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Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack.

ABSTRACT: Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA^-) HSCs remain unknown. To address this issue, we generated induced pluripotent stem cells (iPSCs) from an AA patient who possessed HLA-B4002-lacking (B4002^-) leukocytes. Three different iPSC clones (wild-type [WT], 6pLOH⁺, and B*40:02-mutant) were established from the patient's monocytes. Three-week cultures of the iPSCs in the presence of various growth factors produced hematopoietic cells that make up 50% to 70% of the CD34⁺ cells of each phenotype. When 10⁶ iPSC-derived CD34⁺ (iCD34⁺) cells with the 3 different genotypes were injected into the femoral bone of C57BL/6.Rag2 mice, 2.1% to 7.3% human multilineage CD45⁺ cells of each HLA phenotype were detected in the bone marrow, spleen, and peripheral blood of the mice at 9 to 12 weeks after the injection, with no significant difference in the human:mouse chimerism ratio among the 3 groups. Stimulation of the patient's CD8⁺ T cells with the WT iCD34⁺ cells generated a cytotoxic T lymphocyte (CTL) line capable of killing WT iCD34⁺ cells but not B4002^- iCD34⁺ cells. These data suggest that B4002^- iCD34⁺ cells show a repopulating ability similar to that of WT iCD34⁺ cells when autologous T cells are absent and CTL precursors capable of selectively killing WT HSCs are present in the patient's peripheral blood.

SUBMITTER: Espinoza JL

PROVIDER: S-EPMC5858477 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack.

Espinoza J Luis JL Elbadry Mahmoud I MI Chonabayashi Kazuhisa K Yoshida Yoshinori Y Katagiri Takamasa T Harada Kenichi K Nakagawa Noriharu N Zaimoku Yoshitaka Y Imi Tatsuya T Takamatsu Hiroyuki H Ozawa Tatsuhiko T Maruyama Hiroyuki H Hassanein Hassan A HA Khalifa A Noreldin Amal A Takenaka Katsuto K Akashi Koichi K Hamana Hiroshi H Kishi Hiroyuki H Akatsuka Yoshiki Y Nakao Shinji S

Blood advances 20180201 4

Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA<sup>-</sup>) HSCs remain unknown. To address this issue, we generated induced pluripotent stem cells (iPSCs) from an AA patient who possessed ...[more]

PMID: 29472446

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Project description:BACKGROUND:Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. METHODS:We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. RESULTS:Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. CONCLUSIONS:Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.).

Dataset Information

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack.

Publications

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack.

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