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T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 56, pages 900–908 (2021)Cite this article

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Abstract

The delayed recovery of adaptive immunity underlies transplant-related mortality (TRM) after αβ T cell-depleted hematopoietic stem cell transplantation (HSCT). We tested the use of low-dose memory donor lymphocyte infusions (mDLIs) after engraftment of αβ T cell-depleted grafts.

A cohort of 131 pediatric patients (median age 9 years) were grafted with αβ T cell-depleted products from either haplo (n = 79) or unrelated donors (n = 52). After engraftment, patients received mDLIs prepared by CD45RA depletion. Cell dose was escalated monthly from 25 × 103 to 100 × 103/kg (haplo) and from 100 × 103 to 300 × 103 /kg (MUD). In a subcohort of 16 patients, T-cell receptor (TCR) repertoire profiling with deep sequencing was used to track T-cell clones and to evaluate the contribution of mDLI to the immune repertoire.

In total, 343 mDLIs were administered. The cumulative incidence (CI) of grades II and III de novo acute graft-versus-host disease (aGVHD) was 5% and 2%, respectively, and the CI of chronic graft-versus-host disease was 7%. Half of the patients with undetectable CMV-specific T cells before mDLI recovered CMV-specific T cells. TCR repertoire profiling confirmed that mDLI-derived T cells significantly contribute to the TCR repertoire up to 1 year after HSCT and include persistent, CMV-specific T-cell clones.

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Fig. 1: Overall design of the study, clinical monitoring, and sample collection.
Fig. 2: The cumulative incidence of de novo acute and chronic GVHD after low-dose mDLI.
Fig. 3: Recovery of virus-specific T-cell responses.
Fig. 4: Contribution of mDLI-derived T-cell clones in patient peripheral blood T-cell repertoire.
Fig. 5: Different groups of DLI-derived T-cell clones are found in patient peripheral blood early after infusion and up to 1 year later.
Fig. 6: Dynamics of DLI-derived T-cell clones in patient peripheral blood.

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Acknowledgements

The authors thank the physicians and nursing staff of the HSCT Units 1 and 2 for outstanding patient care, the staff of molecular biology, microbiology, and transplant biology laboratories for excellent service. We are grateful to the “Podari Zhizn” foundation and “Science for children” foundation for continued support of the care of the patients and research in the field of HSCT.

Funding

The study was supported by RFBR grant no. 18-34-20139 (IZ, EK, FV), MM, AM, EO, DC were partly supported by grant  of the Ministry of Science and Higher Education of the Russian Federation no. 075-15-2020-807.

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Authors and Affiliations

  1. Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Sergey Blagov, Ivan V. Zvyagin, Larisa Shelikhova, Rimma Khismatullina, Dmitriy Balashov, Galina Novichkova, Alexei Maschan & Michael Maschan

  2. Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    Ivan V. Zvyagin, Ekaterina Komech, Viktoria Fomchenkova & Dmitriy Chudakov

  3. Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia

    Mikhail Shugay & Dmitriy Chudakov

  4. Department of Statistics, Dmitriy Rogachev National Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Julia Starichkova

  5. Transfusion Medicine Service, Dmitriy Rogachev National Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Elena Kurnikova, Yakov Muzalevskii & Alexei Kazachenok

  6. Transplantation Immunology and Immunotherapy Laboratory, Dmitriy Rogachev National Center of pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Dmitriy Pershin, Maria Fadeeva & Svetlana Glushkova

  7. Stem Cell Physiology Laboratory, Dmitriy Rogachev National center of pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Maria Efimenko & Elena Osipova

  8. Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia

    Dmitriy Chudakov

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  1. Sergey Blagov
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Contributions

MM, IZ, and SB contributed equally to this work. MM designed the study, analyzed data, and wrote the paper, IZ designed the sequencing part, collected and analyzed data, and wrote the paper, SB collected and analyzed data, wrote the paper, LS collected and analyzed data, reviewed the paper, RK, DB, JS, EK, DP, YM, AK, EO, MF, SG collected and analyzed data, EK collected samples, FV sample processing, data analysis, MS bioinformatics, data analysis, DC study design, data analysis, review, GN, AM—study design, paper review.

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Correspondence to Michael Maschan.

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MM received lecturer’s fee from Miltenyi Biotec, all other authors declare no conflict of interest in relation to the current paper.

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Blagov, S., Zvyagin, I.V., Shelikhova, L. et al. T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation. Bone Marrow Transplant 56, 900–908 (2021). https://doi.org/10.1038/s41409-020-01128-2

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