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Utility of novel T-cell-specific extracellular vesicles in monitoring and evaluation of acute GVHD

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Abstract

We have recently reported a new method for detecting T-cell-derived extracellular vesicles (EVs), CD3+CD4+EVs,CD3+CD8+EVs, and CD3+HLA-DR+EVs. In our previous study, CD3+HLA-DR+EVs were released profusely by CD8+T cells, only moderately by T helper1 (Th1) CD4+T cells, and very little from Th2 CD4+T cells in vitro. EVs were measured sequentially in patients undergoing hematopoietic stem cell transplantation (HSCT), and their relationship to GVHD was investigated in comparison with other conventional biomarkers. We analyzed peripheral blood samples from 20 patients (13 children and 7 adults) who underwent HSCT at Tokyo Medical and Dental University Hospital. CD3+CD4+EV and CD3+CD8+EV levels specifically correlated with the CD4+ and CD8+T lymphocyte counts, respectively. CD3+CD8+EVs and CD3+HLA-DR+EVs increased in GVHD and reflected the persistence of GVHD more specifically than soluble IL-2 receptor (sIL-2R). In engraftment syndrome, sIL-2R was markedly elevated, but CD3+HLA-DR+EVs were not. Furthermore, ferritin and sIL-2R markedly increased in hemophagocytic syndrome (HPS) that developed before engraftment; however, the change in CD3+HLA-DR+EVs was marginal. CD3+CD4+, CD3+CD8+, and CD3+HLA-DR+EVs efficiently reflect the cell-mediated immune response, and CD3+CD8+EVs and CD3+HLA-DR+EVs are more useful than other conventional biomarkers, such as sIL-2R, for monitoring and evaluation of acute GVHD.

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Abbreviations

EV:

Extracellular vesicle

HSCT:

Hematopoietic stem cell transplantation

GVHD:

Graft versus host disease

HPS:

Hemophagocytic syndrome

sIL-2R:

Soluble IL-2 receptor

ES:

Engraftment syndrome

PSL:

Prednisolone

MTX:

Methotrexate

TAC:

Tacrolimus

CSP:

Ciclosporin

IFX:

Infliximab

CMV:

Cytomegalovirus

HHV-6:

Human herpes virus 6

BKV:

BK virus

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Acknowledgements

We appreciate all of the staff at the Tokyo Medical and Dental University Hospital who were involved in the medical care of patients with SCT. This work was partly supported by a Grant-in-Aid for Scientific Research (KAKENHI) Grant Number 15K09639 to M.N.

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Authors and Affiliations

  1. Department of Pediatrics, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-city, Tokyo, 180-8610, Japan

    Masayuki Nagasawa

  2. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

    Masayuki Nagasawa, Noriko Mitsuiki, Masakatsu Yanagimachi & Tomohiro Morio

  3. Department of Hematology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

    Masahide Yamamoto, Tetsuya Fukuda & Osamu Miura

  4. Division of Advanced Technology and Development, BML.Inc., Saitama, 350-1101, Japan

    Ryutaro Oba, Akira Igarashi & Kinya Nagata

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  1. Masayuki Nagasawa
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  2. Noriko Mitsuiki
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  3. Masakatsu Yanagimachi
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  4. Masahide Yamamoto
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  5. Tetsuya Fukuda
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Correspondence to Masayuki Nagasawa.

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12185_2021_3113_MOESM1_ESM.pptx

SUPPLEMENTAL FIGURE 1: Correlation of three EVs with CD3+CD4+, CD3+CD8+, and CD3+HLA-DR+ lymphocyte counts. The relation of CD3+CD4+ EVs (A, B, C), CD3+CD8+ EVs (D, E, F), and CD3+HLA-DR+ EVs (G, H, I) with CD3+CD4+ (A, D, G), CD3+CD8+ (B, E, H), and CD3+HLA-DR+ (C, F, I) lymphocyte counts was analyzed. The relation of CD3+HLD-DR+ EVs with CD3+HLA-DR+ lymphocyte counts in patients with (K) or without GVHD (J) was also analyzed. Correlation coefficient (r) is shown in the graph; SUPPLEMENTAL FIGURE 2: Correlation of CD3+HLA-DR+ EVs with leukocyte subsets and correlation between three T-cell-derived EVs. The relation of CD3+HLD-DR+EVs with CD3+lymphocyte (A), total lymphocyte (B), monocyte (C), B cell (D), NK cell (E), and white blood cell (F) counts was analyzed. The relation of CD3+HLD-DR+EVs with CD3+CD4+EVs (G), CD3+HLD-DR+EVs with CD3+CD8+EVs (H), and of CD3+CD4+EVs with CD3+CD4+EVs (I) was also analyzed. Correlation coefficient (r) is shown in the graph; SUPPLEMENTAL FIGURE 3: Correlation of CD3+HLD-DR+EVs with conventional GVHD markers. The relation of CD3+HLD-DR+EVs with conventional GVHD markers, sIL-2R (A), ferritin (B), D-dimer (C), and granulysin (D) was analyzed. Correlation coefficient (r) is shown in the graph. (PPTX 9412 KB)

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Nagasawa, M., Mitsuiki, N., Yanagimachi, M. et al. Utility of novel T-cell-specific extracellular vesicles in monitoring and evaluation of acute GVHD. Int J Hematol 113, 910–920 (2021). https://doi.org/10.1007/s12185-021-03113-x

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