CD34 positive blood cells for allogeneic progenitor and stem cell transplantation

The transplantation of allogeneic peripheral blood progenitor cells (PBPC) provides complete and sustained hematopoietic and lymphopoietic engraftment. In healthy donors, large amounts of PBPC can be mobilized with hematopoietic growth factors. However, the high content of immunocompetent T-cells in apheresis products may expose recipients of allogeneic PBPC to an elevated risk of acute and chronic graft-versus-host disease. Thus, the use of appropriate T-cell reduction, but not depletion might reduce this risk. The hazards of graft rejection and a higher relapse rate can be avoided by maintaining a portion of the T-cells in the graft. The positive selection of CD34+ cells from peripheral blood preparations simultaneously provides an approximately 1000-fold reduction of T-cells. These purified CD34+ cells containing committed and pluripotent stem cells are suitable for allogeneic transplantation and can be used in the following instances: 1. As hematopoietic stem and progenitor cell transplantation instead of bone marrow cells, from HLA-identical family donors; 2. for increasing the stem cell numbers from HLA-mismatched or three HLA-loci different family donors in order to reduce the incidence of rejection but without increasing the T-cell number; 3. boosting of poor marrow graft function with stem cells from the same family donors; 4. transplantation from volunteer matched unrelated donors; 5. split transplantation of CD34+ and T-cells; 6. addition of ex vivo expanded CD34+ cells to blood cell or bone marrow transplantation; 7. generation of antigen specific immune effector cells and antigen presenting cells for cell therapy.     

Pneumoperitoneum without peritonitis after allogeneic peripheral blood stem cell transplantation

Allogeneic blood stem cell transplantation is associated with multiple complications. We report a case of pneumoperitoneum without peritonitis associated with colonic pneumatosis in a patient who had undergone an allogeneic peripheral blood cell transplant     

Trichomonas foetus meningoencephalitis after allogeneic peripheral blood stem cell transplantation

The authors report a case of adrenal metastasis contralateral to a renal cell carcinoma in a 74-year-old patient who had undergone right radical nephrectomy for renal cell carcinoma. Nine months later, computed tomography revealed a hypervascular mass considered to be an aneurysm of the splenic artery. Arteriography led to the diagnosis of hypervascular adrenal tumour. Left adrenalectomy was performed. Histological examination showed a metastasis from renal cell carcinoma. This is an unusual form of renal cancer metastasis. Its treatment and prognosis are discussed.     

Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.     

Clinical utility of tetramer-based immune monitoring in allogeneic stem cell transplantation

The construction and use of Class I human leucocyte antigen (HLA) tetramers has, for the first time, allowed the direct enumeration of CD8(+) T lymphocytes specific for the antigen of interest. Tetramer staining can be combined with functional assays of antigen-specific T cells measuring their production of intracellular cytokines after short-term stimulation with antigen. The advantages of flow cytometric tetramer-based assays are their short turn-around time and their amenability to standardisation. Currently, their main limitation is that only a limited number of Class I HLA tetramers are available. This situation may bias the information derived from such studies. Nevertheless, clinically useful information has been obtained in tetramer-based studies of the regeneration of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-specific CD8(+) T cells after allogeneic stem cell transplantation (SCT). Following myeloablative cytoreductive therapy and SCT, a period of deep cellular immunodeficiency follows until the donor-derived immune system has sufficiently regenerated. As a result of the lack of immunosurveillance, endogenous viruses such as CMV and EBV may reactivate and cause disease. In order to prevent these complications, pre-emptive therapeutic interventions are made, in which antiviral treatment is administered based on frequent viral load measurements. In this way, overtreatment associated with prophylactic strategies is reduced; however, a subgroup of patients developing recurrent reactivations and/or disease remains. Interventions aimed at the prevention of graft versus host disease (GVHD) and the reduction of its severity greatly reduce the rate of (virus-specific) T-cell reconstitution and hence, increase the frequency and severity of viral reactivations. Specifically, T-cell depletion of SCT and the use of antithymocyte globulin as part of the conditioning regimen reduces the (virus-specific) T lymphocytes transferred with the graft, which otherwise would have contributed to the first phase of T-cell regeneration post-SCT. Consequently, patients whose CMV- and EBV-specific CD8(+) T cells fail to regenerate to levels detectable by tetramer-based flow cytometry during the first 3-6 months post-SCT were at highly increased risk for CMV disease and EBV(+) B-lymphoproliferative disease, respectively. Furthermore, delayed reconstitution of the CD4(+) T-cell compartment results in the lack of adequate help for the generation of sufficient antiviral CD8(+) T cells. Conversely, adoptive immunotherapy using CMV- or EBV-specific T cells results in the swift restoration of virus-specific T-cell immunity and the reduction of viral load, unless corticosteroids have to be administered to treat concurrent GVHD. Studies have shown the clinical utility of tetramer-based immune monitoring in the setting of allogeneic SCT and indicate that such assays, extended by functional studies of the virus-specific T cells, may constitute a valuable extension of current viral load monitoring strategies.     

非清髓性异基因造血干细胞移植后早期自然杀伤细胞的重建

目的 研究非清髓性异基因造血干细胞移植(NAST)后早期自然杀伤(NK)细胞的重建情况.方法 分别用流式细胞术直接免疫荧光法、T细胞活化实验、四甲基偶氮唑蓝比色(MTT)法检测10例NAST后白血病患者及10位健康对照者细胞表面标志及体外免疫功能.结果 移植后28～35 d,患者外周血CD+3、CD+4细胞比例降低,分别为(2.03±15.60)%和(22.69±12.29)%,CD+8细胞比例正常或增高,平均为(29.26±8.99)%;T细胞对有丝分裂原反应减低,其增殖反应刺激指数为94.60±44.87;NK细胞比例在正常范围或增高,为(18.77±9.11)%;NK细胞表面IL-2R表达阳性率增高,平均为(3.71±2.23)%,和正常对照组的(2.05±0.94)%相比差异有统计学意义(t=2.116,P=0.044);部分患者NK细胞活性明显增强,移植组与健康对照组分别为(25.30±12.39)%和(16.60±3.53)%(t=2.135,P=0.047).结论 NK细胞在NAST后早期即恢复,当特异性免疫功能仍低下时,它可能在机体抗感染和抗肿瘤中发挥着重要作用.     

Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation

The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed. Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse. Results are less favourable for acute leukemias, although useful responses have been reported. Data are scarce though promising for myelodysplastic syndromes and multiple myeloma. Major treatment-associated toxicities are GVHD and bone marrow aplasia. The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis. Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate. Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism. DLI is a direct demonstration of the graft-versus-leukemia effect (GVL). Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.     

Hemolytic uremic syndrome after allogeneic or autologous hematopoietic stem cell transplantation for childhood malignancies

To identify structural features important for low temperature activity in archaeal proteins, elongation factor 2 (EF-2) genes (aef2) were sequenced from psychrophilic, mesophilic and thermophilic methanogens. Scatter plots were used to compare evolutionary distances for EF-2 amino acid sequences vs. 16S-rRNA sequences from methanogens growing at diverse temperatures. The absence of a temperature bias for the rate of protein vs. nucleic acid evolution demonstrated the importance of comparing closely related proteins in order to identify changes indicative of thermal adaptation. Three-dimensional modelling of the new EF-2 sequences enabled the identification of amino acid residues that may be important for conferring low temperature activity and included greater structural flexibility produced by fewer salt bridges, less packed hydrophobic cores and the reduction of proline residues in loop structures.     

A single centre experience with allogeneic stem cell transplantation for severe aplastic anaemia in childhood

BACKGROUND: The purpose of this study was to investigate the barriers to receiving analgesics for cancer pain in Taiwanese patients. METHODS: The sample consisted of 128 hospitalized patients. All of the subjects were receiving analgesics. Three questionnaires entitled "Barriers Questionnaire-Taiwan Form (BQT)", "Brief Pain Inventory Short Form", and "Pain Management Index (PMI)" were used in this study. Data were analyzed using Student's t-test and Pearson correlation. RESULTS: The results showed that most of BQT subscales including disease progression, time interval, tolerance, injection, addiction, fatalism and side effects were approaching toward the moderate or high end of the scale. 42.1% (n = 54) of the patients had negative PMI scores indicating that they were using less than adequate analgesics for pain. There was a significant difference between those who had adequate medication and those who did not, in terms of disease progression score and the total BQT score. CONCLUSIONS: Overall the result revealed that pain management in these cancer patients was inadequate. Misconceptions on the part of patients still exist. Educational intervention could be an effective means for overcoming such barriers in Taiwanese patients who received analgesics for cancer pain.     

Malignancy-associated remission of systemic lupus erythematosus maintained by autologous peripheral blood stem cell transplantation

Many investigators worldwide are currently exploring the role of peripheral blood stem cell transplantation (PBSCT) in managing autoimmune diseases. We report the case of a woman with systemic lupus erythematosus (SLE) with mucocutaneous and renal involvement, who underwent PBSCT for stage IVB Hodgkin's disease. Following the development of the lymphoma, she has had a prolonged clinical and serologic remission of the SLE. The potential effects of lymphoproliferative disorders and PBSCT on the course of SLE are considered.     

Hematopoietic stem cell transplantation for infantile osteopetrosis

Infantile osteopetrosis is a lethal disorder resulting from a severe defect in the ability of osteoclasts to resorb bone. The only therapy shown to be capable of providing lasting benefit is allogeneic hematopoietic stem cell transplantation (HCT). We report the outcome of 10 patients with infantile malignant osteopetrosis treated with HCT from an HLA A, B, DRB1 matched (n=6) or A or B locus mismatched (n=4) family member or unrelated donor at the University of Minnesota between 1978 and 1997. Eight of 10 patients achieved primary engraftment; secondary graft failure was seen in two patients. Five of 10 patients survive; three with full or partial donor chimerism and two with autologous hematological recovery. Transient or partial donor chimerism can be sufficient to correct the hematological manifestations of osteopetrosis. We recommend early referral for consideration of HCT with a related or unrelated donor as neurosensory manifestations of osteopetrosis are generally not reversible. Donor engraftment may be easier to achieve early in the course of the disease.     

Allogeneic stem cell transplantation for multiple myeloma

Ethanol is added to unleaded gasoline as an oxygenate to decrease carbon monoxide automobile emissions. This introduces inhalation as a new possible route of environmental exposure to humans. Knowledge of the pharmacokinetics of inhaled ethanol is critical for adequately assessing the dosimetry of this chemical in humans. The purpose of this study was to characterize the pharmacokinetics of inhaled ethanol in male and female B6C3F1 mice and F344 rats and to develop a physiologically based pharmacokinetic (PBPK) model for inhaled ethanol in mice, rats, and humans. During exposure to 600 ppm for 6 hr, steady-state blood ethanol concentrations (BEC) were reached within 30 min in rats and within 5 min in mice. Maximum BEC ranged from 71 microM in rats to 105 microM in mice. Exposure to 200 ppm ethanol for 30 min resulted in peak BEC of approximately 25 microM in mice and approximately 15 microM in rats. Peak BEC of about 10 microM were measured following exposure to 50 ppm in female rats and male and female mice, while blood ethanol was undetectable in male rats. No sex-dependent differences in peak BEC at any exposure level were observed. Species-dependent differences were found following exposure to 200 and 600 ppm. A blood flow limited PBPK model for ethanol inhalation was developed in mice, rats, and humans which accounted for a fractional absorption of ethanol. Compartments for the model included the pulmonary blood and air, brain, liver, fat, and rapidly perfused and slowly perfused tissues. The PBPK model accurately simulated BEC in rats and mice at all exposure levels, as well as BEC reported in human males in previously published studies. Simulated peak BEC in human males following exposure to 50 and 600 ppm ranged from 7 to 23 microM and 86 and 293 microM, respectively. These results illustrate that inhalation of ethanol at or above the concentrations expected to occur upon refueling results in minimal BEC and are unlikely to result in toxicity.     

Renal Salmonella enteritidis abscess in a patient with severe aplastic anemia after allogeneic stem cell transplantation

We describe an unusual case of a renal abscess by Salmonella enteritidis in a 32-year-old man with severe aplastic anemia undergoing allogeneic stem cell transplantation. He was receiving immunosuppressive therapy with CsA and corticosteroids for chronic GVHD. He was not neutropenic and had no history of enterocolitis or cholelithiasis before the onset. Four months after the transplantation, he developed an abscess in the upper pole of his right kidney from which Salmonella enteritidis was isolated in culture. He was successfully treated with a combination of percutaneous drainage and washing the cyst through the catheter using piperacillin sodium-containing solution. The possibility of salmonellosis should be considered in the differential diagnosis of such patients.