Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4- subset dynamics and correlates with remission State

Claudia De Lalla, Anna Rinaldi, Daniela Montagna, Laura Azzimonti, Maria Ester Bernardo, Laura M. Sangalli, Anna Maria Paganoni, Rita Maccario, Alessandra Di Cesare-Merlone, Marco Zecca, Franco Locatelli, Paolo Dellabona, Giulia Casorati

Research output: Contribution to journalArticle

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Abstract

Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipidreactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4+ and CD4- subsets that express the NK receptor CD161 and derive from thymic CD4+CD1612 precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ-expressing effectors in the 25 patients maintaining remission. CD4+ cells emerge earlier than the CD4- ones, both displaying CD1612 immature phenotypes. CD4- cells expand more slowly than CD4+ cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4- iNKT cells undergo a substantial expansion burst, resulting in a CD4 +- NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.

Original languageEnglish
Pages (from-to)4490-4499
Number of pages10
JournalJournal of Immunology
Volume186
Issue number7
DOIs
Publication statusPublished - Apr 1 2011

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Natural Killer T-Cells
Stem Cell Transplantation
Leukemia
Pediatrics
Hematopoietic Stem Cell Transplantation
Hematologic Neoplasms
Recurrence
T-Lymphocytes
Adoptive Transfer
Autoimmunity
Tissue Donors
Phenotype

ASJC Scopus subject areas

  • Immunology

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Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4- subset dynamics and correlates with remission State. / De Lalla, Claudia; Rinaldi, Anna; Montagna, Daniela; Azzimonti, Laura; Bernardo, Maria Ester; Sangalli, Laura M.; Paganoni, Anna Maria; Maccario, Rita; Cesare-Merlone, Alessandra Di; Zecca, Marco; Locatelli, Franco; Dellabona, Paolo; Casorati, Giulia.

In: Journal of Immunology, Vol. 186, No. 7, 01.04.2011, p. 4490-4499.

Research output: Contribution to journalArticle

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abstract = "Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipidreactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4+ and CD4- subsets that express the NK receptor CD161 and derive from thymic CD4+CD1612 precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ-expressing effectors in the 25 patients maintaining remission. CD4+ cells emerge earlier than the CD4- ones, both displaying CD1612 immature phenotypes. CD4- cells expand more slowly than CD4+ cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4- iNKT cells undergo a substantial expansion burst, resulting in a CD4 +- NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.",
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