A 2-day MLR procedure for marrow donor selection for allogeneic bone marrow transplantation.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
S Slavin
Publications and source records attributed to S Slavin.
Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.
A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.
Animals↗
Ganciclovir for the treatment of disseminated CMV disease without pneumonia in allogeneic T-lymphocyte depleted bone marrow transplantation.
Treatment with ganciclovir was assessed in 13 patients who underwent allogeneic T-lymphocyte depleted bone marrow transplantation (BMT) for a variety of malignant hematological disorders and subsequently developed severe cytomegalovirus (CMV) disease without pneumonia. The manifestations of CMV disease appeared on days 23-105 (median 51) post BMT, and included gastrointestinal symptoms, weight loss, fever, disturbed liver function, leukopenia and thrombocytopenia. Ganciclovir was administered for 14 days, without the addition of intravenous immunoglobulins. Following therapy, the clinical manifestations subsided in most of the patients, while leukopenia, thrombocytopenia and liver dysfunction resolved in about half of the patients. One patient who experienced recurrent CMV disease responded to a second course of ganciclovir. Poor response to ganciclovir treatment was observed in 2 of the 3 patients with grade 4 graft-versus-host disease (GVHD). Our experience suggests that a 2-week course of ganciclovir may be effective in BMT recipients who develop severe CMV-associated disease without lung involvement, especially when there is no concomitant severe GVHD.
Adolescent↗
Effect of recombinant human manganese superoxide dismutase on radiosensitivity of murine B cell leukemia (BCL1) cells.
Recombinant human manganese superoxide dismutase (SOD) protects cells from oxidative damage and is known to ameliorate post-irradiation damage in mice exposed to whole body or localized chest irradiation. The concept behind the present experiments was to investigate whether it is possible to improve the outcome in leukemia following total body irradiation used as part of the conditioning prior to allogeneic bone marrow transplantation. We determined whether SOD protects leukemic cells from the effects of ionizing irradiation both in vitro and in vivo. Murine B cell leukemia (BCL1) cells, derived from tumor-bearing mice, were irradiated in vitro with or without SOD and injected into BALB/c mice. All mice receiving 10(4) unirradiated BLC1 cells developed leukemia and died within 19-39 days. In vitro exposure of BCL1 cells to 800 cGy or 1600 cGy abolished the potential to induce leukemia by inoculation with 10(4) or 10(6) BCL1 cells, respectively. Addition of SOD in vitro during irradiation increased the resistance of BCL1 cells to ionizing irradiation; all mice receiving 10(6) BCL1 cells previously exposed in vitro to 1200 cGy in the presence of SOD died of leukemia, whereas only 40% of mice receiving a similar inoculum of irradiated BCL1 cells died of leukemia. In contrast, when BCL1-bearing mice were irradiated with 600-800 cGy with or without intravenous injection of SOD (100 mg/kg) 30 minutes prior to irradiation, development of leukemia was unaffected. Residual leukemia cells following therapy were assessed by adoptive transfer of 10(5) spleen cells to secondary BALB/c recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Investigations on the role of inflammatory and anti-inflammatory agents on the treatment of murine B cell leukemia by recombinant human interleukin-2.
Human recombinant interleukin-2 (rIL-2) was used in an effort to find effective biological therapy against the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of Balb/c origin. High dose rIL-2 (10(5) Cetus units 3 times a day for 5 days) was proven to be curative for mice inoculated with up to 10(4) BCL1 cells. Considering the fact that mice which showed more clinical signs of rIL-2 related toxicity had higher leukemia-free survival, and in view of the fact that BCL1 is a totally nonimmunogenic tumor, we have investigated the possible role of nonspecific effects of inflammatory and anti-inflammatory agents in order to speculate on the possible therapeutic role of inflammation on the overall effect of rIL-2 in the treatment of BCL1. According to the results presented in this work, it appears that although mediators of inflammation may play some role against leukemia, their overall effect in comparison with high-dose rIL-2 is relatively insignificant.
Animals↗
Treatment of life-threatening autoimmune diseases with myeloablative doses of immunosuppressive agents: experimental background and rationale for ABMT.
We describe a case of autoimmune-mediated mixed cryoglobulinemia with vasculitis and nephritis that was successfully treated with acute myeloablative immunosuppressive treatment. The case suggests that elimination of autoreactive lymphocytes followed by de novo regeneration of lymphocytes from autologous stem cells that re-acquire unresponsiveness towards self may be successfully accomplished in life-threatening autoimmune diseases. The combination of acute myeloablative immunosuppression followed by syngeneic stem cell transplantation may be an effective treatment for severe autoimmune diseases.
Adult↗
Prevention and treatment of relapse by bone marrow transplantation.
High, myeloablative doses of chemoradiotherapy represent the treatment of choice for a large number of malignant hematological diseases that cannot be successfully treated with conventional chemotherapy. Residual tumor cells following high dose chemotherapy represent the most common treatment failure, resulting in frequent relapse following autologous bone marrow transplantation (ABMT) and even allogeneic bone marrow transplantation (BMT). Graft vs leukemia (GVL) effects mediated by immunocompetent donor lymphocytes represent a major therapeutic potential of allogeneic BMT which results in reduced rate of relapse, especially when immune interactions between immunocompetent donor's T lymphocytes and host allogantigens is apparent, a reaction which might result in graft vs host disease (GVHD). Recent experiments in animal models of murine leukemias suggest that post-transplant immunotherapy may be successfully accomplished by lymphokine-mediated immunotherapy (LMI) and cell-mediated immunotherapy (CMI). Following allogeneic BMT, provided GVHD can be prevented by T-cell depletion, CMI may be amplified by repeated administration of immunocompetent donor's lymphocytes in graded increments following successful induction of chimerism and sustained hematopoiesis. GVL effects induced by CMI may be further potentiated by in-vivo administration of a short course of recombinant human interleukin-2 (rhIL2). Taken together, our data suggest that post-transplant immunotherapy by cytokines and adoptive cell therapy may successfully prevent relapse in patients at high-risk and even result in complete elimination of tumor cells following overt relapse. Thus, immunotherapy may represent an optimal approach for prevention and treatment of minimal residual disease.
Animals↗
Low-dose heparin inhibits acute graft versus host disease in mice.
We have studied the effect of low-dose heparin on GVHD, marrow engraftment and graft-versus-leukemia (GVL) effects in an experimental murine model. Recipient (C57BL/6 x BALB/c) F1 mice were transplanted with C57BL/6 marrow and/or spleen cells and treated with daily sc injection of 5 micrograms heparin for 30 days. We have shown that heparin in low doses attenuates the severity of acute GVHD and reduces the mortality rate from 69 to 37.5% without abrogating the GVL effect induced by the allograft and without impairing marrow engraftment.
Acute Disease↗
Invasive fungal sinusitis in patients undergoing bone marrow transplantation.
Invasive fungal sinusitis is becoming increasingly common in patients undergoing BMT. This study was undertaken to evaluate the incidence, presenting symptoms, diagnosis procedures, treatment and outcome of invasive fungal sinusitis. The study population comprised 423 consecutive BMT patients at Hadassah University Hospital from January 1986 to August 1992. Eleven patients (2.6%) developed invasive fungal sinusitis, 8 had underlying hematologic malignancies and 3 severe aplastic anemia (SAA). Median interval between BMT and fungal sinusitis was 22.5 days (range 2-106 days). Eight of 11 patients had protracted neutropenia (median 8 days with median neutrophil count at the time of fungal sinusitis diagnosis of 0.25 x 10(9)/l). Four patients developed GVHD before fungal sinusitis was diagnosed. Presenting symptoms were fever (100%), orbital swelling (63%), facial pain (54%) and nasal congestion (36%). In 8 patients Aspergillus species were isolated (A. flavus in 7, A. quadrilineatus in 1); in 1 patient Candida albicans was isolated and in the other 2 fungal elements were detected histologically (Fusarium and Mucor, respectively). Six of the patients underwent surgical debridement at diagnosis. Three received granulocyte transfusions. All patients received systemic amphotericin B (7 conventional and 4 amphotericin B colloidal dispersion (ABCD)). Only 2 of the 11 patients responded completely to therapy with a follow-up of 15 months. It appears that invasive fungal sinusitis is a potentially fatal complication in immunocompromised patients post-BMT. Current treatment approaches are largely ineffective and new methods of management of this serious problem are needed.
Adolescent↗
Adoptive transfer of immunity to hepatitis B virus after T cell-depleted allogeneic bone marrow transplantation.
Recipients of allogeneic bone marrow transplantation are pancytopenic for several weeks and immunosuppressed for many months as a result of myeloablative therapy required to eliminate the basic disease and to prevent allograft rejection. After bone marrow transplantation, these patients remain profoundly immunosuppressed by the chemotherapy and immunotherapy used as prophylaxis against graft-vs.-host disease, treatment of established disease or both. These patients are usually dependent on multiple blood products and are therefore at risk for hepatitis B virus infection, which may run a fulminant course. Active immunization against hepatitis B virus in the immediate pre-bone marrow transplantation and post-bone marrow transplantation periods was found to be ineffective, probably because of the absence of T cell-dependent B-cell responses, which persists for approximately 1 yr after bone marrow transplantation. We studied adoptive transfer of immunity to hepatitis B virus through bone marrow transplantation in two populations of patients. The first group (A) consisted of 12 pairs of BMT donors and recipients, in which all bone marrow donors were positive for antibodies to HBc and HBs as a result of previously acquired hepatitis B virus infection and resolution; all recipients were negative to antibodies to HBc and HBs. The second group (B) consisted of eight pairs of donors and recipients in which all the donors were actively immunized against hepatitis B virus before bone marrow transplantation; all recipients were negative for all hepatitis B virus markers. All bone marrow transplantation recipients were monitored for antibodies to hepatitis B virus antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Effect of various cytokine combinations on induction of non-MHC-restricted cytotoxicity.
Efforts were directed to achieve an increased lymphokine-activated non-MHC-restricted killing (LAK) activity greater than that induced by rIL-2 alone. Human peripheral blood (PB) and bone marrow (BM)-derived mononuclear cells (MC) were exposed in vitro to multiple cytokine combinations, including rIL-6, rIL-7, rIFN-alpha and rIFN-gamma in the presence of either suboptimal or optimal doses of rIL-2. Our results have shown that BMMC are a potential source for induction of increased LAK activity upon exposure to multiple cytokine combinations, whereas PBMC could not be successfully stimulated under the same conditions. Fifty-five to 62% of BM-derived samples stimulated with high dose rIL-2 + rIL-7 or rIL-2 + rIL-7 + rIL-6 + rIFN-gamma exhibited a higher degree of cytotoxicity than BM samples stimulated with rIL-2 alone. Exposure of PB-derived large granular lymphocytes (LGL) to various cytokine combinations led to increased proliferation after stimulation with suboptimal dose of rIL-2 in the presence of rIL-6 and rIL-7. This increase was not observed in induction of cytotoxicity. We suggest that BMMC activated by multiple cytokine combinations could play an active role in improving antitumor response in vivo by contributing to the control of minimal residual tumor cell growth, particularly post-BM transplantation.
Bone Marrow↗
Optimization of conditioning therapy for leukemia prior to BMT. I. Optimal synergism between cyclophosphamide and total body irradiation for eradication of murine B cell leukemia (BCL1).
The doses of chemotherapy and radiotherapy and the sequence-dependent influence of CY administration and total body irradiation (TBI) on the eradication of murine B cell leukemia (BCL1) were investigated. Tumor-bearing BALB/c mice were treated with either CY followed by TBI (CY/TBI) or in the reverse (TBI/CY) at different time intervals after injection of 10(6) BCL1 cells. The presence of residual tumor cells after cytoreduction was assessed in secondary BALB/c recipients by monitoring leukemia-free survival. The anti-leukemic effect of CY followed by TBI was significantly better than TBI followed by CY. The survival of secondary adoptive recipients inoculated with 10(5) spleen cells obtained from mice treated with CY/TBI was 54% (57 of 105) compared with 25% (25 of 98) of recipients inoculated with 10(5) spleen cells obtained from mice treated with TBI/CY (p = 0.0001).
Animals↗
Effect of bone marrow T lymphocytes treated with CAMPATH 1G on megakaryocyte colony formation.
Specific populations of lymphocytes play a significant role in the regulation of megakaryocyte (MK) development. CAMPATH 1G (C1G) and CAMPATH 1M (C1M) are T lymphocyte (TL)-specific monoclonal antibodies (MABs) that are routinely employed to reduce graft-vs.-host disease (GVHD) in allogeneic bone marrow transplantation (BMT). Following BMT, engraftment of the erythroid and myeloid lineages is prompt, but prolonged thrombocytopenia often prevails. We therefore studied the effect on MK colony formation of treating donor bone marrow (BM) with the CAMPATH MABs. MK colonies were grown in plasma clots using postirradiation aplastic canine serum (PICS-J) as MK colony-stimulating factor (MK-CSF). C1M, which causes TL destruction by complement-dependent lysis, had no effect on MK cloning efficiency. C1G is not lytic but causes the elimination of TL in the BMT recipients via antibody-dependent cell cytotoxicity (ADCC). Treatment of donor BM with C1G significantly enhanced the number of early burst-forming units (BFU-MK) and late colony-forming units (CFU-MK) and had no effect on granulocyte-macrophage (CFU-GM) or erythroid (BFU-E) colonies. Enhancement of MK cloning efficiency was concentration-dependent between 0.03 and 3 micrograms MAB/10(6) BM mononuclear cells (MNC). Similar results were observed when C1G-treated TL or purified CD4+ TL were co-cultured with untreated autologous BMMNC or peripheral blood (PB) MNC. Conditioned medium (CM) from C1G-treated TL and CD4+ TL contained soluble factors that, when combined with suboptimal doses of PICS-J, potentiated MK growth. C1G in combination with PICS-J also stimulated TL proliferation in a dose-dependent manner. The T cell CM did not contain elevated levels of interleukin-3 (IL-3), IL-6, IL-1 beta, or GM-CSF. Our data provide additional evidence for the involvement of activated TL, and perhaps novel soluble T cell products, in the immunomodulation of megakaryocytopoiesis.
Alemtuzumab↗
Effects of CAMPATH-1 antibodies on the functional activity of monocytes and polymorphonuclear neutrophils.
The rat antihuman lymphocyte monoclonal antibodies CAMPATH-1M and CAMPATH-1G (IgM kappa and IgG2b kappa, respectively) recognize cell surface antigens (CDW52) present on normal T and B lymphocytes as well as on monocytes, with weak expression on neutrophils. In previous studies, when peripheral blood mononuclear cells were treated with CAMPATH-1M and human complement, more than 99% of lymphocytes were killed. The present study indicates that both CAMPATH-1M and -1G bind to peripheral blood neutrophils and monocytes and do not affect the activity of the former cells but decrease the functional activity of monocytes. Decreased functional activity includes suppressed superoxide production by monocytes in response to phorbol myristate acetate (PMA), reduced activation of the cells as indicated by decreased ability to reduce 3-(4.5-dimethylthiazol-2-yl)-2.5 diphenyl-tetrazolium bromide (MTT), reduced tumoricidal activity, and reduced capability to kill Candida albicans. The ability of CAMPATH-1 to suppress the functional activity of monocytes in vitro suggests that in vivo administration of CAMPATH-1G may also affect the function of monocytes.
Alemtuzumab↗
Continuous intravenous administration of rmGM-CSF enhances immune as well as hematopoietic reconstitution following syngeneic bone marrow transplantation in mice.
Lethally irradiated Balb/c mice injected with syngeneic bone marrow cells received recombinant murine granulocyte/macrophage colony-stimulating factor (rmGM-CSF) by continuous intravenous infusion for 4 days. When transplanted with 10(5) marrow cells, treated mice showed higher survival (62% compared with 30% in the control group, p < 0.001) and significantly enhanced hematopoietic recovery manifested by 11-fold increase in the peripheral white blood cell (WBC) count. Day 7 marrow from rmGM-CSF-treated mice resulted in 70% survival in lethally irradiated secondary recipients, while marrow harvested under identical experimental conditions from saline-treated mice had no reconstituting capacity at all. When mice were injected with 10(4) marrow cells, 20% of rmGM-CSF treated mice survived as compared with none in the controls. In vitro preincubation of 10(5) and 5 x 10(5) fresh bone marrow cells with rmGM-CSF prior to transplant significantly improved survival of lethally irradiated mice in comparison with control (12% and 37.5% respectively, p < 0.001). Proliferative responses of lymphocytes obtained from rmGM-CSF-treated mice to mitogens and allogeneic C57BL6 splenocytes as well as non-MHC restricted cytotoxicity against tumor cells were significantly higher in rmGM-CSF-treated mice as compared with controls (p < 0.01). These data suggest that a short course of continuous intravenous infusion of rmGM-CSF following BMT or in vitro culturing of bone marrow cells with rmGM-CSF improves marrow reconstituting capacity. The mechanism may be by enhancing proliferation and function of committed and perhaps even the more primitive progenitor cell.
Animals↗
Immunohematopoietic reconstitution by allogeneic and autologous bone marrow grafts as a means for induction of specific unresponsiveness to donor-specific allografts and modified self in autoimmune disorders.
Explore the source record for details and available documents.
Animals↗
Autologous bone marrow transplantation for stage IV neuroblastoma: the role of soybean agglutinin purging.
Explore the source record for details and available documents.
Antineoplastic Combined Chemotherapy Protocols↗
Low molecular weight heparin for Hickman catheter--induced thrombosis in thrombocytopenic patients undergoing bone marrow transplantation.
BACKGROUND: Patients with an indwelling central venous catheter are prone to development of thrombotic complications. Thrombocytopenia in patients undergoing bone marrow transplantation (BMT) generally is protracted. The management of thrombosis in thrombocytopenic patients is difficult because heparin and warfarin are relatively contraindicated because of the high risk of major bleeding. Low molecular weight heparin (LMWH) is a new class of antithrombotic drug. Enoxaparin (Rhone Poulenc Rorer, Antony, France) is an LMWH that has been shown to be effective in the treatment and prophylaxis of venous thrombosis. Enoxaparin, with its high antithrombotic to anticoagulant ratio, may be safer than standard heparin in patients at high risk of hemorrhagic complications. METHODS: The authors report the cases of five thrombocytopenic patients, undergoing autologous BMT, in whom venous thrombosis developed related to a Hickman catheter. RESULTS: All the patients were treated with Enoxaparin and recovered promptly without hemorrhagic complications. CONCLUSIONS: The authors suggest that Enoxaparin is an effective drug in treating thrombocytopenic patients in whom acute venous thrombosis develops.
Adult↗