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S Slavin

Publications and source records attributed to S Slavin.

At least 145 records · Page 8Linked to original sources
PubMed1996

Induction of graft versus leukemia effects by cell-mediated lymphokine-activated immunotherapy after syngeneic bone marrow transplantation in murine B cell leukemia.

The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/ lymphoma. Allogeneic cell therapy, induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal residual disease provided that graft versus host disease can be prevented or adequately controlled.

Adjuvants, Immunologic↗
PubMed1996

The novel immunomodulator, Linomide, stimulates interleukin-2-induced human natural killer (NK) cell and PHA-stimulated T cell proliferation from normal donors.

Donor-derived cell-mediated immunotherapy has been shown to be an effective tool for reinduction of remission in chronic myeloid leukaemia (CML) patients who have relapsed post-bone marrow transplantation (BMT). Linomide, quinoline-3-carboxamine (LS 2616), is a new immunomodulator shown to increase the number of NK precursors in mice in addition to upregulating the quantity of CD56(+), CD3(-) and CD16(+) NK cells in the peripheral blood of patients following autologous BMT (ABMT). We investigated the in vitro effects of Linomide on NK activity of normal human donors. Large granular lymphocytes (LGLs) and NK cells were incubated overnight with Linomide (0.02-4.8 mg/ml), recombinant human interleukin-2 (IL-2, 75 IU/ml), or a combination of both. Linomide, at 0.02-0.3 mg/ml, augmented IL-2-induced proliferation of LGLs and NK cells in an inversely proportional manner. In contrast, Linomide at 0.6-4.8 mg/ml inhibited IL-2-induced proliferation of LGLs and NK cells in a dose-dependent manner. Linomide was able to potentiate phytohemaglutinin-induced CD3(+) cell proliferation. In addition, supernatants derived from Linomide treated CD3(+) T cells were able to mimic the direct stimulatory effect of Linomide on activated NK cell proliferation. These supernatants were found to have low levels of tissue necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and therefore Linomide stimulation of NK and T cell proliferation may be due to its inhibitory effect on the secretion of these cytokines by activated CD3(+) T cells. Linomide had no effect on cytotoxicity nor on the phenotypic expression of resting and IL-2-activated LGLs or NK cells. In view of our results, Linomide could possibly play a potential role in adoptive cell-mediated immunotherapy post-BMT.

Adjuvants, Immunologic↗
PubMed1996

ASTA-Z 7557 impairs human natural killer (NK) cell activity.

Mafosfamide (ASTA-Z 7557) is a chemotherapeutic agent currently used for purging human bone marrow cells prior to autologous bone marrow transplantation. Adoptive cell-mediated immunotherapy has been shown to have a positive effect on the control of minimal residual disease and reinduction of remission post-bone marrow transplantation. Large granular lymphocytes and natural killer (NK) cells are believed to play a role in this effect. In the present work, we assessed the effect of ASTA-Z on the cytotoxic and proliferative capabilities of large granular lymphocytes (LGLs). The ASTA-Z significantly inhibited peripheral blood and bone marrow-derived LGL proliferation and cytotoxic capabilities, while this effect was less pronounced post-IL-2 treatment. We conclude that ASTA-Z purging may significantly impair the NK cell-mediated graft versus leukemia effect and therefore should be preceded by IL-2 therapy.

Antineoplastic Agents↗
PubMed1996

Second transplantation using allogeneic peripheral blood stem cells in a beta-thalassaemia major patient featuring stable mixed chimaerism.

Allogeneic bone marrow transplantation (BMT) for beta-thalassaemia major carries the risks of disease recurrence due to residual thalassaemic stem cells or true immune-mediated rejection. We report a thalassaemic patient who displayed stable mixed chimaerism with only 5% donor-derived cells for about 5 years after BMT. Displacement of host cells was accomplished by ambulatory non-myeloablative conditioning and allogeneic G-CSF mobilized peripheral blood stem cell transplantation from the same donor, resulting in full reconstitution. Patients featuring stable mixed chimaerism after BMT may benefit from allogeneic cell therapy with immunocompetent lymphocytes and stem cells, whilst avoiding supralethal conditioning.

Bone Marrow Transplantation↗
PubMed1996

Linomide, an immunomodulator that inhibits Th1 cytokine gene expression.

Linomide (LS-2616, quinoline-3-carboxamide) has strong immunomodulating effects in animal models, inhibiting toxic shock, progressive autoimmune disease and cancer. In humans, linomide strongly reduced the appearance of new lesions in multiple sclerosis yet enhanced immune responses after bone marrow transplantation. In contrast to these clear effects in vivo, attempts to show an effect of linomide in vitro have not been successful and its mode of action remains to be elucidated. Here we show that at concentrations effective in vivo, linomide is active on human peripheral blood mononuclear cells (PBMC), severely inhibiting the induction by Staphylococcus aureus enterotoxin B of mRNA of three cytokine genes expressed in Th1 cells, those for IFN-gamma, IL-2, and tumor necrosis factor-beta. Yet, cell viability was not affected by linomide. The extent of inhibition is dose-dependent on linomide. Linomide also blocked induction of IL-2 and IFN-gamma mRNA by phytohemagglutinin. The inhibitory effect is expressed immediately but can be enhanced significantly by a prolonged exposure of PBMC to linomide, reaching 10-fold. These results support the concept that linomide antagonizes the activation of Th1 cells during a cellular immune response.

Adjuvants, Immunologic↗
PubMed1996

Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone.

The effect of halofuginone, a plant alkaloid known to inhibit collagen type I synthesis, on skin collagen content and skin morphology was evaluated in two in vivo models of scleroderma: the murine chronic graft-versus-host disease (cGvHD) and the tight skin mouse. Skin collagen was assessed by hydroxyproline levels in skin biopsies and by immunohistochemistry using anti-collagen type I antibodies. Daily intraperitoneal injections of halofuginone (1 microgram/mouse) for 52 d starting 3 d before spleen cell transplantation, abrogated the increase in skin collagen and prevented the thickening of the dermis and the loss of the subdermal fat, all of which are characteristic of the cGvHD mice. Halofuginone had a minimal effect on collagen content of the control mice. The halofuginone-dependent decrease in skin collagen content was concentration-dependent and was not accompanied by changes in body weight in either the cGvHD or the control mice. Injections of halofuginone (1 microgram/mouse) for 45 d caused a decrease in the collagen content and dermis width in tight skin mice, but did not affect the dermis width of control mice. Collagen content determination from skin biopsies confirmed the immunohistochemical results in the same mice. The low concentration of halofuginone needed to prevent collagen deposition in fibrotic skin without affecting body weight suggests that halofuginone may serve as a novel and promising anti-fibrotic therapy.

Animals↗
PubMed1996

Modulation of experimental systemic lupus erythematosus with linomide.

OBJECTIVE: The objective of this study was to assess the beneficial effects of an early administration of low dose linomide, a new immunomodulator, in an animal model of experimental systemic lupus erythematosus (SLE). METHODS: Experimental SLE was induced in naive BALB/c mice, by immunization with anti-DNA mAb (MIV-7). Control Mice immunized with irrelevant human IgM served as controls. The immunized mice were treated with linomide (0.1 mg/ml in the drinking water), four weeks prior to the first immunization, at an early stage of the disease induction (one month after boost injection), or at a later stage (3 months following boost immunization). The treatment duration was 3 months in all schedules. The follow-up studies continued for 8 weeks after discontinuation of the treatment. The presence in the serum of autoantibodies against ssDNA, dsDNA histones, phospholipids and an irrelevant autoantigen-pyruvate dehydrogenase, was determined by enzyme-linked immunosorbent assay (ELISA). The clinical parameters assessed included erythrocyte sedimentation rate, peripheral blood cell counts and proteinuria. RESULTS: There was a 50-64% decrease in autoantibody levels in the sera of mice immunized with anti-DNA (MIV-7) mAb at the early stage of experimental SLE in mice which received linomide for a period of 3 months. No effect of linomide was noted in mice which received the drug during the later stages of experimental SLE when the disease was fully developed. Linomide had a preventive effect on the induction of experimental SLE in naive mice, when the treatment was initiated before the induction of the disease. This effect was abolished following cessation of the treatment. CONCLUSIONS: Linomide proved to be effective at the early stages of induction of the experimental SLE. However, the autoantibody levels rose following discontinuation of the therapy.

Adjuvants, Immunologic↗
PubMed1996

Salivary immunoglobulins in recipients of bone marrow grafts. III. A longitudinal follow-up of CMV specific antibodies.

Cytomegalovirus (CMV) infection is a major complication of BMT. The oral cavity is a common route for CMV infection, whose protection is provided by salivary anti-CMV antibodies. We developed an ELISA assay for the detection of CMV-specific antibodies in parotid saliva. Saliva of patients receiving BMT from CMV-positive donors was transiently reconstituted with IgG and IgA anti-CMV antibodies shortly after transplantation. The concentration of these antibodies gradually decreased during the 2 months after transplantation and increased again around day 80. A remarkable rise in the salivary concentrations of IgG and IgM anti-CMV was observed shortly after i.v. administration of Sandoglobulin. These results demonstrate, for the first time accurate monitoring of CMV-specific antibodies in saliva using a quantitative ELISA assay. The study suggests that secretion of CMV-specific antibodies in saliva of immunocompromised patients can be reconstituted by donor-derived B and plasma cells transferred with the BM or by i.v. administration of pooled Ig.

Adolescent↗
PubMed1996

Improved single-step PCR assay for sex identification post-allogeneic sex-mismatched BMT.

A method is presented which allows sex-identification simultaneously of both male and female cells in cell mixtures. The sensitivity of this PCR-based assay is one male cell in 10(6) female cells. The test can be used routinely to analyze bone marrow and peripheral blood lymphocytes post-allogeneic sex-mismatched bone marrow transplantation to detect early engraftment or rejection, as well as host cell regeneration.

Amelogenin↗
PubMed1996

Effect of deoxyspergualin on graft-versus-host disease and graft- versus-leukemia in mice.

The effect of 15-deoxyspergualin (DSG) on bone marrow (BM) engraftment and graft-versus-host disease (GVHD) was studied in mice across both major (MHC) and minor (MiHC) histocompatibility barriers. (BALB/c x C57BL/6)F1 mice were inoculated with C57BL/6 cells, CBA mice were given B10.BR cells and BALB/c mice were transplanted with B10.D2 cells. All recipient mice were irradiated lethally or sublethally prior to transplantation. DSG had no effect on engraftment of parental cells in F1 mice at both 2.5 mg/kg and 10 mg/kg given daily for 10 days after treatment. Survival of F1 recipients of C57BL/6 cells increased significantly with 2.5 mg/kg DSG (p < 0.05). Across MiHC, 75% of DSG-treated CBA mice survived transplant for more than 150 days. No effect on GVHD was observed in the B10.D2 --> BALB/c setting. DSG abolished graft-versus-leukemia (GVL) effects in F1 mice transplanted with both BM and spleen cells (20%) of C57BL/6 mice and additionally inoculated with B cell leukemia (BCL1). In summary, in the semi-allogeneic murine models presented here DSG prevented GVHD but at the same time suppressed GVL effects induced by the allograft. For clinical use, DSG might therefore be very useful for prevention of GVHD post-allogeneic bone marrow transplantation for non-malignant diseases or for leukemia.

Animals↗
PubMed1996

Soluble IL-6 receptors (sIL-6R) in hematological patients receiving immunotherapy with IL-2/IFN-alpha or donor lymphocytes following bone marrow transplantation.

Soluble interleukin-6 receptor (sIL-6R) has previously been shown to potentiate the activity of interleukin-6 (IL-6) which may display antitumor activity. Therefore, we evaluated sIL-6R levels in the sera of 15 patients who received cytokine-mediated immunotherapy with (IL-2/IFN-alpha), and 15 patients who received cell-mediated immunotherapy post-BMT, in an attempt to reduce the relapse rate. sIL-6R levels were evaluated pre-, during and post-cytokine or cell-mediated immunotherapy, using IL-6R-specific monoclonal antibodies (McAb) and double-sandwich ELISA. In normal controls, sIL-6R levels were found to be 20 +/- 3 ng/ml. sIL-6R levels increased significantly during IL-2/IFN-alpha immunotherapy in comparison to pre- or post-immunotherapy levels (74 +/- 9 ng/ml vs 46 +/- 6 ng/ml, and 50 +/- 9 ng/ml, respectively) (n = 15) (P < 0.05). sIL-6R levels also significantly increased following donor lymphokine activated killer (LAK) cells, given in addition to IL-2, in comparison to base line levels (87 +/- 3 ng/ml vs 60 +/- 2 ng/ml) (n = 6) (P < 0.05). Increased levels of sIL-6R were observed in BMT patients treated with immunotherapy.

Adolescent↗
PubMed1996

Stimulation of immune reconstitution by interleukin-7 after syngeneic bone marrow transplantation in mice.

Successful outcome of autologous bone marrow transplantation (BMT) is severely handicapped by susceptibility to infection and by a high rate of relapse. While quantitative aspects of the immune system generally return to normal within the first 3-4 months after BMT, the recovery of qualitative immune functions is prolonged. Since interleukin-7 (IL-7) has growth-promoting and differentiating effects on pre-B cells and immature thymocytes, its role in the recovery of immune functions was investigated in BALB/c mice after syngeneic BMT (sBMT). After sBMT, mice treated with human recombinant IL-7 (rIL-7) showed an 11.9-fold increase in thymic cellularity associated with an enhanced response to a mitogenic stimulus compared with the controls. rIL-7 significantly increased RAG-1 expression and promoted V beta 8(D)J gene rearrangement of the T cell receptor in the thymus. Further, the cytokine boosted survival after challenge with influenza virus following sBMT. The finding that rIL-7 induces differentiation and proliferation of immature thymocytes and counteracts post-BMT immune deficiency makes it a promising medium for clinical application in BMT patients.

Animals↗
PubMed1996

Bone marrow transplantation using unrelated and family related donors: the impact of HLA-C disparity.

The clinical outcomes of unrelated and of family related allogeneic bone marrow transplantation (BMT) were correlated with HLA disparity in a study in which molecular phenotyping of HLA-C was performed for unrelated donor-recipient pairs. The study included 30 patients who underwent BMT from unrelated donors and 43 patients who underwent BMT from family related donors. The unrelated group included 14 full match pairs, 12 class-I-C (molecular HLA-C) mismatched pairs, and 4 haploidentical pairs. The family related group included 9 full match pairs, 19 class-I mismatched pairs, and 15 haploidentical pairs. In the unrelated BMT group, the transplant-related complications of mortality, graft-versus-host disease (GVHD), and graft rejection, were significantly higher in molecular HLA-C mismatched than matched patients (67% vs 14%, P < 0.02; 50% vs 7%, P < 0.02; 42% vs 0, P < 0.02). The actuarial survival and the disease free survival (DFS) at 18 months was better for molecular HLA-C matched than for HLA-C mismatched unrelated transplants: 33% vs 18% (P = 0.065, NS), and 29% vs 16%, respectively. For the family related BMT group, the actuarial survival at 18 months was significantly higher for patients who were fully matched compared to those who were class-I mismatched, or those who were haploidentical pairs: 67%, 37%, and 13% respectively (P < 0.02). The actuarial DFS at 18 months of patients who were fully matched and of those who were class-I mismatched was similar, and better than that of haploidentical patients 45%, 37% (NS) and 13% respectively (P < 0.045). A lower incidence of transplant-related mortality occurred in class-I mismatched, family related (37%) than in locus-C mismatched unrelated patients (67%), and no difference was observed in the fully matched family related and unrelated patients. We conclude that a mismatch in locus C may be detrimental to BMT outcome and should therefore be included as a risk factor in the routine pre-BMT HLA phenotyping.

Adolescent↗
PubMed1996

Enhancement of primary and secondary responses to sheep red blood cells and influenza virus in BALB/c mice by recombinant human interleukin-2.

Treatment with recombinant human IL-2 (rIL-2) is being investigated as a new modality for the control of minimal residual disease in conjunction with autologous bone marrow transplantation for a variety of malignant hematological disorders and certain solid tumors. In investigating the functional role of rIL-2 in T cell dependent humoral immune responses, we determined the level of IgG, IgM, and total antibodies activity in BALB/c mice, with or without rIL-2 administration, before primary or secondary immunization with sheep red blood cells (SRBC) or influenza virus A/PR8/34 (H1N1). Our results show the beneficial effect of pretreatment with rIL-2 in enhancing primary and secondary humoral immune responses to SRBC (p < 0.05) and possibly to influenza virus. Administration of well tolerated doses of rIL-2 before inoculation of antigen or infectious agent is not likely to be harmful and may even enhance protective immunological responses.

Animals↗
PubMed1996

Activated allogeneic cell therapy (allo-ACT) for relapsed chronic myelogenous leukemia (CML) refractory to buffy coat transfusions post-allogeneic bone marrow transplantation.

We describe a 17-year-old male patient with chronic myelogenous leukemia (CML) in hematologic and cytogenetic relapse 4 months post-non-T cell-depleted allogeneic bone marrow transplantation for accelerated CML. Two sequential buffy coat transfusion with donor peripheral blood cells (8.9 and 4.8 x 10(7) cells/kg), the second transfusion in combination with in vivo activation of donor cells by human recombinant interleukin-2 (rIL-2) 6 x 10(6) IU/m2 subcutaneously for 3 days, failed to induce remission . The patient responded to an infusion of donor peripheral blood lymphocytes (3.4 x 10(7) cells/kg) pre-activated in vivo with rIL-2 and additionally activated in vivo with rIL-2, 6 x 10(6) IU/m2/day subcutaneously for 3 days. Elimination of the Philadelphia (Ph) clone was confirmed by cytogenetic analysis showing a normal male karyotype and by disappearance of the bcr/abl transcript, using the polymerase chain reaction (PCR). At present, the patient is 26 months post-treatment with no evidence of disease, but with chronic graft-versus-host disease. Our data indicate that allogeneic activated cell therapy (allo-ACT) may provide antitumor effector cells that successfully induce graft-versus-leukemia (GVL) effects even when cell therapy with donor buffy coats was insufficient.

Adolescent↗