing to study composition and diversity of the TRB repertoire in 27 infants with SCID at 3, 6, and 12 months and yearly posttreatment(s). Total RNA from peripheral blood was used as template to amplify TRB rearrangements. Results: TRB sequence analysis showed poor diversity at 3 months, followed by significant improvement by 6 months after cellular therapies. Kinetics of development of TRB diversity were similar in patients with a range of underlying gene defects. However, in patients with RAG and DCLRE1C defects, HCT with no conditioning or immune suppression only resulted in lower diversity than did HCT with conditioning. HCT from a matched donor correlated with higher diversity than did HCT from a mismatched donor. Naive CD4(+) T-cell count at 6 months post-HCT correlated with higher TRB diversity. A Shannon index of diversity of 5.2 or lower 3 months after HCT predicted a need for a second intervention. Conclusions: TRB repertoire after hematopoietic cell therapies for SCID provides a quantitative and qualitative measure of diversity of T-cell reconstitution and permits early identification of patients who may require a second intervention.

【 授权许可】

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