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S Slavin

Publications and source records attributed to S Slavin.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1989

Differential killing of murine B-cell leukemia (BCL1) by photosensitization with merocyanine 540: implications for autologous bone marrow transplantation.

The efficacy of photosensitization by merocyanine 540 (MC540), a lipophilic fluorescent dye, was investigated in the murine B cell leukemia (BCL1). Normal BALB/c mice were injected with BCL1 cells exposed to MC540, followed by photosensitization with white light for 15 min to 2 h. Mice injected with BCL1 cells exposed for 1 or 2 h showed no sign of leukemia. Lethally irradiated mice were successfully reconstituted with mixtures of syngeneic bone marrow (BM) and BCL1 cells treated with MC540 following exposure to white light. Exposure of BM/BCL1 mixtures for 2 h proved to be effective in purging all BCL1 cells without affecting BM viability, as documented by normal hemopoietic reconstitution of all recipients surviving without evidence of leukemia. All recipients of untreated BM/BCL1 cell mixtures developed leukemia within 42 days. Adoptive transfer of 10(6) spleen cells obtained from treated mice into secondary naive syngeneic recipients was carried out in order to test for dormant BCL1 cells in treated recipients. No leukemia developed in any of the secondary recipients. Previous studies indicate that as few as 10, or possibly less, BCL1 cells are sufficient to cause lethal disease in BALB/c recipients. Our results suggest that MC540 may be an extremely potent tool for in vitro elimination of residual tumor cells while leaving uncommitted progenitor hemopoietic cells intact for hemopoietic reconstitution following lethal marrow ablation.

Animals↗
PubMed1989

The use of recombinant cytokines for enhancing immunohematopoietic reconstitution following bone marrow transplantation. I. Effects of in vitro culturing with IL-3 and GM-CSF on human and mouse bone marrow cells purged with mafosfamide (ASTA-Z).

Enhanced colony formation (CFU-GM) in vitro was observed in murine and human bone marrow (BM) cells following pre-incubation for 2-3 days with recombinant murine GM-CSF or natural purified murine IL-3, and recombinant human GM-CSF or IL-3, respectively. Pre-incubation in the presence of both GM-CSF and IL-3 produced additive stimulatory effects. BM cells previously treated in vitro with mafosfamide (ASTA-Z) under conditions identical to those used in the purging of autologous BM grafts, also demonstrated an enhanced cumulative response to combinations of GM-CSF and IL-3, with up to 100-fold increase in CFU-GM as compared with controls (p less than 0.001). In mice, the number of CFU-S was also significantly increased (2-20 times) following incubation of unpurged and purged BM cells in murine IL-3 and/or GM-CSF. Interestingly, the frequency of both CFU-GM and CFU-S in BM cells first purged with ASTA-Z and then cultured with both cytokines was significantly higher (p less than 0.01) than that in fresh, intact BM cells. In addition, mice transplanted with unpurged or purged, cytokine cultured syngeneic BM cells exhibited a significantly (p less than 0.01) earlier reconstitution of peripheral white blood cells and of BM CFU-GM, and a significantly enhanced anti-sheep red blood cell plaque-forming cell response. Overall, the data suggest that it might be possible to enhance immunohematopoietic reconstitution in recipients of unmanipulated, as well as ASTA-Z purged autologous BM following short-term culture of BM cells with recombinant colony stimulating factors prior to bone marrow transplantation.

Animals↗
PubMed1988

Removal of breast cancer cells by soybean agglutinin in an experimental model for purging human marrow.

Soybean agglutinin (SBA) was used as a differential reagent to achieve selective elimination of human breast cancer cells (T-47D cell line) from human marrow contaminated with tumor cells. Two successive cycles of direct agglutination by soluble SBA resulted in depletion of 3.5 logs of tumor cells as determined by radiolabeling, whereas removal of more than 4 logs of tumor cells was demonstrated by a clonogenic bioassay. A more convenient procedure for tumor purge involved the use of SBA bound to either polyglutaraldehyde magnetic beads or to commercial polystyrene magnetic beads. After one cycle of magnetic separation, 2 to 3.5 logs of tumor cells were removed. A second separation cycle using fresh magnetic beads improved depletion to more than 4 logs. Neither of these purging procedures affected the hematopoietic potential of granuloid-macrophage colony-forming unit cells. We suggest the use of SBA bound to magnetic beads as a convenient tool for effective ex vivo purging of marrow aspirates contaminated with metastatic breast cancer cells in patients with advanced disease. A similar procedure is applicable for all SBA-positive neoplasms.

Agglutination↗
PubMed1988

T-cell depleted bone marrow transplantation for plasma cell myeloma. Report of a case and review of the results of BMT for myeloma.

A 37-year-old male patient with advanced refractory plasma cell myeloma underwent T-cell depleted bone marrow transplantation (BMT) after 7 years of active disease previously treated with combination chemotherapy and irradiation. After the BMT there was marked clinical improvement and the patient is currently in good clinical condition two years after the BMT was performed. However, residual myeloma cells are still seen in the marrow and stable levels of paraprotein are still present in the serum. No GVHD was encountered after BMT. The problems of BMT in myeloma are discussed with a review of the current pertinent literature.

Adult↗
PubMed1988

Induction of transplantation tolerance by intraportal injection of allogeneic bone marrow cells. Possible implications for intrauterine bone marrow transplantation across major histocompatibility barriers.

Intraportal inoculation of C57BL/6 marrow cells into sublethally (400 rad) irradiated BALB/c recipients resulted in durable chimerism and the permanent acceptance of C57BL/6 skin allografts. Sublethally irradiated recipients of a similar number of marrow cells inoculated systemically did not develop chimerism or any significant prolongation of the survival of C57BL/6 skin allografts. Consequently, lethal graft-versus-host disease developed only in recipients of intraportal marrow allografts (80%). The intraportal injection of allogeneic C57BL/6 marrow cells into nonirradiated recipients resulted in significant, although not permanent, prolongation of skin allograft survival without durable chimerism, suggesting that the introduction of alloantigens intraportally may favor the induction of nonresponsiveness to alloantigens even across strong major histocompatibility barriers. The relevance of these findings is discussed regarding the intraportal inoculation of allogeneic bone marrow cells for the treatment of genetic disorders in utero through the induction of neonatal tolerance.

Animals↗
PubMed1988

Current problems and future goals in clinical bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) is associated with the cumulative toxicity of high dose chemotherapy and/or radiation therapy regimens currently in use, with acute and chronic graft vs host disease (GVHD), as well as with the consequences of delayed immunological reconstitution due to slow maturation of the immune system and drugs currently used for prevention of GVHD. Although GVHD may be overcome by T-cell depletion it leads to an increased incidence of graft rejection and relapse of the original malignancy. These too represent major problems. Autologous BMT results in high relapse rates due to lack of immune-mediated allogeneic interactions of grafted cells against tumor cells of the host. In view of the fact that experiments in animal models of human disease suggest that antileukemic effects of allogeneic marrow grafts may be partially independent of GVHD, new approaches for amplification of antitumor effects of autologous and allogeneic cells by cytokines and by lymphokine-activated cells are discussed. Evidence for antileukemia effects of IL-2 therapy in animals is presented. Beneficial effects of several cytokines in autologous and allogeneic BMT are suggested by significant facilitation of immunological and hematopoietic reconstitution following transplantation of bone marrow cells treated in vitro with cytokines (including ASTA-Z-purged marrow) and following in vivo administration of cytokines in conjunction with BMT. Overall, in view of several innovative biological interventions, it seems that significant progress in autologous and allogeneic BMT may be underway; the concept yet to be established is that successful and less risky BMT may be accomplished by replacing aggressive chemoradiotherapy regimens with sophisticated immunomanipulations and biological response modifying agents.

Animals↗