Showing papers by "Arnon Nagler published in 2001"
TL;DR: 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.
327 citations
TL;DR: 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.
Abstract: 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...
95 citations
TL;DR: HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown, and the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease is defined.
Abstract: Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.
83 citations
TL;DR: In this article, the authors investigated the immune status of patients with hematologic malignancies treated with a low intensity conditioning in preparation for allogeneic stem cell transplantation, which resulted in rapid engraftment and complete replacement of host with donor hematopoietic cells.
Abstract: We have investigated the immune status of patients with hematologic malignancies treated with a low intensity conditioning in preparation for allogeneic stem cell transplantation. Conditioning consisted of fludarabine, anti-T lymphocyte globulin and low-dose busulfan, followed by infusion of allogeneic blood stem cells. This protocol resulted in rapid engraftment and complete replacement of host with donor hematopoietic cells. Immunological parameters of these patients were compared to those patients who were conditioned by an aggressive myeloablative regimen. Distribution of cell surface markers of lymphocyte subsets from both groups of patients was similar, but different from that of normal control cells. Reduced intensity or non-myeloablative conditioning prior to allogeneic stem cell transplantation (NST), hardly lowered the normal T cell-dependent mitogenic response even during the early period following transplant, while the myeloablative treatments resulted in a suppressed mitogenic reaction and in slow immune recovery. Reactivity of non-MHC restricted cytotoxic T cells was also at a normal level in patients who were treated with NST. We conclude that stem cell engraftment following reduced conditioning may result in early reconstitution of immune responses assessed in vitro. We hypothesize that clinical application of NST may lead to faster development of effective immune responses against residual host-type malignant and abnormal non-malignant hematopoietic cells, although the role of fludarabine on post-transplant infections remains to be investigated in a larger cohort of patients.
80 citations
TL;DR: Treatment of CP‐injected mice with quinolones significantly enhanced CSA in the bone shaft, spleen, lung and bladder on different days and treatment with CP resulted in enhanced colony‐stimulating activity (CSA) in bone shaft and spleen and decreased activity in bladder and lung.
Abstract: We analyzed the effect of the two quinolones moxifloxacin and ciprofloxacin on the repopulation of hematopoietic organs and on the production of cytokines by various organs of cyclophosphamide (CP)-induced leukopenic mice. The effect was compared to that of G-CSF. Cyclophosphamide injection induced a severe leukopenia, with nadir at day 4 post-injection. All the quinolone and G-CSF-treated animals showed WBC>500/microL at the nadir, compared to 50% of saline-treated mice. Cyclophosphamide induced a marked decrease in the number of myeloid progenitors (CFU-C) in bone marrow (BM) and spleen. Quinolone or G-CSF treatment resulted in a 1.4-4.3-fold increase in CFU-C numbers in the BM; no enhancement was observed in the spleen. Treatment with CP resulted in enhanced colony-stimulating activity (CSA) in bone shaft and spleen and decreased activity in bladder and lung. Treatment of CP-injected mice with quinolones significantly enhanced CSA in the bone shaft, spleen, lung and bladder on different days. In normal mice the highest levels of GM-CSF and IL-6 were observed in lung-conditioned medium (compared to bone shaft, spleen and bladder). Injection of CP resulted in a 22.5- and 93-fold decrease in GM-CSF and IL-6 levels, respectively, in lung-conditioned medium, while treatment with quinolones resulted in 2-4-fold increase in GM-CSF with no effect on IL-6 production. G-CSF treatment had no enhancing effect on GM-CSF nor on IL-6 production. We conclude that moxifloxacin and ciprofloxacin administered to CP-injected mice revert some of the immune suppressive effects of cyclophosphamide.
57 citations
TL;DR: The effect of 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 α1(I) gene expression by in situ hybridization.
51 citations
TL;DR: It is shown that it is possible to effectively expand cord blood-derived CD56+ cells, ex vivo, while maintaining their antileukemic capablilities.
50 citations
TL;DR: Non-myeloablative stem cell transplantation (NST): chimerism testing as guidance for immune-therapeutic manipulations
Abstract: Non-myeloablative stem cell transplantation (NST): chimerism testing as guidance for immune-therapeutic manipulations
46 citations
TL;DR: The ability of oral pilocarpine to abrogate cGVHD salivary gland abnormalities may be of clinical significance as the biochemical and immunological composition of saliva provides its protective antimicrobial characteristics.
36 citations
TL;DR: The 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 myeloablatives procedures.
Abstract: 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.
35 citations
TL;DR: High-dose chemotherapy and radiation therapy may be successfully replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.
Abstract: Allogeneic bone marrow or blood stem call transplantation (BMT) represents an important therapeutic tool for the treatment of otherwise incurable malignant and non-malignant diseases Until recently, autologous and allogeneic bone marrow and mobilized blood stem cell transplantations were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartments, and therefore highly toxic myeloablative regimens were considered to be mandatory for the effective eradication of all undesirable host-derived hematopoietic elements Our preclinical and ongoing clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and, less frequently, in patients with other hematologic malignancies, can frequently be accomplished despite the complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy Our cumulative experience has suggested that graft-vs-leukemia (GVL) effects might be a useful tool for the 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 the induction of host-vs-graft tolerance as an initial step may allow the durable engraftment of donor immunocompetent lymphocytes, which may be used for the induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, including malignant, genetically abnormal or self-reactive cells Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using safer conditioning as part of the transplant procedure, with the goal being to induce 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 This hypothesis suggested that effective BMT procedures could be accomplished without lethal conditioning of the host, using new well-tolerated non-myeloablative regimens, thus possibly minimizing immediate and late side-effects related to the myeloablative procedures until recently considered to be mandatory for the conditioning of BMT recipients Recent clinical data presented in this review suggest that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimens, with no major toxicity Thus, new NST approaches may offer the feasibility of safer BMT procedures for a large spectrum of clinical indications in children and elderly individuals, without lower or upper age limits, while minimizing procedure-related toxicity and mortality Taken together, our data suggest that high-dose chemotherapy and radiation therapy may be successfully replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT
TL;DR: Clinical data that will be presented suggests that safe non-myeloablative stem cell transplantation (NST), with no major toxicity can replace the conventional BMT, and may provide an option for cure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality.
Abstract: Allogeneic bone marrow transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion (DLI) following BMT. Thus, eradication of blood cancer cells, especially in patients with CML can be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. The latter working hypothesis suggested that effective BMT procedures may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that safe non-myeloablative stem cell transplantation (NST), with no major toxicity can replace the conventional BMT. Thus, NST may provide an option for cure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality.
TL;DR: The data suggest that the dysregulation of IL-18 andIL-18BP may be important in the pathophysiology of transplant-related complications and that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.
Abstract: Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon-γ (IFN-γ) production and IFN-γ and sIFN-γR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN-γ production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day -10 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL-6R, sIFN-γR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment (p < 0.05). Accordingly, during rejection, IL-18BP serum lev...
TL;DR: It is suggested that radiation-induced toxicity is caused by the deleterious effect of redox-active metal ions, and that compounds which modulate this redox activity may act as radioprotectors.
Abstract: Since zinc desferrioxamine (Zn-DFO) has been shown to be a very potent protector against injuries induced by redox-active metal ions, we examined its protective effect against radiation-induced toxicity. We found that treatment with Zn-DFO given before TBI increased the survival of mice irradiated with 7.5 and 8.5 Gy. Zn-DFO also protected against radiation-induced myelosuppression and body weight loss, while soluble Il6 levels in serum were normalized in mice pretreated with Zn-DFO. We concluded that administration of Zn-DFO prior to TBI protected BALB/c mice from radiation-induced toxicity, increasing survival rates by up to 75%. The biological effect of Zn-DFO is known to result from its effect on the production of intracellular hydroxyl free radicals mediated by redox-active metal ions, and both metal chelation and zinc delivery appear to be equally likely mechanisms for this outcome. We suggest that radiation-induced toxicity is caused by the deleterious effect of redox-active metal ions, and that compounds which modulate this redox activity may act as radioprotectors.
TL;DR: Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associated liver disease, with manageable side effects.
Abstract: Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), which are the standard therapy, give rather disa...
TL;DR: A case of a young patient who developed manifestations of TTP 10 months after BMT with complete recovery following treatment with plasma exchange for 1 month suggests that plasma exchange could be life saving and should be tried in every patient with post-BMT TTP.
Abstract: Recognition of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) following bone marrow transplantation (BMT) has increased in recent years. The use of plasma exchange has greatly improved the outlook of de novo TTP. Fewer data are available on its use in post-BMT TTP but small uncontrolled series showed poor results with low response rates. We present here a case of a young patient who developed manifestations of TTP 10 months after BMT with complete recovery following treatment with plasma exchange for 1 month. This case suggests that plasma exchange could be life saving and should be tried in every patient with post-BMT TTP.
01 Jan 2001
TL;DR: The data suggest that the dysregulation ofIL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications and it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.
Abstract: Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon- g (IFN-g) production and IFN- g and sIFN-gR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN- g production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day 210 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL6R, sIFN-gR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment ( p , 0.05). Accordingly, during rejection, IL-18BP serum levels remained low and similar to pretransplant levels. The mean elevation of IL-18BP detected in association to acute GVHD was significantly higher in comparison to normal engraftment ( p , 0.05). A correlation between IL-18BP, sIFN gR, and sIL6R serum levels was found in all patients. No correlation between IL-18 and IL-18BP serum levels was found in patients undergoing uneventful PBSCT and rejection, whereas a marked increase in both IL-18 and IL-18BP levels was detected during acute GVHD ( p , 0.01). Our data suggest that the dysregulation of IL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications. Furthermore, because preliminary data from our group show that IL-18 blockage ameliorates GVHD in murine models, it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.