Immunomodulation of autoimmunity by linomide.
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Adjuvants, Immunologic↗
Biomedical subjects
S Slavin
Publications and source records attributed to S Slavin.
Enhancement of GVL effect with rhIL-2 following BMT in a murine model for acute myeloid leukemia in SJL/J mice.
A murine model for acute myeloid leukemia (mAML) was used to study graft-vs.-leukemia (GVL) effects on residual leukemic cells across both major (MHC) and minor histocompatibility antigens (mHA) barriers. In addition, the therapeutic effect of recombinant human interleukin-2 (rhIL-2)-administered postsyngeneic and allogeneic bone marrow transplantation (BMT) was examined. SJL/J mice inoculated with mAML cells were exposed later to total body irradiation (TBI) and transplanted with bone marrow cells (BMC) mixed with spleen cells derived from normal syngeneic (SJL/J), congenic (B10.S), or allogeneic (C57BL/6) donor mice. One-half of the mice in each group received low dose rhIL-2 for 3 days starting 1 day post-BMT. Spleen cells from treated recipients were transferred to secondary naive SJL/J mice for in vivo detection of residual tumor cells. At a tumor load of 10(5) cells per animal, none of the mice rescued with SJL/J or B10.S cells was cured since 100% of secondary recipients developed leukemia. Concomitant treatment of recipients of B10.S cells with rhIL-2 induced GVL effects since none of the secondary recipients developed leukemia after 2 years. All adoptive recipients of mice rescued with C57BL/6 cells remained free of leukemia after 2 years whether or not rhIL-2 was injected. The potency of the GVL effects observed across mHA and MHC were tumor-cell dose dependent since fewer animals inoculated with 10(6) mAML cells were cured. Only marginal GVL effects were noticed following syngeneic BMT and rhIL-2. Our results sustain the importance of the GVL effects in the treatment of myeloid leukemia and demonstrate that immunotherapy with rhIL-2 following BMT can enhance the therapeutic effect induced by the allograft.
Animals↗
The role of antibodies to IL-2 receptor and Asialo GM1 on graft-versus-leukemia effects induced by bone marrow allografts in murine B cell leukemia.
The role of various cell subpopulations involved in the graft-versus-leukemia (GVL) effect induced by allogeneic bone marrow transplantation (BMT) was investigated in (BALB/c x C57BL/6)F1 (F1) recipients, inoculated with murine B cell leukemia (BCL1), by using monoclonal murine anti-IL-2 receptor antibodies or rabbit anti-Asialo GM1 antibodies directed predominantly against murine NK cells. F1 mice with BCL1 were irradiated and reconstituted with parental (C57BL/6) bone marrow cells (BMC) or a mixture of BMC and spleen cells and treated in vivo for 10 days with anti-IL-2 receptor antibody or anti-Asialo-GM1 antibody. Both treatments lessened the GVL effects induced by the allograft and resulted in development of leukemia relapse, as documented in vivo by adoptive transfer of 10(5) spleen cells obtained from treated mice into secondary syngeneic adoptive recipients. Our data indicate that IL-2 receptor-positive T cells and possibly IL-2-activated allogeneic NK cells play a key role in inducing GVL following allogeneic BMT.
Animals↗
Prevention and treatment of type I diabetes in NOD mice by linomide.
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Adjuvants, Immunologic↗
Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes.
Allogeneic bone marrow transplantation (BMT) is the treatment of choice for hematologic malignancies resistant to conventional chemotherapy and for patients who are at high risk for relapse. Until recently, no cure could be offered to patients relapsing following allogeneic BMT. We present our long-term observations of the first patient with remission reinduced by allogeneic cell therapy (allo-CT) using donor peripheral blood lymphocytes (PBL). In addition, we review the cumulative international experience with allo-CT used to treat 163 patients, 105 with CML and 58 with other hematologic diseases, who relapsed following allogeneic BMT. The first patient treated by allo-CT was diagnosed with acute resistant pre-B lymphoblastic leukemia (ALL) in extensive third hematologic and extramedullary relapse shortly after BMT. He was given infusions of donor (sister) PBL in multiple increments. Subsequently, he developed mild, reversible graft-vs-host disease (GVHD) in parallel with regression of all hematologic and cytogenetic disease manifestations. More than 8 years after allo-CT, he is disease-free with Karnofsky score 100% and no evidence of residual male cells by PCR. International data show that relapse after BMT was successfully reversed by donor PBL treatment in 97 of 158 evaluable patients; 72/100 (72%) with chronic myeloid leukemia (CML) and 25/58 (44.8%) with other malignant hematologic diseases including acute leukemia, lymphoma, and myelodysplastic syndrome. T cell depletion (TCD) for prevention of GVHD was performed for 60/105 (57%) patients with CML and 31/58 (53.4%) patients with other hematologic malignancies. Complete response after allo-CT was obtained in recipients of both TCD-BMT and unmodified BMT. GVHD due to allo-CT developed in 86/158 (54.4%) of the patients, 63/100 (63.0%) with CML and 23/58 (39.6%) with other hematologic diseases. alpha-interferon (IFN-alpha) was given to 67.9% of patients with CML and 28.1% of patients with other diseases. The cumulative experience shows that allo-CT can successfully reverse chemoradiotherapy-resistant relapse of acute leukemia and even more effectively of chronic leukemia independently of alpha-interferon therapy. Although GVHD was frequent among responders, accompanied occasionally by transient or irreversible marrow aplasia, remissions were also obtained in patients with no GVHD. Allo-CT should therefore be considered as treatment of choice for overt relapse or de novo minimal residual disease post-BMT. Administration of donor peripheral blood lymphocytes in graded increments at an early stage of relapse may be the best approach for combining optimal timing at the stage of minimal disease while controlling and minimizing the risk of GVHD on an individual basis.
Adolescent↗
Severe migratory polyarthritis following in vivo CAMPATH-1G.
CAMPATH-1G is an IgG2b rat antihuman (CDw52) monoclonal antibody (MoAb) which is currently being used for T cell depletion in the setting of allogeneic bone marrow transplantation (BMT). In addition it elicits substantial lymphoid depletion, an effect which is being explored for remission induction in patients with lymphoid malignancies and for treating patients with various autoimmune disorders, in particular rheumatoid arthritis. Recently, in vivo CAMPATH-1G has been introduced to achieve increased immunosuppression in the pretransplant conditioning, for prevention of graft rejection following T cell depleted BMT. Here we describe a patient with T cell lymphoblastic lymphoma who received in vivo CAMPATH-1G as part of the pretransplant conditioning regimen and who, 6 days after the first dose, developed severe migratory polyarthritis. This is the first report of severe migratory polyarthritis as a very unusual complication following CAMPATH-1G MoAb administration.
Adult↗
A controlled trial of recombinant human erythropoietin after bone marrow transplantation.
Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.
ABO Blood-Group System↗
Effective graft-versus-leukemia effects independent of graft-versus-host disease after T cell-depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and recombinant IL-2.
After allogeneic bone marrow transplantation (BMT) for leukemia, beneficial graft-vs-leukemia (GVL) effects are usually accompanied by potentially serious graft-vs-host disease (GVHD). Because T cell depletion is the only effective way to prevent GVHD it seems important to understand whether effective GVL can develop after BMT with T cell depletion in GVHD-free recipients. Well-established C57BL/6-->BALB/c chimeras that were free of GVHD, reconstituted with T cell-depleted allogeneic bone marrow cells, and inoculated 3 mo after BMT with a high inoculation of murine B cell leukemia (BCL1) showed no evidence of disease, whereas all control mice developed leukemia and died within 58 days. Results from adoptive transfer experiments in secondary naive BALB/c recipients indicated that all BCL1 cells were eliminated in the chimeras within 14 days. Hence, complete resistance to BCL1 developed in the chimeras despite complete tolerance to host alloantigens. The GVL effects observed in tolerant chimeras were further amplified by administration of immunocompetent allogeneic C57BL/6 spleen cells, low dose rIL-2, or both for 5 days. Our data suggest that GVL effects can develop even after T cell depletion in the absence of clinically overt GVHD and that GVL can be further amplified by rIL-2, either with or without use of additional immunocompetent donor T cells. Our data may provide the basis for new approaches to induce effective GVL after allogeneic BMT with cell therapy and rIL-2 at the stage of minimal residual disease, while avoiding early GVHD induced by the BMT procedure.
Animals↗
Prediction by a modified mixed leukocyte reaction assay of graft-versus-host disease and graft rejection after allogeneic bone marrow transplantation.
In this report we describe a modified, sensitive MLR test that appears to detect fine antigenic disparities between HLA-identical siblings confirmed as such by serology and the standard MLR test. In a group of 40 consecutive allogeneic bone marrow transplants, reactivity detected by the modified MLR test correlated with the development of rejection of matched marrow grafts and onset of acute graft vs. host disease (aGVHD). Thus, 13/15 positively reacting patient/donor pairs developed one of these complications (P < 0.001), while only 2/25 developed aGVHD in the negatively reacting group. This test may be useful for selecting the most compatible donor when several potential donors are available.
Acute Disease↗
Potential use of interleukin-6 in bone marrow transplantation: effects of recombinant human interleukin-6 after syngeneic and semiallogeneic bone marrow transplantation in mice.
The potential of recombinant glycosylated human interleukin-6 (rhIL-6) for enhancing immunohematopoietic reconstitution and survival after syngeneic and semiallogeneic bone marrow transplantation (BMT) in BALB/c mice subjected to total body irradiation (TBI) was investigated. rhIL-6 produced enhanced reconstitution of white blood cells as assessed on days 8 and 14 after syngeneic BMT and of platelets as assessed on day 10. Moreover, rhIL-6 treatment produced significant improvement of survival in lethally irradiated mice receiving either syngeneic or semiallogeneic BMT with limiting number of BM cells. This effect of IL-6 was not seen with large BM cell inocula producing high survival by themselves. rhIL-6 showed no toxic effects and did not affect the survival of mice that were lethally irradiated but not reconstituted by BM cells. However, the sensitivity of mice to sublethal irradiation was increased by rhIL-6 in the absence of BM cell transplantation. In experimental conditions inducing graft-versus-host disease (GVHD), in which lethally irradiated (BALB/c x C57BL/6)F1 mice received mixtures of BM and spleen cells from C57BL/6 donors, rhIL-6 was found to enhance GVHD manifestations. No consistent enhancement of T-cell in vitro proliferative responses to allogeneic spleen cells or T- and B-cell-dependent mitogens were seen in the splenocytes obtained from recipients of syngeneic or semiallogeneic BMT. Our data suggest that rhIL-6 may be useful in BMT procedures to enhance thrombopoiesis and hematologic recovery, as well as to increase overall survival rates. In addition, the potentiation of GVHD, which is considered to correlate with graft-versus-leukemia effects, may be of interest in enhancing GVHD-dependent antitumor effects in protocols combining radiochemotherapy with BMT.
Animals↗
Prevention of diabetes mellitus in non-obese diabetic mice by Linomide, a novel immunomodulating drug.
Oral administration of the synthetic immunomodulating drug quinoline-3-carboxamide (Linomide) in the drinking water to 5-week-old female non-obese diabetic (NOD) mice resulted in complete protection from insulitis and maintenance of normal glucose tolerance for over 40 weeks (impaired glucose tolerance: treated n = 2 of 18; control n = 17 of 18, p < 0.0001). Delayed administration of the drug at 16 weeks resulted in slowing of the progression to diabetes when assessed at 42 weeks (treated with diabetes n = 7 of 25; control with diabetes 25 of 43, p < 0.0234). No gross changes of immune system cell phenotype or function were observed in the Linomide-treated group. Adoptive transfer of spleen and lymph node cells from treated female NOD mice into sub-lethally irradiated male recipients failed to transfer diabetes, whereas a similar transfer of cells obtained from untreated age-matched controls resulted in diabetes in all secondary recipients (diabetes in control group n = 12 of 13; in Linomide group n = 0 of 11, p < 0.0001). Linomide pretreatment of the secondary recipients also inhibited the transfer of diabetes (diabetes in pretreated group n = 2 of 9, control group n = 12 of 13, p < 0.015), as did adoptive co-transfer of cell mixtures obtained from treated female NOD mice, free of diabetes, and from diabetic NOD female mice (diabetes in Linomide group n = 4 of 9; in control group 7 of 7, p < 0.0337).(ABSTRACT TRUNCATED AT 250 WORDS)
Adjuvants, Immunologic↗
Intracranial haematomas following bone marrow transplantation.
Intracranial haemorrhage (ICH) is a known grave complication of leukaemia and has been described post mortem following bone marrow transplantation (BMT). Ante mortem following BMT, the incidence and significance of ICH is not well defined. The records of 471 bone marrow transplantation recipients over 11 years at the Hadassah University Hospital Bone Marrow Transplantation Department were reviewed. The relevant data of all patients with ICH were analysed. A resolute diagnostic and treatment protocol for subdural haematomas had been employed. The indication for transplantation in 273 of the patients was leukaemia. Thirteen of these patients developed subdural haematomas within 42 days of the transplant, and nine of these haematomas were bilateral. None of the 198 patients with other malignancies or nonmalignant indications for BMT (predominantly aplastic anaemia and beta thalassaemia major) had subdural haematomas. One thalassaemia patient and three leukaemia patients had intracerebral haematomas. There was no mortality or major morbidity from the subdural haematomas, which were all successfully resolved. In contrast, all of the patients with intracerebral haematomas consequently died. Subdural haematomas occur in approximately 5% of patients with leukaemia following BMT, but the clinical outcome is relatively benign. Intracerebral haematomas are a sporadic, lethal complication following BMT.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Health care reform as perceived by first year medical students.
Our study objective was to evaluate the attitudes of first year medical students toward the health care system using a self administered questionnaire to all first year medical students at the medical schools in the University of California system. Of 631 students surveyed, 94% completed the instrument. Students were asked about their attitudes toward and familiarity with concepts in health services, access to care, and managed care. Our findings indicated that most students were unfamiliar with concepts related to health services. Students were concerned about access to care; sixty-six percent of students favor a national health insurance plan. A majority of students supported allowing patients access to the current health care system regardless of the cost or utility of a medical test or procedure. Thirty-nine percent felt that rationing health care in any form (transplants, access to the intensive care unit, etc.) is contrary to the way medicine should be practiced. 72% felt that practicing physicians had a major responsibility to help reduce health care costs. When asked about specific changes intended to control health costs, students identified reform of medical malpractice system (63%) and increased spending on preventive health (60%) as the two proposals most likely to be effective. Students generally held negative attitudes toward managed care organizations; only 10% would chose to receive their care in HMOs. We conclude that first year medical students generally have little understanding of the health care system. Despite this, they hold strong opinions about access to care, managed care organizations and strategies intended to reduce health care spending. It is up to medical educators to find creative methods of introducing these content areas into an already bulging curriculum.
Attitude of Health Personnel↗
Interleukin-3 in combination with granulocyte-macrophage-colony-stimulating factor following bone marrow transplantation in a radiation accident victim.
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Adult↗
Detection of minimal residual disease state in chronic myelogenous leukemia patients using fluorescence in situ hybridization.
Detection of minimal residual disease and relapse remain major problems in chronic myelogenous leukemia (CML) patients following bone marrow transplantation (BMT). In order to disclose the 9;22 Philadelphia translocation, we used a fluorescence in situ hybridization (FISH) technique. BCR and ABL gene fragments were used as probes for the detection of the BCR/ABL fusion product in peripheral blood and bone marrow cells from 11 CML patients in which 5 were post-BMT. The sensitivity and specificity of this approach were compared to conventional cytogenetic and polymerase chain reaction (PCR) methods. FISH demonstrated a high degree of sensitivity (1%) for the detection of the BCR/ABL translocation in these patients. A linear correlation was found between FISH detection of the BCR/ABL fusion product and routine chromosomal analysis (r = 0.995; p < 0.001). Detection of the BCR/ABL signal by FISH was observed in all patients showing a positive PCR signal. A significant reduction in BCR/ABL signal was observed post-transplant (p < 0.001). However, the BCR/ABL translocation was detected in four of five transplanted patients immediately (0.75-2.5 months) following transplant and was found in patients with a low expression of the translocation.
Adult↗
Detection of minimal residual disease after sex-mismatch bone marrow transplantation in chronic myelogenous leukemia by fluorescence in situ hybridization.
Detection of minimal residual disease is one of the major goals in bone marrow transplantation. We used a fluorescence in-situ hybridization technique to detect residual Philadelphia-chromosome positive cells in chronic myelogenous leukemia (CML) patients after sex-mismatch BMT. We analyzed the level of detection using probes for the BCR/ABL fusion product by comparison with results obtained with probes for the Y and X sex chromosomes. Detection of sex-mismatch chromosomes was significantly higher than that of the BCR/ABL translocation. In contrast, a higher specificity of residual tumor cell detection by the BCR/ABL probe was demonstrated because most of the sex-mismatch cells detected by FISH had a normal karyotype. Tumor-specific markers probes are thus superior and more accurate than sex-mismatch probes for detection of MRD in CML patients after BMT.
Adult↗
Treatment of chronic myelogenous leukemia with recombinant human interleukin-2 and interferon-alpha 2a.
The safety, tolerance, and clinical effects of combined therapy with recombinant interferon-alpha (IFN-alpha) and interleukin-2 (rIL-2) administered subcutaneously for 2 courses of 4 weeks each, with 4 weeks interval between courses, given as outpatient therapy have been assessed in 10 patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML). All patients were previously treated with conventional chemotherapy and 3 failed to respond to IFN-alpha administered prior to our study. Median duration of disease from diagnosis was 36 months. Seven patients were in first chronic phase and the other 3 were in blast crisis, second chronic phase, and relapse post-bone marrow transplantation (BMT), respectively. Hematological response (median follow-up 16 months) was observed in 9 patients, with a decline in number of white blood cells and platelets. Elimination of Ph1 was observed in the patient who relapsed post-BMT with complete elimination bcr/abl RNA by polymerase chain reaction. Rebound lymphocytosis and eosinophilia were observed in most of the patients. Toxicity was acceptable. The main adverse effects were fever, chills, fatigue, anorexia, nausea, and vomiting. The side effects were reversible and no interruption of treatment was required. There was no treatment-related hospitalization or deaths. These data suggest that simultaneous subcutaneous IFN-alpha and rIL-2 home therapy is feasible, reasonably well tolerated, and potentially beneficial in CML patients. These observations may have important implications for the treatment of minimal residual disease following allogeneic and autologous marrow transplantation.
Adolescent↗
Entering first-year medical students' attitudes toward managed care.
PURPOSE: To study the attitudes of entering first-year medical students toward reform of the U.S. health care system. METHOD: All 631 first-year medical students at the five medical schools in the University of California System were asked during orientation (late summer of 1992) to complete a self-administered questionnaire regarding their attitudes toward and knowledge about health care reform. Statistical methods used were chi-square tests and factor analyses. RESULTS: Of the 631 students, 594 (94%) responded. Of the respondents, 392 (66%) felt that there should be a national health insurance plan, and 428 (72%) felt that practicing physicians had a major responsibility to help reduce health care costs. When asked about specific changes intended to control health care costs, the students identified reform of the medical malpractice system (374, 63%) and increased spending on preventive health (356, 60%) as the most likely to be effective. The students generally held negative attitudes toward managed care organizations; only 59 (10%) indicated they would choose to receive care in health maintenance organizations. CONCLUSION: The students held strong opinions about access to care, managed care organizations, and strategies intended to reduce health care spending. Medical educators not only need to find creative methods of introducing these content areas into medical school curricula but should also anticipate the need for strategies to deal with negative attitudes held by students.
Adult↗