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

Espinoza, J. Luis; El-Badry, Mahmoud; Chonabayashi, Kazuhisa; Yoshida, Yoshinori; Katagiri, Takamasa; Harada, Kenichi; Nakagawa, Noboru; Zaimoku, Yoshitaka; Imi, Tatsuya; Takamatsu, Hiroyuki; Ozawa, Tatsuhiko; Muto, Hiroyuki; Hassanein, Hassan A.; Noreldin, Amal Khalifa A; Takenaka, Katsuto; Akashi, Koichi; Hamana, Hiroshi; Kishi, Hiroyuki; Akatsuka, Yoshiki; Nakao, Shinji

doi:10.1182/bloodadvances.2017013342

Cited by 29 publications

(24 citation statements)

References 26 publications

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“…Of course, GPI may not be the target in all cases: the escape model is versatile (Risitano, ; Luzzatto & Notaro, ) and if, as a result of mutation in a gene other than PIGA , a different target molecule were missing from a HSC, its progeny might be able to escape damage. This seems to be the case in a group of patients with AA who are heterozygous for the HLA‐B allele 4002 , and who have lost its expression through a somatic point mutation or deletion of this allele (Zaimoku et al , ); and very recently autologous cytotoxic T cells that specifically recognize induced pluripotent stem cell‐derived B4002+ CD34+ cells have been obtained from these patients (Espinoza et al , ). Patients who have B4002 are relatively few and, therefore, their presumed escape mechanism cannot account for what happens in the majority of patients with AA; but a similar mechanism of selection may take place with respect to other HLA alleles (Babushok et al , 2017a).…”

Section: The Source Of Damagementioning

confidence: 99%

Advances in understanding the pathogenesis of acquired aplastic anaemia

Luzzatto

Risitano

2018

Br J Haematol

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This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.

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Section: The Source Of Damagementioning

confidence: 99%

Advances in understanding the pathogenesis of acquired aplastic anaemia

Luzzatto

Risitano

2018

Br J Haematol

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“…13,20 On the other hand, HPV-B19 has been shown to increase secretion of interferon gamma and tumour necrosis factor alpha by recruiting striking CTLs 21 that could trigger an autoimmune response, as our report on AA. 22 This finding could explain the higher percentage of CD8 + T cells and inverted CD4/CD8 ratio in the BM of our patients with severe BMF.…”

Section: Discussionmentioning

confidence: 60%

Acute human parvovirus B19 infection triggers immune‐mediated transient bone marrow failure syndrome, extreme direct hyperbilirubinaemia and acute hepatitis in patients with hereditary haemolytic anaemias: multicentre prospective pathophysiological study

et al. 2021

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Summary A total of 244 patients with hereditary haemolytic anaemias (HHA) were screened for acute symptomatic human parvovirus B19 infection (HPV‐B19) in a prospective study. To assess the risks associated with HPV‐B19 infection, patients were classified into Group I and Group II according to presence or absence (symptoms, signs and specific serology) of acute HPV‐B19 infection respectively. In all, 131 (53·7%) patients had β‐thalassaemia, 75 (30·7%) hereditary spherocytosis (HS), 27 (11·1%) sickle cell anaemia (SCA) and 11 (4·5%) glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. Of 33 (13·5%) patients who presented with symptomatic HPV‐B19 infection, 19 (57·5%) had HS, nine (27·3%) had β‐thalassaemia and five (15·2%) had SCA. In Group I, there were significant differences in the mean white blood cell, red blood cell and platelet counts, haemoglobin concentration, total bilirubin (TB), alanine aminotransferase, aspartate aminotransferase and serum creatinine (all P < 0·001) compared to Group II. In all, 27 (81·8%) patients had arthropathy and bone marrow failure (BMF); 13 (39·4%) had acute kidney injury (AKI), more in SCA (80%); and 12 (36·4%) patients had hepatitis, more in HS (66·8%). Five (15·2%) patients with HS had BMF, AKI, nervous system involvement and extreme hyperbilirubinaemia (TB range 26·3–84·7 mg/dl). Five (15·2%) patients had haemophagocytic syndrome. Two patients with HS combined with Type‐I autoimmune hepatitis presented with transient BMF. Complete recovery or stabilisation was noted at 12 months in every patient except for one patient with SCA who died during the infection. HPV‐B19 must be suspected and screened in patients with HHA with typical and atypical presentations with careful follow‐up.

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“…Induced pluripotent stem cell (iPSC) clones with different phenotypes from cases 1 and 8 were cultured and differentiated into HSPCs using the previously described method (13,14). The HLA expression of each clone in case 1 was as follows: the WT clone (A02:01/A24:02, B35:01/B40:02, C08:01/C03:04), the B*40: 02 mut (B61 2 ) clone (A02:01/A24:02, B35:01/-, C08:01/C03:04), and the 6pLOH clone (A02:01/A02:01, B35:01/B35:01, C08:01/C08: 01) (14). The HLA alleles of each clone in case 8 were as follows: WT clone (A24:02/A01:01, B54:01/B37:01, C01:02/C06:02), B*54: 01 mut (B54 2 ) clone (A24:02/A01:01, -/B37:01, C01:02/C06:02), and 6pLOH clone (A01:01/A01:01, B37:01/B37:01, C06:02/C06:02) (13).…”

Section: Differentiation Of Hspcs From Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Resistance of KIR Ligand–Missing Leukocytes to NK Cells In Vivo in Patients with Acquired Aplastic Anemia

et al. 2020

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The loss of killer cell Ig-like receptor ligands (KIR-Ls) due to the copy number-neutral loss of heterozygosity of chromosome 6p (6pLOH) in leukocytes of patients with acquired aplastic anemia (AA) may alter the susceptibility of the affected leukocytes to NK cell killing in vivo. We studied 408 AA patients, including 261 who were heterozygous for KIR-Ls, namely C1/C2 or Bw6/Bw4, for the presence of KIR-L-missing [KIR-L(2)] leukocytes. KIR-L(2) leukocytes were found in 14 (5.4%, C1 [n = 4], C2 [n = 3], and Bw4 [n = 7]) of the 261 patients, in whom corresponding KIR(+) licensed NK cells were detected. The incidence of 6pLOH in the 261 patients (18.0%) was comparable to that in 147 patients (13.6%) who were homozygous for KIR-L genes. The percentages of HLA-lacking granulocytes (0.8-50.3%, median 15.2%) in the total granulocytes of the patients with KIR-L(2) cells were significantly lower than those (1.2-99.4%, median 55.4%) in patients without KIR-L(2) cells. KIR2DS1 and KIR3DS1 were only possessed by three of the 14 patients, two of whom had C2/C2 leukocytes after losing C1 alleles. The expression of the KIR3DS1 ligand HLA-F was selectively lost on KIR-L(2) primitive hematopoietic stem cells derived from 6pLOH(+) induced pluripotent stem cells in one of the KIR3DS1(+) patients. These findings suggest that human NK cells are able to suppress the expansion of KIR-L(2) leukocytes but are unable to

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

Abstract: Key Points• HLA-lacking iPSCderived HSCs from aplastic anemia patients show a hematopoietic ability similar to wild-type iPSC-HSCs.• iPSC-HSCs that lack HLA-B4002 escape specific T-cell attack.Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number

Cited by 29 publications

References 26 publications

Advances in understanding the pathogenesis of acquired aplastic anaemia

Advances in understanding the pathogenesis of acquired aplastic anaemia

Acute human parvovirus B19 infection triggers immune‐mediated transient bone marrow failure syndrome, extreme direct hyperbilirubinaemia and acute hepatitis in patients with hereditary haemolytic anaemias: multicentre prospective pathophysiological study

Resistance of KIR Ligand–Missing Leukocytes to NK Cells In Vivo in Patients with Acquired Aplastic Anemia

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