Search PubMed⌕ Search

Biomedical subjects

S Slavin

Publications and source records attributed to S Slavin.

At least 163 records · Page 9Linked to original sources
PubMed1996

Allogeneic cell-mediated immunotherapy using donor lymphocytes for prevention of relapse in patients treated with allogeneic bone marrow transplantation for hematological malignancies.

Two major causes of treatment failure in allogeneic BMT for leukemia are graft versus host disease (GVHD) and leukemic relapse. Acute GVHD, mediated by alloreactive donor T lymphocytes originating from the transfused marrow is the most significant cause of transplant-related morbidity and mortality, despite the use of combined prophylaxis with cyclosporine and methotrexate. Effective prevention of GVHD can be accomplished by depletion of donor immunocompetent T cells from the marrow prior to its infusion. Depletion of lymphocytes, however, prevents the immune mediated interaction of donor T cells against residual host tumor cells--the graft versus leukemia (GVL) effect, which significantly contributes to the curative effect of allogeneic BMT. It is still unsettled to what extent GVH and GVL are unseparable or closely related phenomena, and a major question remains whether it would be possible to retain the beneficial antileukemic effects of donor T cells and at the same time prevent or control the risk of GVHD. We have adopted a policy by which an allogeneic BMT is conducted with T cell depleted marrow to minimize the risk of severe acute GVHD, followed by stepwise administration of fresh unirradiated donor lymphocytes for prevention of leukemic relapse. Our data show that the overall relapse free survival was significantly better for patients receiving preventive posttransplant donor lymphocytes, predominantly when transplant was performed in 1st or 2nd CR.

Adolescent↗
PubMed1995

Elevated inflammatory cytokine levels in bone marrow graft rejection.

Graft rejection and graft failure represent major obstacles in allogeneic bone marrow transplantation (BMT). Cytokines possibly play a central role in the inflammatory and allospecific components of allograft rejection. Therefore, we evaluated inflammatory cytokine levels following BMT in 12 consecutive patients with graft rejection (GR). Seven of the patients underwent BMT from siblings (6 matched and 1 mismatched), 4 patients received bone marrow from other family members (3 mismatched and 1 matched), and 1 patient underwent HLA-matched unrelated BMT. Nine of 12 had a sex-mismatched BMT and 5/12 had an ABO-mismatched BMT. Nine of 12 underwent T cell-depleted (Campath anti-CDw52 moAb) BMT. Rejection was defined as marrow hypoplasia with a peripheral white blood cell count < 0.5 x 10(9)/L 21 days after BMT, in conjunction with the absence of donor cells by polymerase chain reaction analysis using a sex-mismatched probe and/or a tumor-specific probe (BCR/ABL). Twenty-five patients who underwent uneventful BMT with no GR served as controls. The levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1 (IL-1) were evaluated by a high sensitive RIA or an enzyme immunoassay. The levels of TNF and IL-6 were found to be higher in 10/12 and 7/7 evaluated GR patients, respectively, as compared with controls (P < 0.05). The level of IL-1 was high only in 2/12 patients. TNF elevation occurred in all patients immediately after GR. TNF and IL-6 levels were significantly higher for patients with early rejection (< 35 days after BMT) as compared with patients with late rejection (> 35 days after BMT) (P < 0.049 and P < 0.006, respectively). Eight patients engrafted after the second transplant (2 only transient). All 6 patients with stable engraftment are alive (4 with basic disease), while the 4 patients who did not engraft and the 2 patients with only transient engraftment died. In the 6 patients with no engraftment or only transient engraftment, the elevated TNF levels remained high; in the 6 patients who had stable engraftment after retransplant, TNF levels, but not IL-6 levels, decreased. In conclusion, a majority of the patients with GR displayed high levels of inflammatory cytokines (TNF and IL-6). Dysregulation of inflammatory cytokines may be involved in the pathogenesis of GR.

ABO Blood-Group System↗
PubMed1995

Analysis of beta-globin mutations shows stable mixed chimerism in patients with thalassemia after bone marrow transplantation.

Beta-thalassemia major (TM) is caused by any of approximately 150 mutations within the beta-globin gene. To establish the degree of chimerism after bone marrow transplantation (BMT), we have performed molecular analysis of beta-globin mutations in 14 patients with TM over a period of 10 years. All patients underwent T cell-depleted allogeneic BMT from HLA-identical related donors, using either in vitro T-cell depletion with CAMPATH 1M and complement or in vivo depletion using CAMPATH 1G in the bone marrow collection bag. To date, at different time periods after BMT, seven patients have some degree of chimerism; six of these patients, all blood transfusion-independent, have donor cells in the range of 70% to 95%, with stable mixed chimerism (MC). The seventh patient has less than 10% donor cells with, surprisingly, only minimal transfusion requirements. The detection of beta-globin gene point mutation, as used here, is a highly specific and sensitive marker for engraftment and MC in patients with thalassemia. In light of its specificity, the method is applicable in all cases of TM, as it is independent of sex and other non-globin-related DNA markers. The high incidence of MC found in our patients may be a consequence of the pre-BMT T-cell depletion. Because MC was associated with transfusion independence, complete eradication of residual host cells for effective treatment of TM and possibly other genetic diseases may prove not to be essential.

Alleles↗
PubMed1995

Induction of tumor immunity by intact irradiated leukemic B cells (BCL1) bearing a tumor-associated cell-surface idiotype and the costimulatory B7 molecule.

The idioptypic (Id) determinant of immunoglobulin expressed on the cell surface of malignant B cells represents a prototypical tumor-associated antigen (TAA), which has been used in a purified soluble form for active immunization in experimental tumor models and human hematological malignancies. Using a spontaneous transplantable murine model of B cell leukemia/lymphoma (BCL1), we have demonstrated the expression of the B7 costimulatory molecules in addition to the previously described Id determinant and class II major histocompatibility antigens. Intact irradiated BCL1 cells bearing these distinct determinants induced long lasting antitumor immunity in naive syngeneic mice. Induction was dose-dependent and most effective when three doses of 30 x 10(6) intact irradiated BCL1 cells were given at intervals of 7-10 days. The induced immunity protected 96% of 28 mice inoculated with a lethal dose of 10(5)-10(6) nonirradiated BCL1 cells and 85% of 27 mice given a second challenge, whereas control mice died on day 20 after inoculation with 10(6) BCL1 cells. Adoptive transfer of splenocytes derived from immune mice did not induce leukemia in syngeneic recipients. Such splenocytes, harvested more than 365 days following immunization and administered together with fresh BCL1 cells to adoptive recipients, were able to confer protection for 90 days, even following a second challenge given 104 days after the first one. BCL1 immune splenocytes transferred into BCL1-bearing mice exerted a therapeutic effect, preventing leukemia onset for at least 180 days. Our results demonstrate the ability of tumor cells to trigger effective anti-tumor immunity. These findings could ultimately be applied to the prevention of tumor relapse in treatment of hematological and other malignancies expressing TAA, class II MHC antigen and costimulatory molecules.

Animals↗
PubMed1995

Role of interleukin-2 in human hematological malignancies.

Clinical studies with Interleukin-2 (IL-2) in human hematologic malignancies were initiated in the late 1980s. Based on clinical studies on various solid tumors, and laboratory research on hematopoietic cells, IL-2 was shown to be effective in 150 acute myeloid leukemia (AML) patients mainly for maintenance therapy in first complete remission, or with residual blast cells in the marrow. IL-2 has also been shown to be effective in remission induction in 10 patients with chronic myeloid leukemia (CML). The role of IL-2 in lymphoma patients remains to be established. IL-2 alone or in combination with Interferon-alpha, may intensify remission and prolong disease-free survival when given post autologous bone marrow transplantation (BMT) to patients with lymphoma and myeloid leukemia, and to a lesser degree, to patients with acute lymphatic leukemia (ALL). IL-2 in combination with HLA-matched or mismatched peripheral blood lymphocytes was also used post autologous BMT in preliminary studies. IL-2 was administered with or without peripheral blood lymphocytes, for prevention of relapse post T-cell-depleted allogeneic BMT in CML, ALL and AML, with encouraging results. The same strategy was shown to be effective in the reinduction of remission in patients with CML, who relapsed post BMT.

Animals↗
PubMed1995

Successful matched unrelated transplantation from a donor with idiopathic thrombocytopenic purpura (ITP).

The case of a 5 year old male is described who had acute myeloblastic leukaemia (AML M5) and was in third remission when he underwent an allogeneic T cell depleted bone marrow transplantation (BMT). The bone marrow was from an HLA matched unrelated donor (MUD) who suffered from chronic idiopathic thrombocytopenic purpura (ITP). In spite of this, the patient had rapid platelet engraftment post BMT (> 50 x 10(9) l-1 on day 20). He is now 12 months post-transplantation and has normal platelet counts, without any clinical or laboratory evidence of ITP. Autoimmune manifestations such as ITP occurring in bone marrow recipients following BMT have been previously reported. Furthermore, severe and protracted thrombocytopenia is a known complication following MUD transplantation and with its respective high risk of graft versus host disease (GVHD). In this case, no signs of ITP could be detected in the recipient despite the fact that the donor had ITP. Our data suggest that in the absence of an alternative choice, a person with ITP should be considered as an appropriate donor for transplantation.

Adult↗
PubMed1995

A longitudinal follow-up of salivary secretion in bone marrow transplant patients.

Salivary gland dysfunction is a common sequela of the bone marrow transplantation procedure. We determined the effect of different bone marrow transplantation protocols on parotid salivary flow rate. Salivary secretion was substantially reduced during conditioning of all the recipients. A gradual flow rate reconstitution could be detected as soon as a few days after the bone marrow transplantation. Eight patients conditioned with total lymph node irradiation and chemotherapy or chemotherapy alone displayed earlier and complete recovery of saliva secretions 2 to 5 months after the grafting. Recovery was delayed and incomplete when total body irradiation was added to the conditioning regimen (seven patients). Six of these patients also developed graft-versus-host disease. The results suggest that total body irradiation induces irreversible damage to the parotid glands resulting in profound xerostomia followed by opportunistic infections. Chemotherapy with or without total lymph node irradiation does not induce such damage.

Adolescent↗
PubMed1995

Involvement of interleukin-2 in immunologic reconstitution following bone marrow transplantation in mice.

Allogeneic or autologous bone marrow transplantation (BMT) is a curative form of treatment for patients with a variety of hematologic disorders. Impaired immune reconstitution following BMT may seriously impede successful outcome. In this study, the immune function of spleen and thymus was investigated in mice exposed to myeloablative total-body irradiation followed by syngeneic BMT. The T cell mitogen-induced proliferation of both splenic and thymic cells was delayed. Spleen cells started to respond only after 21 days, whereas thymic cells remained unresponsive. Kinetic analysis of surface markers revealed the early appearance of spleen cells with the CD3+CD4-CD8- phenotype, and the thymus, despite a low total number of cells, displayed fast recovery of CD3+CD4+CD8+. At the level of mRNA, a mild decrease in interleukin-2 (IL-2) induction following phytohemagglutinin activation of spleen cells correlated with a decrease in IL-2 secretion for only the first 2 weeks following transplantation. The early restoration of IL-2 implies other avenues for investigation of the immune dysfunction and its correction following syngeneic BMT.

Animals↗
PubMed1995

The response of cord blood megakaryocyte progenitors to IL-3, IL-6 and aplastic canine serum varies with gestational age.

Fetal cord blood (CB) is rich in haemopoietic stem cells and progenitors. We studied the clonogenic, proliferative and maturational responses of megakaryocyte (MK) progenitors in CB, from different gestational ages, to various cytokines: IL-3, IL-6, IL-3 + IL-6, and aplastic canine serum (PICS-J), and compared their responses to those of progenitors in adult peripheral blood (PB) or bone marrow (BM). We found that 34-week gestation CB produced some spontaneous colonies 28 +/- 4.7 CFU-MK in the absence of exogenous cytokines, and produced more CFU-MK and BFU-MK in response to IL-3, IL-6 and IL-3 + IL-6 than the other samples tested. Proliferation of CFU-MK was maximal at 34 weeks and decreased gradually toward term. When compared to adult BM or PB, the CB-derived CFU-MK had increased cellularity and contained significantly more cells undergoing fragmentation into platelet-like particles after stimulation with IL-3 or IL-6. Post-irradiation aplastic canine serum (PICS-J) was a highly potent stimulator of MK progenitors at all developmental stages. Our results indicate that CB MK progenitors are exquisitely sensitive to exogenous cytokines and that the magnitude of their proliferative and maturational responses to cytokines is related to developmental age.

Adult↗
PubMed1995

Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT).

MRL-lpr/lpr mice spontaneously develop a severe autoimmune syndrome, characterized by massive generalized lymphadenopathy, arthritis, arteritis, dermatitis and immune complex-mediated glomerulonephritis. Bone marrow transplantation (BMT) from MHC-matched systemic lupus erythematosus (SLE)-resistant donors to susceptible recipients has proved effective in correcting autoimmune manifestations in autoimmune-prone mice. We investigated the effect of syngeneic BMT from MRL/lpr (donor) to immunocompromised MRL/lpr (recipient), after purging the bone marrow inoculum with MoAbs against mature T cells (anti-Thy 1.2). All the untreated mice developed lymphadenopathy and by the age of 36 weeks five of the eight were dead; in contrast, all the mice which underwent syngeneic BMT following acute immunosuppression with total body irradiation (900 cGy) (TBI) remained disease-free. In an additional experiment, it was found that conditioning with cyclophosphamide (CY) before BMT was more effective than TBI in inhibiting delayed-onset autoimmune manifestations (mean survival 350 days in the CY group and 305 days in the TBI group, versus 197 days in untreated controls). Under both immunosuppressive regimens T cell-depleted bone marrow grafts produced far better results than did unmanipulated BMT. Following syngeneic BMT the incidence of proteinuria and the level of serum anti-DNA (dd) antibodies were significantly reduced, compared with that of the age-matched untreated controls. CY was more effective than TBI in reducing the anti-DNA titres. Likewise, T depletion of bone marrow inocula before BMT induced a more drastic drop in autoantibodies, following both CY and TBI conditioning protocols. After syngeneic BMT (either CY or TBI) no signs of lymphadenopathy were observed even at an advanced age. Upon histopathological examination, the BMT-treated mice displayed normal glomeruli with occasional minimal signs of glomerulonephritis. Syngeneic T cell-depleted BMT following acute cytoreduction of anti-self immune lymphocytes may represent a new therapeutic approach for drug-resistant autoimmune diseases.

Animals↗
PubMed1995

Ketotifen therapy in chronic graft-versus-host disease (cGVHD): effect on mast cells and fibroblasts.

Current treatment options for cGVHD are limited. Mast cells (MC) and fibroblasts have been shown to play a role in the murine model of cGVHD. Ketotifen is an anti-H-1 antihistamine with MC-stabilizing properties. We therefore treated eight patients with cGVHD with ketotifen (6 micrograms/day for 3 months). Three additional age- and sex-matched cGVHD patients served as controls. MC count and activation state in cGVHD skin biopsies and the in vitro effect of peripheral blood mononuclear cell (PBMC) supernatants on (i) histamine release by MC; (ii) 3T3-fibroblast proliferation; and (iii) prostaglandin E2 (PGE2) production, were evaluated. Ketotifen therapy resulted in clinical improvement in 4/8 patients, stabilization of the disease in 2/8, while in 2/8 patients the cGVHD progressed and they died of bacterial sepsis. Side effects were minimal. In the skin biopsies the number of MC was found to be 0.58 +/- 0.17 (n = 8) (field x 400) and the MC looked degranulated (toluidine blue staining). Following ketotifen therapy MC number was increased to 1.2 +/- 0.28 (n = 8) (P < 0.05). PBMC supernatants of cGVHD patients stimulated histamine release from cultured rat MC (n = 8) (2.7 +/- 0.5 micrograms/ml; normal values are 2.1 +/- 0.4 micrograms/ml, n = 5). Ketotifen therapy reduced the histamine release level to the normal range (2.0 +/- 0.5 micrograms/ml, P < 0.05) (n = 8). Ketotifen therapy had no significant effect on: (i) 3T3 fibroblast proliferation which was suppressed by cGVHD PBMC supernatants; (ii) the elevated PGE2 production which we observed when fibroblasts were incubated with the PBMC supernatants. These results indicate that ketotifen may play a therapeutic role in cGVHD.

3T3 Cells↗
PubMed1995

Induction of tolerance to experimental anti-phospholipid syndrome (APS) by syngeneic bone marrow cell transplantation.

Previously, we have shown the ability to induce experimental autoimmune conditions (e.g. SLE, APLS, Wegener's granulomatosis) following active immunization with the pathogenic autoantibody emulsified in adjuvant. The mice first develop anti-autoantibodies (Ab2: anti-id) and eventually generate anti-anti-autoantibodies (Ab3: anti-anti-id) which carry the same antigen binding characteristic as the autoantibody (Ab1). The appearance of the specific autoantibodies in mice sera was associated with the emergence of the compatible laboratory and with the clinical findings characteristic to the respective autoimmune disease. The effects of syngeneic bone marrow transplantation (BMT) on experimental anti-phospholipid syndrome (APS) were investigated. BALB/c mice were immunized with anti-cardiolipin monoclonal antibody (MoAb) named CAM and developed elevated serum titres of anti-phospholipid Abs accompanied by prolonged activated partial thromboplastin time, thrombocytopenia and a high percentage of fetal resorptions. These mice were then lethally irradiated and transfused with bone marrow (BM) cells (T cell depleted) from syngeneic naive mice. The titres of antiphospholipid antibodies were reduced in the recipients. The decrease in titre of autoantibodies was found to be related to depletion of antibody forming cells in vivo, associated with reduced proliferative response of lymph node cells to anti-cardiolipin MoAbs. The recipients showed improvement in clinical parameters following syngeneic BMT. The same recipients developed specific unresponsiveness to a second challenge with the anticardiolipin MoAb (CAM), but developed experimental systemic lupus erythematosus upon immunization with a monoclonal anti-DNA antibody. We conclude that acute myeloablative immunosuppression combined with syngeneic bone marrow transplantation may induce a state of tolerance to the pathogenic autoantibodies in mice with experimental APLS. Our results suggest that a similar approach may be useful in treating life-threatening autoimmune syndromes (e.g. catastrophic APLS) in clinical practice.

Animals↗
PubMed1995

Recombinant human interleukin-6 accelerates in-vitro megakaryocytopoiesis and platelet recovery post autologous peripheral blood stem cell transplantation.

Prolonged thrombocytopenia complicated by bleeding episodes represent a major problem following autologous bone marrow transplantation (ABMT). Recombinant human interleukin-6 (rhIL-6) has been shown to be a maturation factor for both mouse and human megakaryocytes. We administered rhIL-6 to a 43 year old woman who developed marked resistant and prolonged thrombocytopenia with bleeding episodes following autologous peripheral blood stem cell transplantation (APBSCT). Twenty days after the initiation of rhIL-6 therapy, the number of megakaryocyte (MK) progenitors (CFU-MK and BFU-MK) cultured from the peripheral blood increased followed by a moderate increase in the number of bone marrow megakaryocytes. The platelet count increased and the bleeding episodes disappeared. Although spontaneous platelet recovery cannot be ruled out in this case it seems that rhIL-6 may be an important thrombopoietic factor for severe thrombocytopenia following APBSCT.

Adult↗
PubMed1995

Inhibition of leukemic cell proliferation by one or more factors released from splenic BCL1 cells.

Irradiated peripheral blood lymphocytes from patients with chronic B-lymphocytic leukemia (B-CLL) have been shown to secrete a factor or factors that caused inhibition of malignant cell proliferation. In the present study, we used the murine B cell leukemia (BCL1) model system to examine the possible secretion of inhibitory factors from irradiated leukemic spleen cells. It was found that under culture conditions, irradiated spleen cells obtained from leukemic mice produce factors capable of suppressing BCL1 cell proliferation in vitro. The release of an inhibitory factor from nonirradiated cells was also observed, albeit to a lower extent. Supernatants collected from cultured nonirradiated and irradiated cells derived from animals at the first week after BCL1 cell inoculation did not affect the proliferation capacity of cells at any stage of the disease, whereas supernatants obtained at more advanced stages exhibited an inhibitory effect on the proliferation of cells derived from the same stages. The suppressive effect of supernatants of irradiated cells was more pronounced when those of 7 days' culture were used, compared to those of nonirradiated cells. The difference in suppression observed between supernatants of irradiated and nonirradiated BCL1 cells may be attributed either to the same factor produced in a larger amount following irradiation or to two (or more) factors--one produced spontaneously, the other induced by irradiation.

Animals↗
PubMed1995

Ex vivo expansion of megakaryocyte precursors by preincubation of marrow allografts with interleukin-3 and granulocyte-macrophage colony-stimulating factor in vitro.

Protracted thrombocytopenia and bleeding remain serious complications in bone marrow transplantation (BMT). Major progress has been made in facilitating myeloid and erythroid engraftment, but little has been made in accelerating thrombopoiesis post-BMT. We report that in vitro preincubation of T cell-depleted BM allografts with a combination of interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 microgram/mL each) (n = 8), for 3 days prior to infusion, expands megakaryocyte (MK) precursors. MK-progenitor proliferation was assessed in plasma clot colony assays and liquid cultures following pre-exposure to IL-3/GM-CSF. We observed a 2.8-fold increase in the number of colony-forming units-megakaryocyte (CFU-MK) (17.3 +/- 5.2 vs. 6.1 +/- 3.4) (p = 0.001) and a two-fold increase in burst-forming units-megakaryocyte (BFU-MK) (0.2 vs. 0.1) (p = 0.01) per 2 x 10(5) cells/mL compared to control BM samples cultured for 3 days in medium alone. In secondary cultures, the continued presence of IL-3 and GM-CSF increased the number of CFU-MK by 200-fold (p < 0.0001) over controls and by 9.7-fold over fresh BM. A 33-fold increase (p < 0.0001) in the number of BFU-MK was elicited compared to controls. In addition, IL-3 plus GM-CSF supported increased cellularity within the colonies. The presence of IL-3 or GM-CSF alone resulted in fewer MK colonies and fewer cells per colony than both cytokines combined. In liquid cultures, the percentage of cells expressing platelet glycoprotein (GP) IIb/IIIa in the continued presence of IL-3 and GM-CSF increased following preincubation, yielding a total of 16.0 +/- 2.3 x 10(4) MK/2 x 10(6) cells at day 10 of culture. We propose that ex vivo preincubation with IL-3 and GM-CSF can expand the number of MK precursors and may facilitate platelet recovery post-BMT.

Bone Marrow Transplantation↗
PubMed1995

Successful immunization of autologous bone marrow transplantation recipients against hepatitis B virus by active vaccination.

Patients undergoing autologous bone marrow transplantation (BMT) are severely immunosuppressed. These patients are exposed to various infections agents due to delayed and efficient reconstitution of their immune system. Forty-eight patients with hemato-oncological malignancies were immunized against hepatitis B virus (HBV) following autologous BMT. Twenty one were vaccinated more than 10 days before BMT, 17 on days 1-9 before and 10 day after BMT. Thirty three patients (68.7%) seroconverted within 40 days after autologous BMT after receiving one dose of the vaccine before autologous BMT with a relatively low level of anti-HBs, whereas in 11 no anti-HBV antibodies could be detected. Nineteen patients remained seropositive but in 11 the seroconversion was only transient no correlation was found between permanent or transient seroconversion and basic disease, conditioning regimens, post-transplant therapy, immunotherapy and day of vaccination in relation to autologous and day of vaccination in relation to autologous BMT. Active HBV immunization of patients with malignancy undergoing autologous BMT is feasible and levels of antibodies, although low, are above the conventional protective titers. Therefore active immunization of some patients may reduce hepatitis-related complications in the setting of autologous BMT.

Adolescent↗