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S Slavin

Publications and source records attributed to S Slavin.

At least 145 records · Page 8Linked to original sources
PubMed1991

Immune response to polio vaccination in bone marrow transplant recipients.

Following a small outbreak of poliomyelitis which occurred in the summer of 1988 in Israel, two sequential doses of inactivated polio vaccine (IPV) were administered to 42 bone marrow transplant (BMT) recipients (aged 2-50 years) who were 6-96 months (median 16 months) after transplantation. Prior to vaccination, only 68-80% patients (n = 42) had protective (greater than or equal to 4) antibody levels against the three serotypes of poliovirus, compared with 92-96% (n = 25) before BMT (p = 0.02 for types 1 and 3). After the second dose of IPV, 89-98% (n = 27) of the recipients had protective antibody levels. The pre-vaccination antibody titers were lower than before BMT (p = 0.006, 0.0007 and 0.0008 for types 1,2 and 3, respectively). After the first dose of IPV, antibody titers rose in the 42 patients (p = 0.002, 0.043 and 0.002 for types 1, 2 and 3, respectively) and following the second dose, a further increase in antibody levels was noted. Regression analysis revealed that graft-versus-host disease, pre-BMT polio antibody titers, age and type of transplantation (allogeneic versus autologous) were significant explanatory variables for the specific antibody levels, while the time lapse between BMT and vaccination, and primary disease proved of no significance. Vaccination against poliovirus after BMT is advocated, as it reinstates and raises the lost specific humoral immunity.

Adolescent↗
PubMed1991

Effect of exogenous recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor on neutrophil function following allogeneic bone marrow transplantation.

Functional activity of peripheral blood granulocytes was assessed in seven patients and in their normal donors following allogeneic bone marrow transplantation (BMT). Functions studied included superoxide generation (O2-), intracellular killing of Staphylococcus aureus, phagocytosis, and killing of Candida albicans. Neutrophils were tested following preincubation with 300 pM granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.2 nM granulocyte colony-stimulating factor (G-CSF), or buffered solution (diluent) as control. Our data indicate that following BMT, both recipients and their normal donors show GM-CSF- and G-CSF-induced increases in: 1) O2- production in response to fMet-Leu-Phe (fMLP), 2) killing of S. aureus, and 3) phagocytosis of C. albicans. In two patients that showed low candidacidal activity, GM-CSF and G-CSF markedly enhanced the cytotoxic activity of the cells. Our studies indicate that GM-CSF and G-CSF increase "oxygen-dependent" oxidative activities in neutrophils from BMT recipients and their normal donors and enhance the antimicrobial activity of the cells.

Adult↗
PubMed1991

Transient elevation of serum lactic dehydrogenase following autologous bone marrow transplantation.

Transient elevated levels of serum lactic dehydrogenase (LDH) were reported immediately following autologous bone marrow transplantation consecutively in 15 patients. Isoenzyme 2 was the predominant elevated isoenzyme of LDH, suggesting that the source of LDH is either hemolysis of RBCs, which occurs during freezing and thawing of bone marrow in the bags and in vivo following infusion of residual dimethyl sulfoxide.

Adolescent↗
PubMed1991

The effect of in vitro T lymphocyte depletion on generation of IL2-activated cytotoxic cells.

The effect of immunocompetent lymphocyte depletion on precursors and effector cells of IL2 activated non-MHC restricted cytotoxic cells (LAK) generated from bone marrow (BM) or peripheral blood was investigated. Lymphocyte depletion was carried out by using Campath-1, a monoclonal rat anti-human lymphocyte antibody recognizing CDW52, that binds human complement and is used routinely in clinical bone marrow transplantation (BMT). The results indicate that LAK precursors derived from BM cells are sensitive to Campath-1 treatment, while a variable degree of sensitivity was demonstrated in LAK precursor cells derived from peripheral blood. In contrast, effector LAK cells generated in vitro were shown to be resistant to treatment with Campath-1 and complement. We hypothesize that if indeed IL2-dependent non-MHC restricted cytotoxic cells play a role in vivo in the immediate post-BMT period, a T lymphocyte depletion procedure such as the Campath-1 may have the capacity to reduce, at least temporarily, the graft-versus leukemia effects mediated by such anti-tumor effector mechanisms.

Animals↗
PubMed1990

The use of parabiosis for investigating the mechanism of transplantation tolerance in bone marrow chimeras induced by total lymphoid irradiation.

The mechanism of transplantation tolerance in total lymphoid irradiation (TLI)-induced semiallogeneic bone marrow chimeras without clinical evidence of graft-versus-host disease (GVHD) was investigated using the technique of surgical parabiosis. When held in parabiosis with normal BALB/c mice, BALB/c---- (BALB/c x C57BL/6)F1 (BALB----F1) chimeras survived 7-9 days, significantly (P less than 0.001) shorter than the 12-19 day survival of normal F1 hybrids kept in parabiosis with normal BALB, and in contrast to indefinite (greater than 200 days) survival of syngeneic BALB parabiotic partners. When C57 skin grafts were placed on BALB mice held in parabiosis with BALB----F1 chimeras, C57 skin grafts survived 50-60 days, in contrast to 10-14 days in normal BALB recipients (P less than 0.001). Lethal GVHD, induced in sublethally irradiated F1 recipients by 10(7) BALB spleen cells, could not be delayed or prevented by cotransfer of 10(7) to 30 x 10(7) tolerant BALB spleen cells obtained from stable BALB----F1 chimeras. GVHD reactivity of BALB spleen cells isolated from BALB----F1 chimeras tolerant of C57 could not be recovered by depletion of Lyt2 cytotoxic suppressor cells. Taken together, in the absence of suppressive capacity by suppressor cells, these data support functional clonal deletion as the primary mechanism responsible for the maintenance of unresponsiveness to host alloantigens in TLI-induced semiallogeneic chimeras, since no protection against induction of GVHD could be documented in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia.

It is now widely accepted that immunocompetent lymphocytes in allogeneic bone marrow grafts exert an antileukemic effect that contributes to the cure of leukemia. Graft vs leukemia (GVL) effects independent of graft vs host disease were investigated in allogeneic bone marrow chimeras tolerant of host and donor alloantigens. The role of Thy1.2, L3T4 and Lyt2 T lymphocytes as effector cells of GVL were investigated in (BALB/c x C57BL/6)F1 mice inoculated with murine B-cell leukemia and subsequently conditioned with total lymphoid irradiation and cyclophosphamide (200 mg/kg). Mice were reconstituted with C57BL/6 bone marrow cells depleted of well-defined T-cell subsets or enriched for stem cells by the soybean agglutination method. Detection of residual tumor cells, an indicator for efficacy of GVL, was carried out by adoptive transfer of peripheral blood or spleen cells obtained from treated chimeras into secondary naive BALB/c recipients at different time intervals following bone marrow transplantation. Treatment of the primary marrow inoculum with monoclonal anti-Thy1.2 or anti-Lyt2 abolished the GVL effects and all secondary BALB/c recipients developed leukemia within 60 days. On the other hand, the treatment with monoclonal anti-L3T4 did not influence the effect of GVL and all treated recipients remained without leukemia. The data suggest that T cells may mediate GVL effects in the absence of graft vs host disease and in circumstances where tolerance to conventional alloantigens is elicited. Effector cells of GVL across the major histocompatibility complex (MHC) in the murine B-cell leukemia tumor model system appear to be Thy1.2+ Lyt2+ L3T4-. Induction of GVL effects by allogeneic cells tolerant of host MHC suggests that these effects may be independent of graft vs host disease.

Agglutinins↗
PubMed1990

Interstitial pneumonitis after total body irradiation: effect of partial lung shielding.

The potential beneficial effects of partial lung shielding were investigated in 44 patients conditioned by whole body radiotherapy as part of the conditioning for bone marrow transplantation (BMT). The first 23 patients were irradiated with fractionated total body irradiation (TBI) to a total dose of 12 Gy. In the second series of 21 patients a 50% transmission lung shield was utilized following 6 Gy TBI. This treatment was combined in the second group with four fractions of 1.5 Gy total lymphoid irradiation (TLI), given in 2 d. The rate of idiopathic interstitial pneumonitis (IP) was 26% in the first group, compared to none in the second.

Adolescent↗
PubMed1990

Effect of cyclosporine A and methylprednisolone on the graft-versus-leukemia effects across major histocompatibility barriers in mice following allogeneic bone marrow transplantation.

The effect of post-transplant immunosuppressive agents used in anti-GVHD prophylaxis on leukemic relapse was tested using a murine model of originally spontaneous, subsequently transplantable and non-immunogenic B cell leukemia (BCL1). (BALB/c x C57BL/6)F1 mice inoculated with 10(7) BCL1 cells were conditioned by total lymphoid irradiation (TLI) (1600 cGy), cyclophosphamide (200 mg/kg) or total body irradiation (TBI) 750 cGy and reconstituted with C57BL/6 (C57) bone marrow cells (30 x 10(6] or 10 x 10(6) bone marrow cells with additional 2 x 10(6) donor-type spleen cells, respectively. Mice were treated by cyclosporine A (CSA) 20 mg/kg i.p., or methylprednisolone (MP) 10 mg/kg i.p. for 10 days each and one group of controls received no post-transplant therapy. Stable chimerism was documented in all recipients with greater than or equal to 90% donor-type C57 cells in the peripheral blood. Eighty-nine percent of the mice treated by CSA following conditioning with TLI developed leukemia within 70 days, whereas none of the MP-treated mice and none of untreated chimeras showed any evidence of leukemia for more than 150 days. Adoptive transfer experiments using 10(5) spleen cells obtained from recipients conditioned with TBI were done to monitor residual leukemic cells following different post-transplant treatments. Eight-five percent of recipients of spleen cells obtained from mice treated with CSA developed leukemia in contrast with 33% and 25% when spleen cells were obtained from mice treated with MP or untreated controls, respectively (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The use of recombinant cytokines for enhancing immunohematopoietic reconstitution following bone marrow transplantation. II. The influence of lymphokines on CFU-GM colonies from human untreated, ASTA-Z or Campath-1M treated bone marrow.

Patients undergoing bone marrow transplantation (BMT) are subjected to the risk of pancytopenia in the immediate post-BMT period. Recipients of bone marrow (BM) autografts purged in vitro by chemical agents such as mafosfamide (ASTA-Z) are even more likely to develop a delayed engraftment. In a previous study in mice, we showed earlier immunohematopoietic reconstitution after syngeneic marrow grafting with BM cells precultured with single or combined cytokines. In this work we determined optimal culture conditions for the use of single and various cytokine combinations in order to activate progenitor cells following in vitro cultures of untreated, ASTA-Z purged or T cell-depleted human BM preparations prior to BMT. The best single cytokine for enhancing CFU-GM was found to be GM-CSF (0.1 mg/ml) which produced an increase of up to 8-fold over controls after 3 days' incubation. Addition of recombinant human interleukin 3 (rhIL3) (0.1 mg/ml) to rhGM-CSF had an additive effect. The same enhancing effect of in vitro CFU-GM by both cytokines was observed following ASTA-Z purging of BM cells obtained from patients undergoing autologous BMT. Similarly, depletion of lymphocytes from BM using the monoclonal rat anti-human lymphocyte antibody Campath-1M and human complement did not diminish the beneficial influence of rhIL3 and rhGM-CSF. When combined with rhGM-CSF and rhIL3, rhIL1 and rhIL2 had no appreciable enhancing effect on CFU-GM and occasionally even reduced it. We suggest that enhancement of differentiation of hematopoietic progenitor cells may be accomplished by in vitro incubation of BM cells without continuous administration of cytokines in vivo following BMT.

Antineoplastic Agents↗
PubMed1990

The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD?

Graft-versus-leukemia (GVL) is a major component of the overall beneficial effects of allogeneic bone marrow transplantation (BMT) in the treatment of leukemia. Although several clinical trials have suggested a direct relationship between GVL effects and acute and chronic graft-versus-host disease (GVHD), it is not yet known whether GVL can be separated from GVHD. However, several investigations in murine models of human leukemia indicate that the two may be at least partially separable. Moreover, analysis of clinical data from the International Bone Marrow Transplant Registry suggest that allogeneic BMT may be more advantageous than syngeneic BMT, regardless of the GVHD. Likewise, T lymphocyte depletion is associated with an increased incidence of relapse, independently of GVHD. Recent investigations in murine leukemia suggest that GVL-like effects may be inducible following syngeneic BMT by recombinant cytokines with no overt GVHD. Taken together, current data in experimental animals and man suggest that GVL may be at least partially separable from GVHD. Hence, further understanding of effector and target cells of GVL as well as our ability to induce antitumor effector cells, especially those that are MHC nonrestricted, may lead to new approaches for potentiating anti-tumor effector mechanisms without inducing severe, clinically overt GVHD. Successful attempts in these directions may also lead to improved results following autologous BMT as a result of activation of GVL-like effects by recombinant cytokines that are capable of activating effector cells with anti-leukemic activity in vivo, such as recombinant human IL2, alpha interferon or perhaps a synergistic combination of factors.

Animals↗
PubMed1990

Lectin-binding properties of Burkitt's lymphoma cell lines: application to bone marrow purging.

The efficacy of binding of several lectins to different Burkitt's lymphoma (BL) cell lines was investigated. Soybean agglutinin (SBA), peanut agglutinin (PNA), wheat germ agglutinin (WGA), and Sambucus nigra agglutinin (SNA) bound strongly to all BL cell lines. Because SBA has been used safely in clinical bone marrow transplantation (BMT) as part of the procedure for T-cell depletion and hence does not bind to the stem cells, we chose this lectin to establish a model for purging BL cells from human bone marrow. Using a two-step purging procedure with tumor cell agglutination by SBA in solution, a 2-log depletion could be accomplished. Using SBA-coated magnetic beads, we could improve BL cell depletion to greater than 4 logs. Because SBA seems to have a broad specificity for BL cells with concomitant enrichment in hematopoietic progenitor cells, the use of SBA-coated magnetic beads could be of interest for autologous BMT for lymphomas as well as other hematological malignancies and solid tumors with positive binding to SBA.

Agglutination↗
PubMed1990

Immunotherapy in conjunction with autologous bone marrow transplantation.

Although high-dose chemoradiotherapy used for conditioning prior to autologous bone marrow transplantation (BMT) represent an effective tool for eradication of certain malignant hematological disorders, relapses indicate that the last tumor cell is unlikely to be completely eradicated. We are investigating several approaches for controlling residual tumor cells escaping from chemoradiotherapy by cellular adoptive immunotherapy and amplification of natural defense mechanisms, using recombinant human IL2 (Cetus, Emeryville CA), in a murine model of leukemia/lymphoma disease (BCL1).

Animals↗
PubMed1990

IL-2 activated cell-mediated immunotherapy: control of minimal residual disease in malignant disorders by allogeneic lymphocytes and IL-2.

The present experiments were designed to investigate whether it might be possible to combine their therapeutic benefits of autologous BMT and allogeneic BMT following administration of T-lymphocyte depleted marrow allografts with additional immunotherapy following BMT. The tumor model used for investigating graft vs leukemia (GVL) effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. Immunotherapy with high dose recombinant human interleukin-2 (IL2) (10(5) Cetus units x 3/day intraperitoneally (IP) for 5 days) produced significant anti-tumor effects in BCL1-bearing mice. BALB/c mice inoculated with 10(3) BCL1 leukemia cells received were treated on day -1 with cyclophosphamide 100 mg/kg and transplanted with normal syngenic BM cells on day 0. High-dose IL2 (100,000 Cetus Units x 3/day IP x 5 consecutive days) was initiated on day +1, +7, or +21 following BMT. Optimal time for administration of IL2 was noted at 3 weeks post-BMT with 90% of the mice surviving with no evidence of disease greater than 1 year. An experimental model designed to study GVL effects in a state of minimal residual disease following T-cell depleted allogeneic BMT indicated that mice receiving low dose of BCL1 challenge (10(4] were successfully treated by either IL2 (2 x 10(4) Cetus units x 2/day IP x 3 days), allogeneic spleen cells (10(6) on day +1, 10(7) on day +5 and 5 x 10(7) on day +9) alone and certainly following a combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Selective abrogation of alloreactivity via priming in the presence of aphidicolin, a specific inhibitor of DNA polymerase.

Aphidicolin, a specific and direct inhibitor of eukaryotic DNA polymerase alpha, was used to investigate its impact on immunologic reactions in vitro. Dose response curve of the inhibitory effect was studied in murine and human primary allogeneic responses, as well as the proliferative responses to both PHA and Con A mitogens. The presence of aphidicolin during the allosensitization phase in secondary MLR of mice splenocytes resulted in complete abolishment of the subsequent response directed against the priming alloantigens, whereas alloreactivity to unrelated alloantigen-bearing cells was inhibited to a much lesser degree. The allosensitized aphidicolin-treated cells lost the ability to respond to subsequent PHA stimulation, but were capable of exerting a high responsiveness to Con A. The presence of aphidicolin during the allosensitization phase in secondary MLR of human mononuclear cells resulted in markedly decreased alloreactivity directed against the priming cells, but spared the subsequent response to unrelated alloantigens and to both PHA and Con A mitogenic stimuli. It is suggested that aphidicolin may be used for selective inactivation of proliferating cells without interfering with immunologic functions of other quiescent subsets. Aphidicolin may thus be a useful agent for induction of specific unresponsiveness in experimental models of allogeneic transplantation.

Animals↗
PubMed1989

Prognosis following local or regional recurrence after conservative surgery and radiotherapy for early stage breast carcinoma.

Factors which influence patient prognosis following a breast recurrence or regional nodal recurrence after initial treatment of early-stage invasive breast carcinoma with conservative surgery and radiotherapy are not well known. Ninety patients treated at the Joint Center for Radiation Therapy treated from 1968-1981 had a recurrence in the treated breast before (84) or simultaneous with (6) distant metastases. Sixty-five patients had salvage mastectomy (median subsequent follow-up in patients without further disease, 32 months; range, 1-123 months). The five-year rate of further recurrence in this group was 37%. The most important variable associated with subsequent outcome was the histology of the recurrent tumor. There were no further recurrences among 10 patients with purely non-invasive cancer or 10 patients with predominantly non-invasive disease and only focal areas of invasion. In contrast, 17/45 patients (38%) with predominantly infiltrating tumors suffered further local-regional recurrences (6) or distant metastases (11) following mastectomy (5-year actuarial rate, 55%) (p less than 0.05). Ten patients developed regional nodal failures without evidence of simultaneous breast recurrence (1 internal mammary, 3 supraclavicular, 1 both supraclavicular and axillary, and 5 axillary). Only 3 of these 10 (all with axillary node failures) did not have simultaneous distant metastases; they remain alive without evidence of further distant or local-regional recurrence following salvage treatment 1, 59, and 87 months after recurrence. We conclude that the great majority of the patients (88% in this series) who have a breast recurrence following initial conservative surgery and radiation therapy for early stage breast carcinoma will have disease limited to the breast clinically and tumors amenable to salvage mastectomy. Salvage mastectomy appears to be effective treatment for patients with an isolated breast recurrence, especially if the recurrence is predominantly or wholly non-invasive.

Adult↗