Biomedical subjects

A Nagler

Publications and source records attributed to A Nagler.

At least 19 recordsLinked to original sources

PubMed2003

Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements.

The ALL-1 gene is directly involved in 5-10% of acute lymphoblastic leukemias (ALLs) and acute myeloid leukemias (AMLs) by fusion to other genes or through internal rearrangements. DNA microarrays were used to determine expression profiles of ALLs and AMLs with ALL-1 rearrangements. These profiles distinguish those tumors from other ALLs and AMLs. The expression patterns of ALL-1-associated tumors, in particular ALLs, involve oncogenes, tumor suppressors, antiapoptotic genes, drug-resistance genes, etc., and correlate with the aggressive nature of the tumors. The genes whose expression differentiates between ALLs with and without ALL-1 rearrangement were further divided into several groups, enabling separation of ALL-1-associated ALLs into two subclasses. One of the groups included 43 genes that exhibited expression profiles closely linked to ALLs with ALL-1 rearrangements. Further, there were evident differences between the expression profiles of AMLs in which ALL-1 had undergone fusion to other genes and AMLs with partial duplication of ALL-1. The extensive analysis described here pinpointed genes that might have a direct role in pathogenesis.

Chromosome Aberrations↗

PubMed2003

Factors associated with survival in patients with progressive disease following autologous transplant for lymphoma.

Our objectives were to assess survival and predictors for survival among lymphoma patients whose disease had progressed after autologous bone marrow (ABMT) or stem cell transplantation (ASCT). Patients transplanted at Hadassah University Hospital between October 1983 and February 1999 were included. We compared survival of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) after relapse or progression. Predictors for survival were assessed in a multivariate model. Of 88 transplanted patients with HD and 152 with NHL, relapse/progression occurred in 27 (31%) and 75 (49%), respectively. Median survival postrelapse was 25 months for HD and 7.5 months for NHL (P=0.12). Seven relapsed patients with HD (26%) and 10 (13%) with NHL survived >4 years. In NHL, longer postrelapse survival was associated with indolent histologies (P=0.007). On multivariate analysis, factors associated with survival included attainment of remission postrelapse (for both diseases), use of prophylactic immunotherapy (for HD), LDH level and time from transplant to relapse (for NHL). The short-term prognosis for patients with disease progression postautologous transplant may be somewhat better for HD compared to NHL. Long-term survival is poor in both diseases. However, the survival times in the current study are twice as long as those previously reported. Treatment regimens with the potential for achieving remission may have an impact on survival.

Disease-Free Survival↗

PubMed2003

Induction of oral tolerance in bone marrow transplantation recipients suppresses graft-versus-host disease in a semiallogeneic mouse model.

Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 x 10(7) splenocytes from C57BL/6 donor mice into (C57BL/6 x Balb/c)F1 recipient mice, which received 7 Gy (60)Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 micro g/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system.

Administration, Oral↗

PubMed2003

Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias.

Chronic myeloid leukemia in blast crisis (BC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) are associated with extremely poor outcome. Allogeneic transplantation during BC or active leukemia is most often unsuccessful due to high-rates of both treatment-related complications and relapse. Long-term results are significantly better if a second chronic phase or remission can be achieved prior to transplantation. Similarly, DLI given for the treatment of post-transplant relapse is more successful when given during a second remission. In this study we report our results with a previously unreported approach consisting of short-term treatment with imatinib mesylate (formerly, STI571) to induce or maintain remission, followed by allogeneic transplantation or DLI and the impact on transplantation/DLI outcome. Sixteen patients were treated either in preparation for transplantation (n = 12), for DLI (n = 1), or for both (n = 3). Ten had CML in BC; seven myeloid and three lymphoid BC. Six patients had Ph(+) ALL. The donors were matched unrelated (n = 9), matched siblings (n = 5) or haplo-identical (n = 2). Eleven of 15 patients given imatinib pre-transplant were transplanted in complete hematologic response. Engraftment and GVHD rates were not different from expected. Seven patients had grade II-III hepatic toxicity after transplantation. After a median follow-up of 10 months (range, 3-16 months) six remain alive, two after further therapy. The 1-year survival rate was 25%. Four patients were given imatinib prior to DLI, all had complete response. Two remain in remission >6 months from relapse. In conclusion, treatment with imatinib allows transplantation in a more favorable status or maintaining remission with low toxicity until transplantation is feasible. Pre-transplant imatinib seems safe and not associated with excess post-transplant complications. Imatinib may have substantial activity in combination with DLI. Further study of a larger group of patients is required to assess the impact on long-term outcome and the role of post-transplant imatinib in controlling residual disease.

Adult↗

PubMed2003

Sialometrical and sialochemical analysis of patients with chronic graft-versus-host disease--a prolonged study.

Patients with graft-versus-host disease (cGVHD) suffer from oral dryness and increased levels of oral infections and mucosal pathologies. The purpose of the current study was dual: 1) to investigate the salivary functional (sialometry) and compositional (sialochemistry) alterations induced by the disease during a 12-month period following the onset of the disease; and 2) to evaluate the effect of Salagen 30 mg/d on the salivary biochemical and immunological composition in cGVHD patients. Significant higher concentrations of salivary sodium (Na), magnesium (Mg), total protein (TP), albumin (Alb), epidermal growth factor (EGF), and total IgG accompanied by a concomitant increase in total IgA that did not reach significant value was observed in cGVHD patients in comparison with controls at both resting and stimulated conditions (p < 0.05) while salivary levels of potassium (K), calcium (Ca), and phosphate (P) were not altered. Two weeks of oral Salagen 30 mg/d resulted in normalization of the salivary biochemical and immunological compositional alterations in the cGVHD patients. Oral pilocarpine was able to reduce and normalize the elevated levels of Na, Mg, TP, Alb, EGF, IgG, and IgA salivary concentrations at both resting and stimulated conditions. The ability of oral pilocarpine to normalize and reverse salivary biochemical and immunological alterations induced by cGVHD is parallel to its stimulatory effect on salivary flow rates, as we previously showed. As the biochemical and immunological composition of the saliva results in its antimicrobial protective characteristics, the ability of oral pilocarpine (Salagen) to abrogate cGVHD salivary gland abnormalities may be of clinical importance.

Adolescent↗

PubMed2002

High-dose chemotherapy with autologous stem cell transplantation is an effective treatment of primary refractory Hodgkin's disease. Retrospective study of the Polish Lymphoma Research Group.

We analysed the treatment outcome of primary refractory HD patients managed with high-dose chemotherapy and haematopoietic cell transplantation. Data of 65 adult patients who underwent HDC/ASCT in nine Polish centres for primary resistant Hodgkin's disease between June 1991 and July 2000 were collected retrospectively. Response rate to HDC/ASC: CR, 54%; PR, 20%; less than PR, 15%; early deaths, 11%. Actuarial 3-year OS and PFS were 55% and 36%, respectively. In multivariate analysis, lack of bulky lymph nodes and use of immunotherapy were favourable factors for both OS and PFS. IPF <3 at the time of transplantation was predictive for PFS. However, the prognostic impact of immunotherapy should be interpreted with caution since this group included more patients who achieved CR after HDC/ASCT. The results of HDC/ASCT are encouraging and confirm earlier findings. The role of immunotherapy should be further investigated in prospective trials.

Adolescent↗

PubMed2002

Chimerism testing and detection of minimal residual disease after allogeneic hematopoietic transplantation using the bioView (Duet) combined morphological and cytogenetical analysis.

Recurrent disease remains a major obstacle to cure after allogeneic transplantation. Various methods have been developed to detect minimal residual disease (MRD) after transplantation to identify patients at risk for relapse. Chimerism tests differentiate recipient and donor cells and are used to identify MRD when there are no other disease-specific markers. The detection of MRD does not always correlate with relapse risk. Chimerism testing may also identify normal hematopoietic cells or other cells not contributing to relapse. In this study we report our initial experience with a novel system that provides combined morphological and cytogenetical analysis on the same cells. This system allows rapid automatic scanning of a large number of cells, thus increasing the sensitivity of detection of small recipient population. The clinical significance of MRD detection is improved by identifying the morphology of recipient cells. Identification of recipient characteristics within blasts predicts overt relapse in leukemia patients and precedes it by a few weeks to months. Identification within mature hematopoietic cells may not be closely associated with relapse. The system also allows chimerism testing after sex-mismatched transplants, within cellular subsets, with no need for sorting of cells. The system merits further study in larger scale trials.

Automation↗

PubMed2002

Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis.

BACKGROUND: Mast cells, the key cells of immediate hypersensitivity type reactions, have also been postulated to have a central role in influencing tissue remodelling and fibrosis occurring in the skin. OBJECTIVE: Our aim was to investigate the direct role of human mast cells (HMC) in skin fibrotic processes, by assessing the effects of the addition of the human mast cell line HMC-1 to human skin fibroblasts, and to identify the responsible mediators. METHODS: HMC-1 sonicates were added to human skin fibroblasts and the following parameters were evaluated: proliferation ([3H]-thymidine), collagen synthesis ([3H] proline), activity of matrix metalloproteinases (MMPs) (zymography) and tissue inhibitors of metalloproteinases (TIMPs) (reverse zymography), and collagen gel contraction. RESULTS: HMC-1 sonicate increased significantly both proliferation and collagen production in the human skin fibroblasts and these properties were not affected by heating of the sonicate (56 degrees C, 30 min, or 100 degrees C, 3 min). Two main mast cell mediators, histamine and tryptase, were found to be responsible for the increase in fibroblast proliferation and collagen production. HMC-1 sonicate did not display any pre-formed gelatinase activity, and its addition to the fibroblasts did not change their pro-MMP-2 and MMP-2 activity. On the other hand, HMC-1 were found to possess TIMP-1 and TIMP-2. Addition of HMC-1 had no effect on fibroblasts TIMP-1 but induced a dose-dependent increase of TIMP-2 activity. In addition, HMC-1 sonicate seeded together with the fibroblasts in tri-dimensional collagen gel significantly enhanced their contraction. CONCLUSION: We have shown that human mast cells, by granule-stored and therefore quickly releasable mediators, increase human skin fibroblast proliferation, collagen synthesis, TIMP-2 and collagen gel contraction. Therefore, mast cells have a direct and potentiating role in skin remodelling and fibrosis.

Cell Division↗

PubMed2002

Dexamethasone inhibits maturation, cytokine production and Fc epsilon RI expression of human cord blood-derived mast cells.

BACKGROUND: Mast cells are responsible for eliciting the early phase and for contributing to the development of the late phase of allergic reactions, through the release of cytokines and other inflammatory mediators. OBJECTIVE: To assess whether the glucocorticoid dexamethasone has a direct effect on mast cell progenitor maturation and on mature cord blood-derived mast cell properties. METHODS: Mast cells were obtained by culturing human umbilical cord blood mononuclear cells with stem cell factor, IL-6 and prostaglandin E2. Mast cell numbers were assessed by Toluidine Blue staining and immunocytochemistry of tryptase positive cells. The expression of Fc epsilon RI, CD49d and c-kit was assessed by flow cytometry. Histamine release was determined by a radioenzymatic assay. Cys-LT, GM-CSF and TNF-alpha production and release were determined by ELISA. RESULTS: Dexamethasone (10(-6) M-10(-9) M) time- and dose-dependently inhibited the maturation of the mast cell progenitors. Dexamethasone did not affect the basal expression of Fc epsilon RI, CD49d and c-kit, but it inhibited the IgE-dependent enhanced expression of Fc epsilon RI. Dexamethasone (10(-6) M-10(-9) M) had no significant effect on Fc epsilon RI-dependent histamine release or the synthesis and release of Cys-LT from the mature mast cells. However, pre-incubation of the mast cell cultures with dexamethasone for 1 h, prior to cross-linking of Fc epsilon RI, dose-dependently inhibited the production and secretion of both GM-CSF and TNF-alpha. CONCLUSIONS: From these in vitro data we propose that glucocorticosteroids are effective drugs in the management of allergic inflammation due to their capacity to inhibit mast cell development, IgE-dependent Fc epsilon RI expression and mast cell production of GM-CSF and TNF-alpha.

Administration, Topical↗

PubMed2002

Genetic susceptibility to Hodgkin's lymphoma and to secondary cancer: workshop report.

Although the occurrence of familial Hodgkin's lymphoma (HL) is a rare event, genetic susceptibility as a cause of HL and its influence on treatment outcome may not be rare. However, results obtained from the analysis of HL families will probably have broad implications with regard to understanding common pathogenic factors leading to the development of the disease. The description of anticipation among the affected offspring of HL patients further strengthens the view that heritable factors contribute to development of HL. Moreover, the finding that particular human leukocyte antigen (HLA) alleles are associated with susceptibility to HL may be regarded as a hint to the presence of an as yet undefined infectious agent, leading to the growth of a malignant lymphoma cell clone in those patients that are more susceptible to this agent due to their HLA genotype. In addition, since an intrinsic genomic instability was observed in a proportion of HL patients, it is plausible that these patients are not only susceptible to the causation of HL, but are also at a higher risk of developing therapy-related (TR) secondary cancers following treatment. Estimation of sister chromatid exchange was established as a tool to identify patients at higher risk of TR cancer. In this context the use of therapeutic agents known to increase genomic instability should be carefully considered prior to determing the best treatment. The future identification of heritable factors contributing to HL will be of importance both with regard to diagnosis as well as treatment of HL patients.

Age of Onset↗

PubMed2001

Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone.

The effect of dermal application of halofuginone-an inhibitor of collagen type I synthesis-on skin collagen and collagen alpha1(I) gene expression in an animal model of scleroderma and chronic graft versus host disease (cGvHD) was evaluated. Halofuginone-containing cream was applied on the tight-skin mouse (Tsk) and skin biopsies were taken for collagen staining by sirius red and for collagen alpha1(I) gene expression by in situ hybridization. In addition, cell proliferation was evaluated by immunostaining for proliferation cell nuclear antigen (PCNA) alone or in combination with collagen alpha1(I) probe. The number of mast cells was assessed by toluidine blue. Dermal application of halofuginone (0.01%) for 60 days was as good as systemic administration (1 microg/mouse/day) in reducing collagen alpha1(I) gene expression in skin biopsy and almost as good in reducing skin width. Halofuginone was stable and effective only at acidic pH. The effect of halofuginone (0.03%) was time-dependent. After 40 days of daily treatment, a significant reduction in the collagen alpha1(I) gene expression was observed and further decrease was observed after 60 days. The reduction in collagen alpha1(I) gene expression and the reduction in the proliferation of dermal fibroblasts probably occur in the same subset of cells. No effect of halofuginone on the proliferation of keratinocytes or on mast cell number was observed. These results suggest that target-oriented application of halofuginone may become a novel therapy for fibrotic disorders in general and for scleroderma in particular.

Administration, Topical↗

PubMed2001

High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group.

PURPOSE: To determine whether a combination of high-dose therapy and autologous stem-cell transplantation (ASCT) is superior to conventional-dose consolidation and maintenance chemotherapy as postremission therapy in adults with lymphoblastic lymphoma. PATIENTS AND METHODS: One hundred nineteen patients were entered onto this prospective randomized trial from 37 centers. Patients received standard remission induction therapy, and responding patients were randomized either to continue with a conventional consolidation/maintenance protocol (CC) or to receive high-dose therapy and ASCT. In some centers, patients with HLA-identical sibling donors were registered on the trial but proceeded to allogeneic bone marrow transplantation (BMT) without randomization. RESULTS: Of the 119 patients entered, 111 were assessable for response to induction therapy. The overall response rate was 82% (56% complete response, 26% partial response). Of the 98 patients eligible for randomization, 65 were randomized, 31 to ASCT and 34 to CC. Reasons for failure to randomize included patient refusal (12 patients), early progression or death on induction therapy (eight patients), excessive toxicity of induction regimen (six patients), and elective allogeneic BMT (12 patients). With a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for the CC arm and 55% for the ASCT arm (hazards ratio = 0.55 in favor of the ASCT arm; 95% confidence interval [CI], 0.29 to 1.04; P =.065). The corresponding figures for overall survival are 45% and 56%, respectively (hazards ratio = 0.87 in favor of the ASCT arm; 95% CI, 0.42 to 1.81; P =.71). CONCLUSION: The use of ASCT in adults with lymphoblastic lymphoma in first remission produced a trend for improved relapse-free survival but did not improve overall survival compared with conventional-dose therapy in this small randomized trial.

Adolescent↗

PubMed2001

Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice.

Stem cell homing into the bone microenvironment is the first step in the initiation of marrow-derived blood cells. It is reported that human severe combined immunodeficient (SCID) repopulating cells home and accumulate rapidly, within a few hours, in the bone marrow and spleen of immunodeficient mice previously conditioned with total body irradiation. Primitive CD34(+)CD38(-/low)CXCR4(+) cells capable of engrafting primary and secondary recipient mice selectively homed to the bone marrow and spleen, whereas CD34(-)CD38(-/low)Lin(-) cells were not detected. Moreover, whereas freshly isolated CD34(+)CD38(+/high) cells did not home, in vivo stimulation with granulocyte colony-stimulating factor as part of the mobilization process, or in vitro stem cell factor stimulation for 2 to 4 days, potentiated the homing capabilities of cytokine-stimulated CD34(+)CD38(+) cells. Homing of enriched human CD34(+) cells was inhibited by pretreatment with anti-CXCR4 antibodies. Moreover, primitive CD34(+)CD38(-/low)CXCR4(+) cells also homed in response to a gradient of human stromal cell-derived factor 1 (SDF-1), directly injected into the bone marrow or spleen of nonirradiated NOD/SCID mice. Homing was also inhibited by pretreatment of CD34(+) cells with antibodies for the major integrins VLA-4, VLA-5, and LFA-1. Pertussis toxin, an inhibitor of signals mediated by Galpha(i) proteins, inhibited SDF-1-mediated in vitro transwell migration but not adhesion or in vivo homing of CD34(+) cells. Homing of human CD34(+) cells was also blocked by chelerythrine chloride, a broad-range protein kinase C inhibitor. This study reveals rapid and efficient homing to the murine bone marrow by primitive human CD34(+)CD38(-/low)CXCR4(+) cells that is integrin mediated and depends on activation of the protein kinase C signal transduction pathway by SDF-1.

ADP-ribosyl Cyclase↗

PubMed2001

MRI of mannosidosis.

MR findings in three patients with mannosidosis are reported. They all had diploic space widening with underdevelopment of the sinuses, prominent periventricular Virchow-Robin spaces and perioptic CSF spaces. Two had tight foramen magnum, one of which was associated with a cervical syrinx and markedly widened perioptic CSF spaces with papilledema.

Brain↗

PubMed2001

Nonmyeloablative stem cell transplantation for the treatment of cancer and life-threatening nonmalignant disorders: past accomplishments and future goals.

Allogeneic bone marrow transplantation (BMT) or blood stem cell transplantation represents an important therapeutic tool for the treatment of otherwise incurable malignant and nonmalignant diseases. Until recently. autologous and allogeneic BMT or mobilized blood stem cell transplantation was used primarily to replace a malignant, genetically abnormal, or deficient immunohematopoietic compartment, and therefore highly toxic myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies have indicated that more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus eradication of blood cancer cells, especially in patients with chronic myelogenous leukemia and less frequently in patients with other hematologic malignancies, can frequently be achieved despite complete resistance of such tumor cells to the maximum tolerated doses of chemoradiotherapy. Our cumulative experience suggests that graft vs leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases, it appears that induction of host vs graft tolerance as the first step may allow durable engraftment of immunocompetent donor lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, whether they are malignant, genetically abnormal, or self-reactive. Based on this rationale, we speculate that the therapeutic benefit of BMT may be increased by using safer conditioning as part of the transplantation procedure, with the goal of inducing host vs graft tolerance to enable subsequent induction of GVL, possibly graft vs tumor, or even graft vs autoimmunity effects, rather than attempting to eliminate host cells with hazardous myeloablative chemoradiotherapy. Our hypothesis suggests that effective BMT procedures might be accomplished without lethal conditioning of the host, using new, well-tolerated nonmyeloablative regimens, possibly minimizing immediate and late side effects related to myeloablative procedures. Recent clinical data suggest that effective BMT procedures may be accomplished with nonmyeloablative stem cell transplantation (NST) regimens, with no major toxicity. Thus new NST approaches may make BMT procedures safer for a spectrum of clinical indications in children and elderly individuals without lower or upper age limits, while minimizing procedure-related toxicity and mortality. Our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by more effective alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures with safer and more effective treatment of patients requiring BMT.

Animals↗

PubMed2001

The effect of pilocarpine on salivary constituents in patients with chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a complex clinical entity with various target organs, including the salivary glands. Oral pilocarpine (Salagen(R)), 30 mg/day, can ameliorate cGVHD-induced xerostomia and improve the flow rate from the major salivary glands. The purpose here was to evaluate the effect of this drug at 30 mg/day on salivary biochemical and immunological composition in cGVHD patients. Significantly higher concentrations of salivary sodium (Na), magnesium (Mg), total protein, albumin, epidermal growth factor (EGF) and total IgG, accompanied by a concomitant increase in total IgA which did not reach significance, were observed in cGVHD patients in comparison with controls, in both resting and stimulated conditions (p < 0.05), while salivary potassium, calcium and phosphate were not altered. Two weeks of oral pilocarpine, at 30 mg/day, resulted in normalization of the altered salivary biochemical and immunological composition in the cGVHD patients. Oral pilocarpine was able to reduce and normalise the elevated Na, Mg, total protein, albumin, EGF, IgG and IgA concentrations in both resting and stimulated conditions. The ability of oral pilocarpine to normalise and reverse the salivary biochemical and immunological alterations induced by cGVHD parallels its known stimulatory effect on salivary flow rates. As the biochemical and immunological composition of saliva provides its protective antimicrobial characteristics, the ability of pilocarpine to abrogate cGVHD salivary gland abnormalities may be of clinical significance.

Administration, Oral↗

PubMed2001

Ex vivo expansion of CD56+ cytotoxic cells from human umbilical cord blood.

The immune-mediated effect of natural killer (NK) and cytotoxic T cells against residual tumor cells previously was shown to prevent relapse and reinduce remission after bone marrow transplantation. Human umbilical cord blood is a rich source of cytotoxic CD56+ cells including fetal NK cells (CD16(-)CD56+1) with high lytic capabilities upon activation with interleukin-2 (IL-2). Cord blood transplantations are reported to be associated with lower risk of graft-vs-host disease, which may jeopardize the graft-vs-leukemia effect. Therefore, our goal was to expand and amplify, ex vivo, cord blood-derived CD56+ cell-mediated cytotoxic activity. Cord blood-derived CD56+ cells were separated using anti-CD56 monoclonal antibody and immunomagnetic beads. The cells were expanded in the presence of irradiated feeder cells and various concentrations of IL-2. Maximal fold expansion (152 +/- 29) was achieved on day 22 by culturing the cells in the presence of irradiated autologous lymphocytes. Irradiated murine stromal cells yielded 42 +/- fourfold expansion (p < 0.05). FACS analysis at the peak of expansion revealed that the cells were 96% +/- 1% CD56+. Interferon-gamma levels significantly decreased throughout the culture period (from 1,034 +/- 34 pg/mL to 21 +/- 8 pg/mL) as did IL-6 levels (from 11,535 +/- 1,452 pg/mL to 323 +/- 161 pg/mL) whereas tumor necrosis factor-alpha levels did not change. The expanded cells manifested potent lytic capabilities against K562 and Colo-205 cell lines (70.9% +/- 2.0% and 48.2% +/- 4.0%, respectively) (n = 5) (effector-to-target ratio 25:1). Coculturing the expanded NK cells with fresh ALL blasts resulted in 85% +/- 1% inhibition of colony growth in methylcellulose (n = 2). In addition, the CD56+ expanded cells induced 44% +/- 7.5% apoptosis of K562 target cells (n = 3). It is possible to effectively expand cord blood-derived CD56+ cells, ex vivo, while maintaining their antileukemic capablilities.

Animals↗

PubMed2001

Low-intensity conditioning is sufficient to ensure engraftment in matched unrelated bone marrow transplantation.

OBJECTIVE: Matched unrelated bone marrow transplantation (BMT) for patients with hematological malignancies is associated with a high incidence of transplant-related complications due to high doses of chemoradiotherapy administered pre-BMT to ensure engraftment. The aim of this study was to investigate the feasibility of low-intensity conditioning for BMT from matched unrelated donors. MATERIALS AND METHODS: Sixteen patients with hematologic malignancies underwent non-T-cell-depleted BMT following a low-intensity conditioning regimen consisting of fludarabine monophosphate 30 mg/m(2)/day for 6 days, busulfan 4 mg/kg/day for 2 days, anti-T lymphocyte globulin 10 mg/kg/day for 4 days. Seven of the patients suffered from chronic myelogenous leukemia, four from acute lymphoblastic leukemia, four from acute myelogenous leukemia, and one from Ki-1 non-Hodgkin's lymphoma. Three of the patients had secondary leukemia and two were post-autologous BMT (ABMT). All patients were transplanted from fully matched unrelated donors. RESULTS: Fifteen of the 16 patients had 100% donor chimerism; no graft rejection was observed. None of the patients developed >Grade II veno-occlusive disease, sepsis, multiorgan failure, or renal or pulmonary toxicity. Four patients died posttransplant; one of thrombocytopenia and severe hemorrhagic cystitis, one of central nervous system toxicity, one of Grade IV graft-vs-host disease, and one following relapse (9 months post-BMT). Survival and disease-free survival at 36 months are 75% (95% confidence interval 46-90%) and 60% (95% confidence interval 30-80%), respectively. CONCLUSION: These results indicate that low-intensity conditioning is sufficient to ensure stable engraftment of bone marrow grafts in a matched unrelated setting.

Adolescent↗