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S Slavin

Publications and source records attributed to S Slavin.

At least 73 records · Page 4Linked to original sources
PubMed1999

Multiformic modulation of endotoxin effects by linomide.

Linomide is a potent immunomodulator that either enhances or suppresses certain immunological processes. Of particular interest is this compound's capacity to inhibit a variety of organ-specific autoimmune diseases. Here, we report on the effects of linomide on several immunological reactions elicited by endotoxin (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease that develops within 24 h following footpad injection of LPS. Linomide also inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse macrophage monolayers. On the other hand, treatment with linomide significantly increased the levels of IL-1beta (mice and less in rats), IL-6 (rats), and TNF-alpha (mice) in serum samples collected 2 h following injection with LPS. The increased production of proinflammatory cytokines in linomide-treated mice was also indicated by the enhanced lethal effect of LPS in these mice. The finding of elevated levels of these cytokines in animals with suppressed EIU is also in line with previous observations of an inverse relationship between EIU severity and levels of TNF-alpha. Data recorded here underscore the unique capacity of linomide to both enhance and suppress the immune system.

Adjuvants, Immunologic↗
PubMed1999

The use of soybean agglutinin (SBA) for bone marrow (BM) purging and hematopoietic progenitor cell enrichment in clinical bone-marrow transplantation.

Soybean agglutin (SBA) is a plant lectin that has been used to fractionate bone marrow cells. It binds bone marrow mononuclear cells, including mature myeloid, erythroid, and lymphoid cells, but has very low binding affinity and no toxic effect to the human hematopoietic cells. In this article we describe the possibilities of enriching bone-marrow-derived CD34+ hematopoietic progenitor cells using SBA. As the method is simple and elegant. SBA is of vast importance to the field of clinical bone marrow transplantation.

Adult↗
PubMed1999

The role of thiotepa in allogeneic stem cell transplantation in patients with leukemia.

Graft versus host disease (GVHD) and recurrence of basic disease are major obstacles to a successful allogeneic bone marrow transplantation (BMT) outcome. One of the possibilities of maintaining the therapeutic potential of marrow allografting in the absence of GVHD is to intensify the conditioning regimen administered pre-T-cell depleted BMT in order to compensate for the loss of GVH related graft versus leukemia (GVL) effect. In order to do so we used a preparative regimen consisting of three alkylating agents-Busulfan (BU), Thiotepa (TTP) and Cyclophosphamide (CY)-for T-cell depleted allogeneic stem cell transplantation (SCT) instead of the standard BU-CY protocol. The effect of this intensified regimen was investigated in 30 consecutive leukemia patients who underwent T-cell depleted SCT from HLA identical siblings. Sixteen of the patients were males and 14 females, of median age 24 (5-43) years. Fourteen patients had acute myelogenous leukemia (AML), ten acute lymphoblastic leukemia (ALL), four chronic myelogenous leukemia (CML) and two myelodysplastic syndrome. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was normal, with WBC >1.0x10(9)/l at day +18 (10-32), ANC >0.5x10(9)/l at day +21 (9-33) and platelets >25x10(9)/l at day +30 (14-69). Regimen related toxicity (RRT) was moderate and transplant related complications comparable to other conventional conditioning protocols. Overall survival and disease free survival (DFS) at 60 months follow up was 50%. Only three patients (10%), with ALL, relapsed and subsequently died. From the current data it would appear that TTP does not significantly improve BMT outcome in patients with leukemia, when compared to the standard BU-CY conditioning. However, our results with the BU-TTP-CY combination followed by T-cell depleted allogeneic SCT could provide the basis for a prospective randomized study comparing this protocol with the standard BU-CY regimen.

Adolescent↗
PubMed1999

Allogeneic cell-mediated immunotherapy for eradication of minimal residual disease: comparison of T-cell and IL-2 activated killer (LAK) cell-mediated adoptive immunotherapy in murine models.

In the course of allogeneic bone marrow transplantation (BMT), avoiding graft-versus-host disease (GVHD) while retaining the antileukemic effects of the T cells remains a major challenge. T-cell depletion (TCD) reduces the incidence of GVHD but increases the relapse rate after allogeneic BMT. We attempted to develop a regimen that would retain or increase the graft-versus-leukemia effect induced by donor T cells while preventing GVHD. Immunosuppressed mice were given immunocompetent donor cells, i.e., fresh lymphocytes or lymphokine-activated killer (LAK) cells differing from the host in major (MHC) or minor (MiHC) histocompatibility antigens. Engraftment of donor cells was documented by polymerase chain reaction analysis. Administration of MHC- and MiHC-incompatible allogeneic LAK cells, especially in conjunction with recombinant interleukin-2 (rIL-2), increased disease manifestations and mortality associated with GVHD. On the other hand, irradiated LAK cells or TCD-LAK cells prevented GVHD in both mice models studied. Phenotypic analysis of LAK cells demonstrated that CD8(+)-equivalent (Lyt-2) T cells are of significance in aggravation of GVHD. The in vitro cytotoxic capacity of LAK cells against MHC-nonrestricted target cells was not reduced by either irradiation or TCD. These results provide the background for designing improved protocols for immunotherapy of residual disease after BMT. In addition, the data imply that antitumor effects may be retained by irradiated rIL-2-activated allogeneic cells without causing GVHD. Whereas unmodified allogeneic LAK cells can induce more effective graft-versus-leukemia effects at the cost of GVHD, irradiated allogeneic donor LAK cells might play some role in eradication of minimal residual disease following autologous or allogeneic BMT without causing GVHD.

Animals↗
PubMed1999

Differential effects of CD4+ and CD8+ cells on lymphocyte development from human cord blood cells in murine fetal thymus explants.

The possibility that mature lymphocytes play a role in the regulation of human T cell development was studied in the experimental model of fetal thymus organ cultures (FTOC), by reconstituting lymphocyte-depleted murine fetal thymus (FT) lobe with cells isolated from human umbilical cord blood (CB). Cultures were incubated with human cytokines (IL-7, FLT-3 ligand and Steel Factor), or remained untreated. When CD4+, or CD8+ CB cells, were co-cultured with FT explants, they expanded and maintained their original phenotypic markers, with no significant effect of the cytokines. Cultures of human hematopoietic stem cells (CD34+) gave rise to CD4+CD8- cells, which were mainly CD3-, with no indication of further intermediate developmental stages. However, a limited number of CD4+CD8+ (double positive [DP]) cells were detected when the CD34- cells were co-cultured with CD4+ cells from the same CB samples. In contrast, FT with unseparated CB cells resulted in the different CD4/CD8 subsets, and their numbers increased in the presence of cytokines. The appearance of DP cells depended on the presence of either CD4+ or CD8+ cells in the cultured CB samples. Hence, DP cells were not detected when the CB was depleted of CD4+ and CD8- cells ("depCB") before culture, and they appeared when depCB were co-cultured with either CD4+ or CD8+ cells. In contrast, CD4+ cells inhibited the development of CD8+CD3+ cells, and this was most pronounced in the absence of the cytokines. There was no symmetrical down-regulatory effect of CD8+ cells on the development of CD4+CD3+ cells. Addition of IL-15 to the cytokine mixture led to an increased proportion of CD56+ cells in cultures of CD34+ cells. The presence of CD4+, and not CD8+ cells, interfered with this process. Our results thus imply differential effects of CD4+ and CD8+ cells on thymocytopoiesis.

ADP-ribosyl Cyclase↗
PubMed1999

Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies.

We have analyzed the factors associated with engraftment in 216 recipients of T-cell depleted allogeneic HLA identical sibling marrow transplants using Campath 1 monoclonal antihuman lymphocyte (CD52) antibodies. The patient population consisted of 168 patients with hematologic malignancies, 26 with severe aplastic anemia (SAA), and 22 with hemoglobinopathies, half of whom received marrow treated in vitro with Campath-1M (IgM) and half received marrow with Campath-1G (IgG2b isotype). Patients with durable engraftment had fast hematopoietic recovery: SAA patients reached ANC > 0.5 x 10(6)/L on Day 14; those with leukemia attained ANC > 0.5 x 10(6)/L on Days 18, 17, and 15 for ANLL, ALL and CML respectively, while patients with thalasemia reached ANC > 0.5 x 10(6)/L on Day 21. Overall, 24 patients (17 with leukemia, 4 with SAA, and 3 with thalassemia) suffered graft failure: 10 patients (all grafted with Campath-1M) rejected their grafts, while 14 others (9 grafted with Campath-1M, and 5 with 1G isotype) never engrafted (p = 0.009). Multivariate analysis revealed that neither pretransplant protocol, nor stage of disease or type of antibody used, donor sex and ABO match had any impact on engraftment. The variables favorably associated with engraftment were older age (p = 0.030, RR = 1.016) and CFU-GM number (p = 0.013, RR = 1.001). Patients with ANLL or SAA had a better chance to engraft (p = 0.027, RR = 1.400; and p = 0.003, RR = 2.677, respectively) compared to patients with thalassemia (p = 0.001, RR = 0.551). A higher concentration of Campath-1 antibody in vitro and in vivo adversely affected engraftment. Our data show that satisfactory engraftment can be achieved in patients transplanted with Campath-1 treated marrow allografts. However, despite the measures undertaken to prevent rejection, graft failure still poses a problem. Further pretransplant immunosuppression and perhaps more selective T-cell depletion may reduce the increased graft failure in these patients.

ABO Blood-Group System↗
PubMed1999

Nonmyeloablative conditioning to induce bilateral tolerance after allogeneic bone marrow transplantation in mice.

We recently described a new nonmyeloablative method to induce stable and specific transplantation tolerance to allogeneic tissues in adult mice. It included total lymphoid irradiation (TLI) of recipients with six fractions of 200 cGy each, inoculation with donor bone marrow (BM) cells and cyclophosphamide (Cy) for selective elimination or inactivation of residual donor-reactive cells of the host, and infusion with T-cell depleted donor BM cells after Cy. Here, we investigated the possibility to induce stable bilateral graft-vs-host and host-vs-graft transplantation tolerance using non-T-cell depleted allogeneic BM. Our results show that the dose of BM required for the induction of transplantation tolerance was inversely correlated with the intensity of the conditioning. Transfer of a low dose (3 x 10(6)) of total donor BM cells to recipients preconditioned with a less intensive regimen (two or three TLI fractions instead of six) diminished graft-vs-host disease (GVHD)-related mortality of recipients to 40% and converted 89% of the survivors into GVHD-free mixed hematopoietic chimeras that maintained donor skin allografts >180 days. A tenfold increase in the number of donor BM cells (3 x 10(7) instead of 3 x 10(6)) reduced the rate of GVHD-related mortality of recipients to 20% and resulted in bilateral transplantation tolerance in 100% of nonirradiated survivors.

Animals↗
PubMed1999

The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases.

Graft-versus-host disease (GVHD), graft rejection, disease recurrence and long-term toxicity remain significant obstacles to successful allogeneic bone marrow transplantation (BMT) in children with genetic diseases. In an attempt to improve results, we used a preparative regimen consisting of three alkylating agents, busulfan (BU), thiotepa (TTP) and cyclophosphamide (CY), for T cell-depleted allogeneic bone marrow transplantation instead of the conventional BU-CY protocol. The effect of this intensified regimen was investigated in 26 consecutive children with genetic diseases who underwent T cell-depleted BMT from HLA-identical siblings. Sixteen patients were males and 10 females, of median age 5 (0.2-14) years. The diseases included beta-thalassemia major, osteopetrosis, severe combined immunodeficiency, Wiskott-Aldrich syndrome, familial agranulocytosis, congenital idiopathic hemolytic anemia (CIHA), Gaucher's disease, Niemann-Pick disease, Hurler's syndrome, and adrenoleukodystrophy. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was as expected, with WBC >1.0 x 10(9)/l at day +19 (10-33), ANC >0.5 x 10(9)/l at day +22 (10-56) and platelets >25 x 10(9)/l at day +32 (18-131). Transplant-related mortality was 19%. Overall survival and disease-free survival (DFS) at 60 months follow-up were both 77%. Our results with the BU-TTP-CY regimen followed by T cell-depleted BMT in genetic diseases may provide a basis for prospective comparison with the standard conditioning regimen of BU-CY in the management of children suffering from these conditions.

Adolescent↗
PubMed1999

Prevention and treatment of graft-versus-host disease by down-regulation of anti-host reactivity with veto cells of host origin.

Control of graft-versus-host disease (GVHD) post allogeneic spleen cell transplantation was partly achieved by administration of host-type lymphocytes. (C57BL/6 x BALB/c) F1 mice were conditioned by total body irradiation and transplanted with parental C57BL/6 spleen cells to induce severe GVHD. Infusion of mature host-type lymphocytes did not change the degree of chimerism but protected most of the recipients from lethal GVHD. Treatment of host-type blood cells with anti-CD8 antibodies resulted in loss of the GVHD protective effects mediated by host cells, whereas after treatment of the host with anti-CD4 antibodies protective host cells given 4 days after induction of GVHD resulted in successful rescue of all transplanted recipients from lethal GVHD. Administration of host blood cells could effectively protect against GVHD induced by donor spleen cells and low-dose rIL-2. GVHD protection resulted from down-regulation of alloreactive donor T cells and not by rejection of GVHD effector cells. Taken together, administration of host hematopoietic cells particularly host CD8+ T cells, may be considered for prevention or control of GVHD following allogeneic bone marrow transplantation, thus also explaining the increased resistance of mixed chimeras to GVHD.

Animals↗
PubMed1999

Donor lymphocyte infusion post-non-myeloablative allogeneic peripheral blood stem cell transplantation for chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease symptomized by failure to generate superoxide and recurrent bacterial and fungal infections. Allogeneic bone marrow transplantation (BMT) is one of the therapeutic options available. However, it presents considerable risk to the recipient, especially if the patient is already at an advanced stage of disease, after repeated bacterial and fungal infections and organ damage. We present a case report of a 6-year-old child with long-standing CGD, severe clubbing, and jeopardized pulmonary function after multiple bacterial pulmonary infectious episodes, who had failed treatment with sulphamethazole trimethoprim, multiple antibiotic courses, itraconazole, as well as steroid and interferon-y therapy. He underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from his HLA-matched MLC non-reactive sister following non-myeloablative conditioning. His ANC did not fall below 0.2 x 10(9)/l, his lowest WBC was 0.6 x 10(9)/l, and his platelets did not fall below 28 x 10(9)/l. He had normal engraftment, with no mucositis or organ toxicity. Neither parenteral nutrition nor platelet infusions were necessary. Partial donor chimerism following alloPBSCT was converted to full donor chimerism and superoxide production reverted to normal after donor lymphocyte infusions (DLI) from his HLA-matched sister. Twenty four months post transplant the patient is well, with stable and durable engraftment, 100% donor chimerism, normal superoxide production, no GVHD, and stabilization of his pulmonary condition. We suggest that alloPBSCT preceded by non-myeloablative conditioning and followed by DLI may constitute a successful mode of therapy for patients suffering from advanced CGD with recurrent infectious episodes resulting in organ dysfunction, enabling them to achieve full donor chimerism and normal superoxide production with minimal risk of transplant-related toxicity and GVHD.

Child↗
PubMed1999

Enhancement of hematopoietic reconstitution with recombinant cytokines: effect of rhIL-6 in combination with rhGM-CSF and rhIL-3 on unmodified or T cell-depleted bone marrow.

We have investigated the response of unmanipulated and lymphocyte-depleted BM cells (BMC), pretreated with monoclonal rat antihuman lymphocyte (CD52) antibody (Campath-1G) used for prevention of GvHD, to incubation with rhIL-6 alone or in combination with rhGM-CSF, rhIL-3, or both. We investigated optimal conditions needed for incubation of human BMC under conditions that can be upscaled for clinical application prior to autologous (auto-BMT) and allogeneic blood or BM transplantation (allo-BMT). When used as a single agent, rhIL-6 showed no or a minimal effect in enhancing in vitro CFU-GM colony formation of human BMC. A potent additive effect was obtained when rhIL-6 was added to rhGM-CSF, rhIL-3, or a combination of both. Binding of the mAb Campath-1G, which is used for in vivo and in vitro depletion of immunocompetent lymphocytes to BMC, did not reduce the enhancing effect of a combination of rhGM-CSF and rhIL-3 on CFU-GM in the presence or absence of rhIL-6. Our present and previously published observations suggest that enhancement of hematopoiesis by rhIL-6 and other hematopoietic growth factors is T cell independent. Based on the present observations, pilot clinical studies to determine the potential benefit of in vitro activation of BMC prior to BMT with various cytokine combinations, including rhIL-6, seems justified. Our goal is to enhance hematopoietic reconstitution in vivo, focusing on possible enhancement of platelet reconstitution in vivo toward safer auto-BMT and more effective allo-BMT with better engraftment of T cell-depleted allografts while avoiding GvHD.

Alemtuzumab↗
PubMed1999

Activation of the recombination activating gene 1 (RAG-1) transcript in bone marrow of senescent C57BL/6 mice by recombinant interleukin-7.

The level of the recombination activating gene 1 (RAG-1) mRNA in bone marrow cells decreases to a minimal level by the age of 10 months. Recominbant interleukin-7 (rIL-7) is a potent proliferative stimulus for B cell progenitors and upregulates RAG-1 expression in lymphocyte precursors. To investigate the stimulatory effect of rIL-7 on the expression of RAG-1 in old mice, we compared the level of RAG-1 message in short-term bone marrow cultures of cells from mice aged 1 month and 18 months. We found similar levels of RAG-1 mRNA in bone marrow cells of young mice before and after 24 hours of incubation. No RAG-1 mRNA was detected in bone marrow cell cultures prepared from old mice after 24 hours of incubation. However, when rIL-7 was added to the culture medium, RAG-1 mRNA was detected after 24 hours of incubation and its level was similar to that measured in cells from young mice. The expression of RAG-1 was dose-dependent, with 20 ng of rIL-7 per 10(6) old nucleated cells yielding the maximal response. Our results indicate that despite the low or no RAG-1 expression in bone marrow cultures of old mice, the potential to activate RAG-1 in B-cell precursors is still present, and immunoglobulin heavy chain (V(H)D(H)J(H)) rearrangement may be enhanced by rIL7.

Aging↗
PubMed1999

Graft-versus-lymphoma effect after allogeneic peripheral blood stem cell transplantation for primary central nervous system lymphoma.

Allogeneic peripheral blood stem cell transplantation (allo PBSCT) is a recognized treatment modality for hematological malignancies resistant to conventional chemoradiotherapy. The post-transplant immune-mediated graft-versus-leukemia effect has major curative potential. In this case presentation, the allogeneic approach to resistant recurrent primary central nervous system (CNS) lymphoma using peripheral blood stem cells from an HLA identical sibling after immuno-suppressive non-myeloablative conditioning, was examined clinically. The patient in question had relapsing refractory primary CNS lymphoma and is the first to be treated with this modality. She developed early skin and liver-localized grade II graft-versus-host disease after allo PBSCT, which then responded to short-term treatment. Chimeric studies at the time showed 100% donor cells and repeated magnetic resonance imaging of the brain revealed gradual shrinkage of the tumor. Three months after transplant the cerebral mass was no longer evident and currently, 30 months after transplantation, the patient continues to be disease free. The absence of any signs of malignancy suggests the development of a durable graft-versus-lymphoma effect in this brain tumor and indicates that this effect may be achieved even after non-myeloablative conditioning.

Adult↗
PubMed1999

The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice.

The aim of this study was to ascertain the potential usefulness of the antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for "prevention" experiments; and (b) 2-3-mm fragments allowed to grow to 1 cm for "intervention" studies. Both groups received either 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention and intervention experiments, a significant diminution of tumor size and weight was observed in the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor blood flow in linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of tumors from linomide-treated animals revealed marked avascularity. Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels. Taken together, our data indicate that in VHL disease, therapy directed at inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.

Administration, Oral↗
PubMed1999

Revising the unsatisfactory breast augmentation.

Revising an unsatisfactory result after breast augmentation requires a thorough understanding of the cause of the abnormality to develop a rational and effective treatment plan to achieve the best possible result. Often, more than one manipulation is required to correct the deformity. Using the techniques presented here, successful revision can be performed in the vast majority of cases.

Adult↗
PubMed1999

Allogeneic cell therapy in murine B-cell leukemia (BCL1): 1. Alloimmune-mediated graft-versus-leukemia (GVL) effects induced by unmodified and in vitro rIL-2-activated bone marrow and lymphocytes from different lymphoid compartments.

We have investigated the efficacy of graft-versus-leukemia (GVL) effects induced by cells obtained from different syngeneic and allogeneic lymphoid compartments, by comparing the response to cell therapy with syngeneic (BALB/c x C57BL/6)F1 (H-2d/b) (F1) or allogeneic C57BL/6 (H-2b) (B6) lymphocytes in F1 recipients inoculated with B-cell leukemia (BCL1) of BALB/c (H-2d) origin. Eradication of BCL1 was confirmed in vivo by adoptive transfer of 10(5) spleen cells obtained from treated mice into syngeneic BALB/c recipients. Immunotherapy induced by allogeneic but not syngeneic spleen and lymph node lymphocytes was therapeutically more effective than thymocytes and bone marrow cells (BMC). Alloreactive cells could be further activated in vivo with recombinant human interleukin-2 (rIL-2). The GVL effect of allogeneic lymphocytes was cell-dose-dependent; a heavy leukemia load was more efficiently eradicated after three doses than after a single dose of allogeneic spleen cells (100% versus 23% disease-free survival rate of secondary adoptive recipients respectively). The GVL effect induced by allogeneic spleen cells was preserved after ex vivo exposure of cells to 250 cGy, but not 500 cGy or more. Interestingly, GVL was preserved following administration of ex vivo irradiated (500 cGy) spleen cells when rIL-2 was administered in vivo (p < 0.05). Syngeneic effector cells did not induce GVL, regardless of in vitro and in vivo activation with rIL-2. Our data suggest that allogeneic but not syngeneic (in analogy to autologous) cell therapy may be an effective tool to control residual leukemia following high-dose chemo-radiotherapy. The feasibility of augmenting GVL by successive doses of activated allogeneic donor lymphocytes, partly inactivated in vitro by low-dose ionizing irradiation to prevent severe graft-versus-host disease (GVHD), may lead to safer therapeutic approaches that can be used to reduce the incidence of relapse while avoiding the risk of uncontrolled GVHD.

Animals↗