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Biomedical subjects

S Slavin

Publications and source records attributed to S Slavin.

At least 199 records · Page 11Linked to original sources
PubMed1994

Development of antibodies to hepatitis B virus surface antigen in bone marrow transplant recipient following treatment with peripheral blood lymphocytes from immunized donors.

Bone marrow transplantation (BMT) recipients are immunosuppressed and are at risk for contracting severe infections. Recently, adoptive transfer of immunity against hepatitis B virus (HBV) was documented in BMT recipients receiving bone marrow from 'naturally' HBV-infected individuals who recovered spontaneously, or those transplanted with bone marrow cells obtained from actively immunized donors. Furthermore, reconstitution of the immune system in a BMT recipient who was a hepatitis surface antigen (HBsAg)+/HBV DNA+ carrier with HBV immune bone marrow cells led to clearance of the replicating virus, presumably through adoptive cell-mediated immunotherapy. We report three cases of induction of immunity to HBV by selective adoptive transfer by i.v. injection of peripheral blood lymphocytes (PBL) obtained from BMT donors who were actively immunized against HBV after harvesting of bone marrow. All three BMT recipients developed anti-HBs antibodies. In one BMT case in whom antibodies to HBsAg developed following adoptive transfer of immune PBL, a mild booster effect was documented in the BMT recipient upon immunization with a recombinant hepatitis B vaccine. The two remaining patients lost their antibodies to HBsAg in association with relapse of leukaemia. This immune manipulation may open the door to evaluation of adoptive transfer of immunity to HBV through selective transplantation of HBV immune lymphocytes in selected patients such as those with persistent HBV infection, as well as liver transplant recipients who require protection of the graft against HBV re-infection.

Adolescent↗
PubMed1994

Salivary immunoglobulins in recipients of bone marrow grafts. I. A longitudinal follow-up.

Patients receiving bone marrow transplantation (BMT) are prone to a variety of bacterial, viral and fungal infections in their oral cavity. We have therefore followed alterations in salivary Ig levels associated with BMT. Most of the patients were transplanted with allogeneic, MHC-matched BM after T cells were depleted by ex vivo treatment with an anti-lymphocytic monoclonal antibody (Campath-1) and autologous complement. Parotid saliva was collected at various time intervals before and after BMT, and IgM, IgG and IgA concentrations were determined by an enzyme linked immunosorbent assay (ELISA). A gradual fall in Ig levels was detected following patient's conditioning with a combination of chemo- and radiation therapy beginning 10 days prior to BMT. A rise in the titer of salivary Ig could be detected as early as 4 days post-BMT, which increased continuously and reached plateau levels within 2-3 weeks. However, about 3 weeks later the Ig titers decreased again and persisted at low levels for variable periods of time. A second increase in salivary Ig was detected approximately 2 months post-BMT, which persisted for prolonged periods of time. These results suggest that Ig secreted by donor B-lymphocytes and plasma cells passively transferred with the BM can rapidly reconstitute the salivary IgM, IgG and IgA of the immunocompromised recipient. However, when these cells cease to produce Ig the patients are still immunoincompetent and therefore enter a second phase of salivary Ig deficiency which may render them highly susceptible to opportunistic oral infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Salivary immunoglobulins in recipients of bone marrow grafts. II. Transient secretion of donor-derived salivary IgA following transplantation of T cell-depleted bone marrow.

Patients undergoing bone marrow transplantation (BMT) have decreased levels of salivary Ig over long periods of time. However, shortly after transplantation, a transient rise of Ig concentration in their saliva gland is detected. In order to trace the origin of this Ig, seven BM donors were immunized with tetanus toxoid (TT) 4-7 days prior to BMT harvesting. Four patients received BM from non-immunized donors. All but one of the patients had no detectable anti-TT IgA in their parotid saliva prior to BMT. Recipients of T cell-depleted BM from pre-immunized donors transiently displayed high titers of salivary anti-TT IgA 7-28 days after transplantation. No significant anti-TT IgA titers were detected in saliva of patients grafted with non-immunized BM. We conclude that antibody-producing cells activated in the donor are passively transferred with the BM to the recipient. IgA committed cells home to the mucosa-associated lymphoid tissues (MALT) and continue to secrete antibodies until senescence.

Adolescent↗
PubMed1994

Successful purging of murine plasmacytoma by mafosfamide (ASTA-Z).

Mafosfamide (ASTA-Z) is a chemotherapeutic agent currently in use for in vitro purging of tumor-bearing human BM cells prior to autologous bone marrow transplantation (ABMT). We tested the efficacy of ASTA-Z against mouse plasmacytoma cells MOPC-315 (MOPC), a model of human multiple myeloma. BALB/c mice were injected intraperitoneally with different doses of MOPC preincubated with ASTA-Z. All control mice receiving > or = 10(4) MOPC intraperitoneally (ip) died within 23 days. All recipients of ASTA-Z pretreated MOPC remained healthy for > 180 days. To simulate the clinical situation, BALB/c mice received lethal doses of 10(3) MOPC ip prior to ABMT. Subsequently, mice were treated with cyclophosphamide 200 mg/kg one day prior to syngeneic BMT with 10(7) BMC containing 10(6) MOPC; 90% of the mice receiving unpurged syngeneic BMC died within 45 days whereas all mice transplanted with ASTA-Z-treated BMC/MOPC mixtures remained disease-free for > 100 days. Our results suggest that a similar approach may be successful in patients with multiple myeloma and residual disease prior to cryopreservation of their BM for ABMT. Bone marrow purging with ASTA-Z is effective and under certain conditions could be critical for prevention of relapse following ABMT, provided that effective elimination of residual disease in the host can be achieved by the conditioning regimen prior to ABMT.

Animals↗
PubMed1994

Total lymphoid irradiation, anti-lymphocyte globulin and Campath 1-G for immunosuppression prior to bone marrow transplantation for aplastic anemia after repeated graft rejection.

Allogeneic BMT for severe aplastic anemia is associated with a significant rate of graft rejection, especially in patients who have been previously transfused. We report a child with aplastic anemia who rejected donor marrow twice despite adequate immunosuppression as part of the conditioning therapy but engrafted successfully following combined administration of three modalities of immunosuppression: antithymocyte globulin, total lymphoid irradiation and the monoclonal antibody Campath-1G. Restriction fragment length polymorphism studies > 1 year after BMT show full donor hematopoiesis with no evidence of autologous recovery.

Alemtuzumab↗
PubMed1994

Eosinophils activation in post-autologous bone marrow transplanted patients treated with subcutaneous interleukin-2 and interferon-alpha 2A immunotherapy.

We evaluated eosinophils morphology, physical properties and antileukemic activity in autologous bone marrow transplanted (ABMT) patients treated with subcutaneous recombinant interleukin 2 (rIL-2) and recombinant human interferon alpha 2a (IFN alpha) given as outpatient immunotherapy. All patients receiving rIL-2/IFN alpha therapy developed peripheral blood eosinophilia of 20-40% peaking at 2-4 weeks of therapy. While on rIL-2/IFN alpha therapy the eosinophils became hypodense and hypersegmented. The antibody dependent cell-mediated cytotoxic activity (ADCC) of the eosinophils against the human B-cell lymphoma cell line (Raji) was depressed post-ABMT. Prolonged (28 days) in vivo rIL-2/IFN alpha immunotherapy enhanced ADCC activity of the eosinophils and brought them to normal levels. Similarly, rIL-2/IFN alpha immunotherapy enhanced the depressed cytotoxic activity of neutrophils post-ABMT to normal levels. Thus, eosinophils and neutrophils from rIL-2/IFN alpha-treated ABMT recipients may be targeted toward tumor cells by antibody, and express tumoricidal activity. No effect of rIL-2/IFN alpha was observed on monocyte-dependent ADCC activity which remained normal post-ABMT. We conclude that in addition to their effect on lymphocytes, cytokine-mediated immunotherapy consisting of subcutaneous low doses of riL-2 and IFN alpha may mediate their therapeutic effects in cancer therapy by increasing the number of eosinophils and enhancing the antitumor activity of eosinophils and neutrophils, provided that tumor-specific or tumor-associated antibodies are present.

Adolescent↗
PubMed1994

Ciprofloxacin enhances hematopoiesis and the peritoneal neutrophil function in lethally irradiated, bone marrow-transplanted mice.

We analyzed the effect of in vivo ciprofloxacin and ceftazidime treatment on the development of myeloid progenitors and on the survival of lethally irradiated mice rescued with syngeneic bone marrow transplantation (BMT). Ciprofloxacin treatment (15 mg/kg per dose three times daily for 5 days) enhanced myeloid progenitor (colony-forming cell [CFU-C]) number in the bone marrow and the survival of mice transplanted with suboptimal doses (1 x 10(5) of s[Ngeneic bone marrow cells (BMC). Twenty days postirradiation, 50% (38 of 76) of saline-treated mice transplanted with 1 x 10(5) cells died compared with 25% (19 of 76) of ciprofloxacin-treated mice (p < 0.05). Similarly, ciprofloxacin treatment enhanced survival of mice transplanted with 1 x 10(6) syngeneic bone marrow cells: 50% (38 of 76) of saline-treated mice died within 20 days vs. 15% (12 of 80) of ciprofloxacin-treated mice. In contrast, treatment with ceftazidime did not affect progenitor cell number or survival. On day 8 postirradiation, although lethally irradiated mice transplanted with 1 x 10(5) BMC treated with ciprofloxacin demonstrated similar white blood cell (WBC) and red blood cell (RBC) counts as saline-treated mice, a (1.9 +/- 0.2)-fold increase in the percentage of polymorphonuclear cells (PMN) was observed in the peripheral blood of ciprofloxacin-treated mice. On day 5 postirradiation, ciprofloxacin-treated mice showed a (1.6 +/- 0.2)-fold increase in the number of peritoneal PMN and a 6.5-fold increase in their antibacterial activity towards Salmonella typhimurium in comparison with saline-treated mice.

Animals↗
PubMed1994

Effect of total lymphoid irradiation on natural killer cells and cytotoxic and primed T lymphocytes.

Total lymphoid irradiation (TLI), which results in prolonged depression of the number and function of T and B cells, augments the natural killer (NK) cell activity. Small doses of irradiation (200-400 cGy) in vitro did not reduce the lytic activity of TLI-induced NK cells, whereas irradiation with 1,500 and 3,000 cGy decreased NK function by 50-70%. Addition of TLI spleen cells, containing a high proportion of large mononuclear cells, to cytotoxic T lymphocytes (CTL), generated in vitro by one-way mixed lymphocyte reaction and tested against 51Cr labeled target cells, suppressed the lytic activity 27-57% of that observed following the addition of normal spleen cells. The suppressive effect induced by spleen cells of TLI-treated mice was H2 nonrestrictive. Primed T lymphocytes (PTL) stimulated with irradiated allogeneic cells were inhibited by cocultured TLI spleen cells, causing inhibition of 57% as measured by secondary proliferative response and 86% inhibition by primary response to a third strain of cells. Our results, together with previously published data, indicate that TLI-induced suppressor cells inhibit the generation of PTL and CTL. Secondary proliferative responses of T cells primed to alloantigens are suppressed, as is the lysis of target cells by CTL. All suppressive phenomena presented here are antigen nonspecific.

Animals↗
PubMed1993

Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics.

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood-vessel walls, cells, including malignant ones, must recognize and associate with the sub-endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM-glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-Asp (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the alpha IIb-beta 3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, but not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16-F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF-6,5 to mice inhibited the formation of B16-F10 colonies in experimental and spontaneous models of metastases. Moreover, SF-6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrin-dependent cell-cell and cell-ECM interactions.

Animals↗
PubMed1993

Spontaneous and IL-2-induced anti-leukemic and anti-host effects against tumor- and host-specific alloantigens.

The graft-vs-leukemia (GVL) effect and its connection to graft-vs-host disease (GVHD) were studied in F1 hybrid mice after parental bone marrow transplantation. (BALB/c x C57BL/6) F1 mice (F1) were sublethally and lethally irradiated and inoculated with 10(4) BCL1 cells, a murine leukemia of BALB/c (BALB) origin. Subsequently mice were transplanted with F1 (syngeneic), BALB (allogeneic to the host but syngeneic to the tumor), C57BL/6 (B6) (allogeneic to both host and tumor) spleen cells, or spleen cells mixed with syngeneic (F1) bone marrow cells, respectively. Fresh BALB (H-2d) and B6 (H-2b) spleen cells, which induce equally strong GVHD in the F1 recipient against H-2b and H-2d alloantigens, respectively, were assayed for their ability to induce GVL effects on BCL1 (H-2d) cells with and without in vivo administration of human rIL-2. In order to increase the GVL effects, spleen cells were incubated for 4 days with rIL-2 to generate IL-2-activated killer cells. The results of adoptive transfer experiments showed that only immunocompetent B6 cells led to consistent eradication of leukemia. Neither BALB nor syngeneic F1 cells induced curative GVL effects regardless of whether spleen cells were further stimulated with rIL-2 in vitro, in vivo, or both. Our data support the theory that GVL effects are caused by T cell-dependent immune responses of allogeneic T cells and not by MHC-nonrestricted NK or rIL-2-activated NK cells, independently of the GVHD process itself. Hence, recognition and killing of tumor cells is most probably a MHC-restricted T cell-dependent process.

Animals↗
PubMed1993

Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide).

Linomide is a synthetic immunomodulator that enhances natural killer cell activity and significantly activates several lymphocytic cell subpopulations in both experimental animals and humans. In this study we examined the effect of linomide (80 mg per kg per day in drinking water) on mice with chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE), a T-cell-mediated organ-specific autoimmune disease that resembles human multiple sclerosis. None of the mice (n = 17) that were treated with linomide from day 7 after disease induction developed any clinical or histopathological signs of CR-EAE, as compared to 19 of 20 untreated controls that were severely paralyzed and had extensive demyelinating lesions in the central nervous system. Linomide-treated animals were also resistant to an induced attack by a booster injection with a murine spinal cord homogenate. When administered to mice exhibiting severe clinical signs of paralysis, linomide inhibited both spontaneous and induced relapses. Linomide treatment protected mice from passively induced CR-EAE as well, when given from the day of injection with myelin-basic-protein-specific lymphocytes. Lymphocytes obtained from linomide-treated mice had a reduced in vitro proliferative response to the myelin basic protein and to the tuberculin purified protein derivative, whereas the mitogenic response to concanavalin A was not affected. Natural killer cell and lymphokine-activated killer cell activities were enhanced. These results suggest that linomide regulates autoimmunity in the absence of systemic immunosuppression. Since linomide is very well tolerated in experimental animals and humans, it might be used in the treatment of multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1993

[Hematopoietic growth factor (GM-CSF) after autologous bone marrow transplantation. A randomized, double-blind, multicenter study in 91 cases of non-Hodgkin's malignant lymphomas].

To a great extent, the risks of autologous bone marrow transplantation are related to neutropenia. Although the efficacy of the recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) on neutrophil recovery has appeared in numerous open trials, only a few randomized studies have hitherto been published. Ninety-one patients with non-Hodgkin's malignant lymphoma treated with ablative chemotherapy followed by purged or unpurged bone marrow transplantation were entered in a placebo-controlled, double-blind randomized study; 44 patients received GM-CSF (E. coli) in doses of 250 micrograms/m2/day, and 47 received a placebo. Treatment was administered daily as continuous infusion started on the day of transplantation and pursued until the absolute number of neutrophils reached 0.5 x 10(9)/l during 7 days or, if this failed, during 30 days. The median time of neutrophil recovery was 14 days in patients on rhu GM-CSF and 21 days in patients on placebo (P < 0.0001). Patients who received a mafosfamide-purged bone marrow also had a rapid neutrophil recovery (median: 16 days versus 20.5 days; P = 0.013). The stay in hospital was shorter in the rhu GM-CSF group (median: 23 days versus 28 days; P < 0.05). No significant difference in the number of days with fever, infections, antibiotics administered and overall survival was detected between the two groups. The main toxicity ascribable to rhu GM-CSF was a capillary leakage syndrome found in 3 patients. Thus, after purged or unpurged autologous bone marrow transplantation rhu GM-CSF significantly reduces the duration of both neutropenia and hospital stay.

Adolescent↗
PubMed1993

Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide.

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.

Adjuvants, Immunologic↗
PubMed1993

Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor.

Chronic hepatitis B virus (HBV) infection is still a major cause of liver disease for which no definite therapy is available. We describe here a hepatitis B surface antigen (HBsAg) carrier patient with active viral replication (HBV DNA positive) who was treated for leukemia by bone marrow transplantation (BMT) from an HBV immune donor. Following BMT from the antibody to hepatitis B core antigen (anti-HBc) positive/anti-HBs positive bone marrow donor, immune reconstitution of the recipient's bone marrow resulted in clearance of the circulating HBsAg, as well as HBV DNA. The patient acquired immunity against HBV, which lasted for more than 8 months posttransplantation. Therefore, this report provides evidence that adoptive transfer of specific immunity against HBV through allogeneic BMT may lead to clearance of persistent HBV infection. Furthermore, the data support the hypothesis that the HBsAg carrier state is most probably the result of an inefficient immune response against HBV, implying that clearance of HBV may be facilitated by adoptive cellular immunotherapy.

Bone Marrow Transplantation↗
PubMed1993

Minimal residual disease in murine B-cell leukemia (BCL1) detected by PCR.

Small proportions of leukemic cells escaping chemo-radiotherapy and/or dormant leukemic cells present in undetectable amounts in patients post therapy, i.e. minimal residual disease (MRD), are a source for relapse. The study of MRD and its treatment in a murine model for human B-cell leukemia/lymphoma, (BCL1), should lead to an improved understanding of the human disease. The standard assay for MRD in experimental mice is the adoptive transfer of spleen cells from experimental animals into naive secondary syngeneic recipients. We describe here the detection of MRD in BCL1-carrying BALB/c mice using the polymerase chain reaction (PCR). A BCL1 specific sequence from the rearranged VH-region was amplified yielding a 456 bp long fragment. PCR products hybridized to the cloned BCL1 sequence allowed the detection of a single BCL1 cell. This assay, therefore, reveals the presence of very small numbers of leukemic cells without sacrificing experimental animals.

Animals↗
PubMed1993

Normal hematopoietic reconstitution following ASTA-Z 7557-purged grafts in the absence of in vitro CFU-GM colony growth.

Hematopoietic reconstitution was assessed in 26 consecutive patients who underwent autologous bone marrow transplantation (ABMT) with ASTA-Z 7557 purged bone marrows. Of the 26, 17 had acute non-lymphoblastic leukemia (ANLL), 7 had acute lymphoblastic leukemia (ALL), 1 had non-Hodgkin's lymphoma (NHL) and 1 had multiple myeloma (MM). Twelve patients had practically no CFU-GM growth after ASTA-Z treatment. No statistical difference was observed in hematopoietic reconstitution between patients with or without in vitro CFU-GM colony growth. No significant linear correlation was observed between CFU-GM content in the treated graft and day of engraftment. In vitro CFU-GM growth has no predictive value in assessing hematopoietic recovery in vivo. Patients with no CFU-GM growth demonstrated normal engraftment.

Adolescent↗
PubMed1993

Various methods of breast reconstruction after mastectomy: an economic comparison.

This study is an economic comparison of various methods of breast reconstruction after mastectomy. The hospital bills of 287 patients undergoing breast reconstruction at three institutions from June of 1988 to March of 1991 were analyzed. The procedures examined included mastectomy, implant and tissue-expander reconstruction, and TRAM and latissimus pedicle flaps, as well as free TRAM and free gluteal flaps. These procedures were subdivided into those which were performed at the time of mastectomy and those performed at a later admission. In addition, auxiliary procedures (i.e., revision, nipple reconstruction, tissue-expander exchange, and contralateral mastopexy/reduction) also were examined. Where appropriate, these procedures were subdivided into those performed under general or local anesthesia and by inpatient or outpatient status. Data from the three institutions were converted to N.Y.U. Medical Center costs for standardization. A table is presented that summarizes the costs of each individual procedure with all the pertinent variations. In addition, a unique and novel method of analyzing the data was developed. This paper describes a menu system whereby other data regarding morbidity, mortality, and revision rates may be superimposed. With this information, the final cost of reconstruction can be extrapolated and the various methods of reconstruction can be compared. This method can be applied to almost any complex series of multiple procedures. The most salient points elucidated by this study are as follows: The savings generated by performing immediate reconstruction varies between $5092 (p < 0.05) for free gluteal flaps and $10,616 (p < 0.05) for pedicled TRAM flaps.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗