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Stem cell transplantation

Pre-transplant donor CD4− invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease

Leukemia volume 31, pages 903–912 (2017)Cite this article

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Abstract

Clinically useful pre-transplant predictive factors of acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT) are lacking. We prospectively analyzed HSC graft content in CD34+, NK, conventional T, regulatory T and invariant natural killer T (iNKT) cells in 117 adult patients before allo-SCT. Results were correlated with occurrence of aGVHD and relapse. In univariate analysis, iNKT cells were the only graft cell populations associated with occurrence of aGVHD. In multivariate analysis, CD4− iNKT/T cell frequency could predict grade II-IV aGVHD in bone marrow and peripheral blood stem cell (PBSC) grafts, while CD4− iNKT expansion capacity was predictive in PBSC grafts. Receiver operating characteristic analyses determined the CD4− iNKT expansion factor as the best predictive factor of aGVHD. Incidence of grade II-IV aGVHD was reduced in patients receiving a graft with an expansion factor above versus below 6.83 (9.7 vs 80%, P<0.0001), while relapse incidence at two years was similar (P=0.5).The test reached 94% sensitivity and 100% specificity in the subgroup of patients transplanted with human leukocyte antigen 10/10 PBSCs without active disease. Analysis of this CD4− iNKT expansion capacity test may represent the first diagnostic tool allowing selection of the best donor to avoid severe aGVHD with preserved graft-versus-leukemia effect after peripheral blood allo-SCT.

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Acknowledgements

We are grateful to the NIH Tetramer Core Facility for providing CD1d tetramer reagents, the clinical investigation center (CIC) of Necker Hospital for their participation in clinical studies, the ‘Ligue Nationale contre le Cancer’, the APHP (Assistance Publique des Hopitaux de Paris), the ‘Cancéropole d’Ile de France’, and the ‘Institut National du Cancer’ for supportive grants. MM thanks Prof JV Melo (Adelaide, Australia) for critical reading of the manuscript. MM also acknowledges the educational grants received from the ‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). The Saint-Antoine hospital group (MTR, MM) is supported by several grants from the national Hospital Clinical Research Program (‘PHRC’) from the French National Cancer Institute.

Author contributions

MTR, MB and OH collected the data. MTR, FS, AG, DS, AB, EP, SNK, MM and OH provided the patients’ data. HTN, MC and OL provided materials and expertise in cell phenotyping. MTR, MB, NB, SU and OH analyzed the data. MTR, MB, MM, NB, SU and OH wrote and commented on the manuscript. All authors approve the final manuscript.

Key points

(1) Graft CD4− iNKT cell ex vivo expansion capacity is the best graft parameter capable of predicting the occurrence of acute GVHD after allogeneic stem cell transplantation from PBSC. (2) Donor CD4− iNKT cell expansion capacity test could be used to select the best donor before performing allogeneic stem cell transplantation with PBSC.

Author information

Author notes

  1. M-T Rubio

    Present address: 16Current address: Service d’Hématologie et de Médecine Interne, Hôpital Brabois, CHRU Nancy, France.,

  2. M-T Rubio and M Bouillié: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France

    M-T Rubio, M Bouillié, T Coman, F Suarez, D Sibon, E Paubelle & O Hermine

  2. Service d’Hématologie Clinique et de Thérapie Cellulaire, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France

    M-T Rubio, A Gomez & M Mohty

  3. INSERM UMRs 938, Centre de Recherche de l’hôpital Saint Antoine, Paris, France

    M-T Rubio, A Gomez & M Mohty

  4. Université Pierre et Marie Curie, Paris, VI, France

    M-T Rubio, A Gomez & M Mohty

  5. Institut Hospitalo-Universitaire (IHU) Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France

    M-T Rubio, M Bouillié, T Coman, F Suarez, E Paubelle, M Cavazzana & O Hermine

  6. Unité de Recherche Clinique, Paris Centre Necker Cochin, Hôpital Tarnier, Paris, France

    N Bouazza & S Urien

  7. Département de Biothérapie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    H Trebeden-Nègre

  8. Service d’Hématologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France

    F Suarez, D Sibon, E Paubelle & O Hermine

  9. Therapeutic Apheresis Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

    A Brignier

  10. Service d’Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    S Nguyen-Khoc

  11. Biotherapy Department, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

    M Cavazzana

  12. INSERM U1163, Laboratory of Human Lymphohematopoiesis, Paris, France

    M Cavazzana

  13. Département de Biologie des Tumeurs, INSERM U932, Institut Curie, Paris, France

    O Lantz

  14. Centre d'Investigation Clinique, CICBT507 IGR/Curie, Paris, France

    O Lantz

  15. INSERM CIC 1419, EAU08 Université Paris Descartes, Paris, France

    S Urien

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  1. M-T Rubio
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Correspondence to M-T Rubio or O Hermine.

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Rubio, MT., Bouillié, M., Bouazza, N. et al. Pre-transplant donor CD4− invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease. Leukemia 31, 903–912 (2017). https://doi.org/10.1038/leu.2016.281

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