[Treatment of acquired a plastic anemia: an update].
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Anemia, Aplastic↗
Biomedical subjects
Seiji Kojima
Publications and source records attributed to Seiji Kojima.
Autoantibodies frequently detected in patients with aplastic anemia.
Although accumulating evidence strongly suggests that aplastic anemia (AA) is a T cell-mediated autoimmune disease, no target antigens have yet been described for AA. In autoimmune diseases, target autoantigens frequently induce not only cellular T-cell responses but also humoral B-cell responses. We hypothesized that the presence of antigen-specific autoantibodies could be used as a "surrogate marker" for the identification of target T-cell autoantigens in AA patients. We screened a human fetal liver library for serologic reactivity against hematopoietic stem/progenitor cell antigens and isolated 32 genes. In 7 of 18 AA patients, an immunoglobulin G (IgG) antibody response was detected to one of the genes, kinectin, which is expressed in all hematopoietic cell lineages tested including CD34+ cells. No response to kinectin was detected in healthy volunteers, multiply transfused non-AA patients, or patients with other autoimmune diseases. Epitope mapping of IgG autoantibodies against kinectin revealed that the responses to several of the epitopes were shared by different AA patients. Moreover, CD8+ cytotoxic T cells raised against kinectin-derived peptides suppressed the colony formation of granulocyte macrophage colony-forming units (CFU-GMs) in an HLA class I-restricted fashion. These results suggest that kinectin may be a candidate autoantigen that is involved in the pathophysiology of AA.
Anemia, Aplastic↗
Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.
Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants. Acute megakaryocytic leukemia (AMKL) develops in approximately 20% to 30% of the cases with TMD. Recently, acquired mutations in the N-terminal activation domain of the GATA-1 gene, encoding the erythroid/megakaryocytic transcription factor GATA-1, have been reported in Down syndrome-related AMKL (DS-AMKL). To understand the multistep leukemogenesis in Down syndrome, GATA-1 mutations were investigated in patients with TMD. We show here that mutations in the GATA-1 gene were detected in 21 of 22 cases with TMD. Most of the mutations in TMD were located in the regions including exon 2 and were essentially identical to those observed in DS-AMKL. In the DS-AMKL cell line, MGS, which itself expresses only a truncated mutant of GATA-1, expression of full-length GATA-1 induced the differentiation toward the erythroid lineage. However, expression of the short form of GATA-1 did not induce erythroid differentiation. These results indicate that expression of GATA-1 with a defective N-terminal activation domain contributes to the expansion of TMD blast cells and that other genetic changes contribute to the development of AMKL in Down syndrome.
Age Factors↗
Protective effects of glutathione on 5-fluorouracil-induced myelosuppression in mice.
The protective effects of glutathione (GSH) administration on myelosuppression induced by 5-fluorouracil (5-FU) were investigated in female BALB/c mice. Animals were allocated to four groups (16 mice/group). GSH was given orally at a dose of 800 mg/kg to groups 3 and 4 for 21 consecutive days (day 0 to day 20). 5-FU was repeatedly administered at a dose of 40 mg/kg to groups 2 and 3 for 1 week (day 7 to day 13) by gavage. Group 3 served as a combined treatment group and group 1 as a non-treated control group. The total observation period was 3 weeks. Body weight was measured once a week. A decrease in body weight due to 5-FU treatment was observed in groups 2 and 3 on day 14. Although the body weight in group 2 had not increased by 1-week after cessation of 5-FU treatment, the value in group 3 markedly recovered. Hematology, total nucleated myelocyte count and histopathology of bone marrow were carried out on day 14 and day 21. In groups 2 and 3, these examinations showed thrombocytopenia, leukopenia, reticulocytopenia and myelosuppression on day 14. However, platelets and bone marrow were less affected in group 3 than in group 2. On day 21, the thrombocytopenia in groups 2 and 3 was resolved. The myelosuppression, leukopenia and reticulocytopenia resolved in group 3, but not in group 2. Although simple microcytic anemia occurred delayed on day 21, it was less severe in group 3 than in group 2. Therefore, GSH may have preventive effects against 5-FU-induced hematopoietic toxicity, and accelerate recovery after cessation of 5-FU treatment.
Administration, Oral↗
Induction of complete remission of hypoplastic leukemia with antithymocyte globulin.
A 13-year-old boy was admitted to a local hospital because of pancytopenia. A bone marrow aspiration and biopsy revealed severely hypocellular marrow with no obvious leukemic cells. The diagnosis was severe aplastic anemia, and the patient was treated with antithymocyte globulin and cyclosporin A. A trilineage response was obtained, and the patient became transfusion-independent within 2 weeks. Two months later, the peripheral blood count normalized with an increased bone marrow cellularity. However, the patient was readmitted 5 months later for recurrence of the pancytopenia. A bone marrow aspiration revealed hypocellular marrow with morphologically blastoid cells. A surface marker study revealed the presence of a single clone that was positive for CD7, CD33, CD34, and HLA-DR. A diagnosis of hypoplastic leukemia was made on the basis of morphology and the surface marker studies. Retrospectively, the laboratory findings were the same as those seen at the onset of the disease. The patient did not respond to combination chemotherapy consisting of vincristine, prednisolone, cyclophosphamide, L-asparaginase, and doxorubicin, but administration of etoposide resulted in complete remission. An in vitro study revealed that >95% of the leukemic cells of this patient could be lysed after an incubation with antithymocyte globulin and human AB serum or baby rabbit serum. These findings suggest the efficacy of antithymocyte globulin in treating certain hypoplastic leukemias.
Adolescent↗
Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia.
We examined the expression of granule constituent genes in myeloid progenitor cells during proliferation and differentiation in patients with severe congenital neutropenia (SCN). The heterozygous mutation of the neutrophil elastase gene was identified in two of four patients. The CD34+/granulocyte-colony stimulating factor receptor (G-CSFR)+ cells of SCN patients showed defective responsiveness to G-CSF in serum-deprived culture. The CD34+/G-CSFR+ cells expressed low levels of the granule constituent mRNAs. The transcription levels of primary granule enzyme genes in CD34+/G-CSFR+ cells were gradually enhanced and then decreased when cells were induced toward myeloid lineage with G-CSF in normal subjects. However, the primary up-regulation and the following down-regulation of these enzyme transcriptions were not clearly observed in SCN patients. No differences in expressions of the lactoferrin gene were seen between normal subjects and patients with SCN. We hypothesize that the abnormal regulation of the transcription in primary granule constituents might involve the defective proliferation and differentiation of myeloid cells in patients with SCN.
Bone Marrow Cells↗
New application of terahertz time-domain spectrometry (THz-TDS) to the phonon-polariton observation on ferroelectric crystals.
A new instrument for terahertz time-domain spectroscopy (THz-TDS) has been developed. It consists of a composite THz-TDS system and a high throughput (Martin-Puplett) interferometer. The instrument is for use in the qualitative study of optoelectronic constants of materials. The spectral transmission intensity and phase shift related to phonon-polariton dispersion have been measured between 100 cm(-1) and 3 cm(-1) on ferroelectric crystals of industrial interest. These include bismuth titanate Bi4Ti3O12 (a key material for FeRAM), lithium niobate LiNbO3 (a typical nonlinear crystal for parametric oscillator applications) and lithium heptagermanate Li2Ge7O15 for surface elastic wave filter applications. The complex dielectric constants are well reproduced by the phonon-polariton dispersion relation based on the Kurosawa formula. The instrument details and phonon-polariton dispersion results are described.
Anisotropy↗
Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children.
Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) after immunosuppressive therapy (IST). It is uncertain whether the increased survival time simply discloses the natural history of AA as a premalignant disease or whether secondary disease is related to the therapy itself. Between November 1992 and September 1997, 113 AA children with normal cytogenetics at diagnosis were treated with IST using antithymocyte globulin, cyclosporin, and danazol with or without granulocyte colony-stimulating factor (G-CSF). We assessed risk factors for developing MDS/AML by Cox proportional hazards models. Twelve of 113 patients developed MDS between 9 and 81 months following the time of diagnosis, giving a cumulative incidence of 13.7 +/- 3.9%. The following cytogenetic abnormalities were observed at the time of diagnosis of MDS: monosomy 7 (6 patients), monosomy7/trisomy21 (1 patient), trisomy 11 (1 patient), del (11) (9?:14) (1 patient), add (9q) (1 patient), add 7 (q 32) (1 patient), and trisomy 9 (1 patient). The number of days of G-CSF therapy and nonresponse to therapy at 6 months were statistically significant risk factors by multivariate analysis. The present study suggests a close relationship between long-term use of G-CSF and secondary MDS in nonresponders to IST.
Acute Disease↗
Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program.
We retrospectively analyzed results for 154 patients with acquired severe aplastic anemia who received bone marrow transplants between 1993 and 2000 from unrelated donors identified through the Japan Marrow Donor Program. Patients were aged between 1 and 46 years (median, 17 years). Seventy-nine donor-patient pairs matched at HLA-A, -B, and -DRB1 loci, as shown by DNA typing. Among the 75 mismatched pairs, DNA typing of 63 pairs showed that 51 were mismatched at 1 HLA locus (18 HLA-A, 11 HLA-B, 22 HLA-DRB1) and 12 were mismatched at 2 or more loci. Seventeen patients (11%) experienced either early or late graft rejection. The incidence of grade III/IV acute graft versus host disease and chronic graft versus host disease was 20% (range, 7%-33%) and 30% (range, 12%-48%), respectively. Currently, 99 patients are alive, having survived for 3 to 82 months (median, 29 months) after their transplantations. The probability of overall survival at 5 years was 56% (95% confidence interval, 34%-78%). Multivariate analysis revealed the following unfavorable factors: transplantation more than 3 years after diagnosis (relative risk [RR], 1.86; P =.02), patients older than 20 years (RR, 2.27; P =.03), preconditioning regimen without antithymocyte globulin (RR 2.28; P =.04), and HLA-A or -B locus mismatching as determined by DNA typing. Matching of HLA class I alleles and improvement of preparative regimens should result in improved outcomes in patients with severe aplastic anemia who receive transplants from unrelated donors.
Adolescent↗
Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors.
Human herpesvirus 6 (HHV-6) infection was studied in 82 bone marrow transplant (BMT) recipients (72 allogeneic, 10 autologous). All recipients and 30 donors were seropositive for HHV-6 antibody at the time of bone marrow transplantation. Thirty-one recipients (37.8%) had HHV-6 viremia 2-4 weeks after transplantation. The incidence of HHV-6 viremia was significantly higher among allogeneic BMT recipients than in autologous BMT recipients (P=.011). Therefore, the following analyses of allogeneic BMT recipients were carried out (n=72). Geometric mean antibody titers (log(10)) were significantly higher in recipients without viremia than in those with viremia (1.84+/-0.39 vs. 1.61+/-0.42; P=.022). Logistic regression analysis demonstrated that leukemia or lymphoma is an independent risk factor (P=.031) for HHV-6 viremia. Rash occurring within 1 month after transplantation was observed in 17 (54.8%) of 31 recipients with HHV-6 viremia but in only 8 (19.5%) of 41 recipients without HHV-6 viremia (P=.001).
Adolescent↗
Aplastic anemia in the Orient.
Aplastic anemia (AA) is more common in Asia than in Europe or the United States. This may be due in part to the high incidence of hepatitis-associated AA in Asia. The management of AA has evolved rapidly in Japan during the last decade. Advances in the treatment of AA have largely been the result of prospective collaborative studies of immunosuppressive therapy and the large registry of bone marrow transplantation data. These studies have revealed several differences in clinical outcome between Western and Eastern patients, differences that may reflect the effects of genetic background on response to treatment or development of adverse effects.
Anemia, Aplastic↗
Epstein-Barr virus-specific T-cell cytotoxicity is mediated through the perforin pathway in patients with lymphoproliferative disorders after allogeneic bone marrow transplantation.
The in vivo cytotoxic mechanism of Epstein--Barr virus (EBV)-specific cytotoxic lymphocytes was examined in a patient who suffered with EBV-associated lymphoproliferative disease (LPD) after bone marrow transplantation (BMT). His peripheral CD8+ T-cell count was significantly increased and >70% of these cells were EBV-specific by fluorescence-activated cell sorter (FACS) analysis for interferon-gamma production. Intracellular perforin expression was markedly increased in CD8+ T cells by FACS analysis. The lymphocytes from this patient had cytotoxic activity against autologous EBV+ lymphoblastoid cell lines which were completely inhibited by concanamycin A, an inhibitor of perforin, and a anti-human leucocyte antigen (HLA)-class I monoclonal antibody. These results suggest that the cytotoxicity was mediated by the perforin, in an HLA-class I-restricted manner. We performed serial intracellular perforin analyses in another patient who also showed endogenous expansion of EBV-specific CD8+ T cells that coincided with an increased EBV-DNA load. Perforin expression in the CD8+ and CD4+ T cells paralleled the EBV-specific CD8+ T cells and EBV-DNA load, which also suggests that perforin mediates EBV-specific cytolysis in vivo and is responsible for effective immunosurveillance against EBV reactivation after BMT. Evaluation of host immunity against EBV by determining perforin expression in lymphocytes and EBV-specific lymphocytes along with quantification of EBV-DNA may be useful for predicting the clinical course of patients with EBV-associated LPD after BMT.
Biomarkers↗
Evolution of myelodysplastic syndrome and acute myelogenous leukaemia in children with hepatitis-associated aplastic anaemia.
In hepatitis-associated aplastic anaemia (HAA), an immune-mediated mechanism is solely responsible for the development of pancytopenia. We retrospectively analysed the clinical outcome of 61 children with HAA, diagnosed between 1988 and 1996. Of 61 patients, 41 did not receive bone marrow transplantation (BMT) and their survival rate at 7 years was 61.4 +/- 9.3%(+/- SE). Five of these 41 patients developed myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) 7-57 months after the diagnosis of HAA. The incidence of MDS/AML in severe HAA patients who did not receive BMT (n = 30, 27.0 +/- 10.8%) appeared to be similar to that of severe idiopathic AA patients (n = 155, 14.7 +/- 3.7%) treated in the same period.
Adolescent↗
Treatment responses of childhood aplastic anaemia with chromosomal aberrations at diagnosis.
The clinical outcome of childhood aplastic anaemia (AA) with aberrant cytogenetic clones at diagnosis was surveyed. Among 198 children with newly diagnosed AA registered with the AA Committee of the Japanese Society of Paediatric Hematology between 1994 and 1998, cytogenetic studies of bone marrow (BM) cells were completed in 159 patients. Apart from one Robertsonian translocation, seven patients (4.4%) showed clonal chromosomal abnormalities in hypoplastic BM without myelodysplastic features. The patients included six girls and one boy with a median age of 11 years (range 5-14 years). Six patients had del(6), del(5), del(13), del(20), or -7, and one showed add(9). Four patients responded to the first immunosuppressive therapy (IST: cyclosporin A plus anti-thymocyte globulin) and one obtained a spontaneous remission. Cytogenetic abnormalities remained in two patients with an IST response. On the other hand, two patients showed no IST response. One did not respond to repeat IST and died of acute graft-versus-host disease after an unrelated-BM transplant. Another obtained a complete response after a successful BM transplant. No haematological findings at diagnosis predicted the treatment response. No significant morphological changes developed during the course of the illness. A literature review revealed that half of 24 AA patients with chromosomal abnormalities responded to the first IST, and that +6 was the sole predictable marker for IST unresponsiveness. These results suggest that IST can be applied as the initial therapy for AA with cytogenetic abnormalities in the absence of completely matched donors.
Adolescent↗
Transient pancytopenia associated with parvovirus infection in a healthy child.
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Child↗
Successful engraftment of unrelated donor stem cells in two children with congenital amegakaryocytic thrombocytopenia.
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Child, Preschool↗
Monitoring of active HHV-6 infection in bone marrow transplant recipients by real time PCR; comparison to detection of viral DNA in plasma by qualitative PCR.
Twelve (46%) of the 26 patients had human herpesvirus 6 (HHV-6) viremia after bone marrow transplant (BMT). All isolates were recovered from the samples obtained at 2 weeks after BMT. The sensitivity and the specificity of detection of viral DNA in plasma by qualitative polymerase chain reaction (PCR) for monitoring active virus replication were 92% and 97% respectively. Moreover, the positive (85%) and negative (99%) predictive values were also high. The patients with HHV-6 viremia showed a clear peak in HHV-6 DNA in peripheral blood mononuclear cells (PBMCs) at 2 weeks after BMT, which was measured by real time PCR. The virus DNA level in PBMCs between the two groups (patients with viremia and patients without viremia) was statistically different at 2 weeks after BMT (P = 0.033). In patients with HHV-6 viremia, mean HHV-6 DNA copy number was higher in the samples collected at 2 weeks after BMT than the samples collected at any other time period.
Bone Marrow Transplantation↗
Random mutagenesis of the pomA gene encoding a putative channel component of the Na(+)-driven polar flagellar motor of Vibrio alginolyticus.
PomA and PomB are integral membrane proteins and are essential for the rotation of the Na(+)-driven polar flagellar motor of Vibrio alginolyticus. On the basis of their similarity to MotA and MotB, which are the proton-conducting components of the H(+)-driven motor, they are thought to form the Na(+)-channel complex and to be essential for mechanochemical coupling in the motor. To investigate PomA function, random mutagenesis of the pomA gene by using hydroxylamine was carried out. We isolated 37 non-motile mutants (26 independent mutations) and most of the mutations were dominant; these mutant alleles are able to inhibit the motility of wild-type cells when greatly overexpressed. The mutant PomA proteins could be detected by immunoblotting, except for those with deletions or truncations. Many of the dominant mutations were mapped to the putative third or fourth transmembrane segments, which are the most conserved regions. Some mutations that showed strong dominance were in highly conserved residues. T1861 is the mutation of a polar residue located in a transmembrane segment that might be involved in ion translocation. P199L occurred in a residue that is thought to mediate conformational changes essential for torque generation in MotA. These results suggest that PomA and MotA have very similar structures and roles, and the basic mechanism for torque generation will be similar in the proton and sodium motors.
Amino Acid Sequence↗