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D J Gottlieb

Publications and source records attributed to D J Gottlieb.

67 records · Page 4Linked to original sources
PubMed1992

IL-2 infusion abrogates humoral immune responses in humans.

Although IL-2 infusion enhances cell-mediated cytotoxicity in patients with neoplastic disease, administration is paradoxically associated with a modest fall in total serum IgG and an increased risk of infection. We now show that the adverse effects of IL-2 infusion on the humoral immune system are substantial. Although IL-2 induces the B cell growth and differentiating factors IL-4 and IL-6, infusion abrogates primary antibody responses entirely and reduces secondary antibody responses 50-fold following antigen challenge. There is no evidence of the generation of cells with suppressive activity on B cells but IL-2 increases the ratio of circulating virgin:memory cells. These results may help to explain the increased rate of bacterial infection in patients receiving IL-2. As IL-2 plays a central role in the generation of an immune response, the finding that it is also sufficiently immunosuppressive to inhibit primary- and secondary-type antibody responses suggests that exploration of the underlying mechanisms may provide insights into immune system homeostasis and may offer new approaches to therapeutic immunosuppression.

Adolescent↗
PubMed1991

Homeostatic action of interleukin-4 on endogenous and recombinant interleukin-2-induced activated killer cell function.

Cytokine-secreting, major histocompatibility complex-unrestricted activated killer (AK) cells are toxic to a wide range of virus-infected or malignant target cells and may be generated endogenously, eg, after bone marrow transplantation, or by infusion of cytokines such as recombinant interleukin-2 (rIL-2). Although AK cells secrete cytokines such as gamma-interferon and tumor necrosis factor, which are themselves able to recruit fresh cytokine-secreting AK cells, activation in both settings is short-lived, implying the existence of homeostatic regulatory mechanisms. We now demonstrate one mechanism by which rapid homeostasis is achieved. We show that IL-4 is produced in patients with both endogenously and exogenously generated AK cells. The cytokine was detected in serum after marrow transplantation, and IL-4 transcripts appeared in circulating lymphocytes during rIL-2 infusion. Although IL-4 inhibited the induction phase of AK cell function, it had no significant inhibitory effect on the ability of AK cells from these individuals to respond to restimulation. Nonetheless, neutralization of the IL-4 induced during cell activation doubled the half-life of AK function, once activating stimuli were removed, from 18 to 44 hours and produced a 2-log increase in AK cell secretion of tumor necrosis factor and gamma-interferon. These data suggest that IL-4 induced in vivo during lymphocyte activation abbreviates AK cell responses once the triggering stimuli have been removed. Neutralization of endogenous IL-4 in vivo by appropriate monoclonal antibodies might prolong the duration of AK function.

Bone Marrow Transplantation↗
PubMed1991

Interleukin 2 infusion induces haemopoietic growth factors and modifies marrow regeneration after chemotherapy or autologous marrow transplantation.

Administration of interleukin 2 (IL2) to patients with minimal residual malignant disease following myeloablative chemo-radiotherapy may augment immune reconstitution and reduce the risk of relapse by increasing cytotoxic effector function and cytokine dependent killing directed at residual malignant cells. The ability of IL2 generated activated killer cells to inhibit haemopoietic progenitor cells and to release gamma-interferon (gamma IFN) and tumour necrosis factor (TNF) may, however, retard haemopoietic recovery, as both TNF and gamma IFN inhibit normal myelopoiesis in vitro. To determine the effect of IL2 infusion on myeloid regeneration in vivo, we have examined haemopoietic recovery in patients receiving this cytokine following autologous marrow transplantation or ablative chemotherapy. We find that IL2 infusion accelerates neutrophil recovery and that granulocyte-macrophage colony stimulating factor (GMCSF) and IL3 mRNA become detectable in circulating mononuclear cells. Induction of TNF by IL2 may also contribute to subsequent acceleration of myelopoiesis by initiation of GM-CSF mRNA synthesis in patient marrow fibroblasts. These results show that IL2 infusion may facilitate myeloid recovery when administered during the period of haemopoietic regeneration following ablative chemoradiotherapy.

Acute Disease↗
PubMed1991

Effect of a change in house staff work schedule on resource utilization and patient care.

Concern is frequently expressed by health care providers and consumers that the work environment of physicians-in-training may adversely affect their performance. This article documents the effects of changing from a traditional rotational overnight call schedule for house staff to a schedule designed to reduce sleep deprivation, distribute admissions more evenly throughout the week, and improve continuity of inpatient care on the internal medicine service of a large, university-affiliated Veterans Affairs Medical Center. In a prospective, time-series study, the hypothesis that this change would improve the efficiency and quality of medical care was evaluated by comparing the hospital course of the patients admitted during 4-week periods prior to and following the change in work schedule. The patients in the preintervention group do not differ significantly from those in the postintervention group in any identifiable clinical characteristics. The length of stay was shorter (10.9 vs 9.3 days) and the number of laboratory tests ordered per patient was smaller (24.0 vs 19.0) for patients cared for under the new work schedule compared with those cared for under the traditional work schedule. Resident physicians also committed fewer medication errors under the new work schedule (16.9 vs 12.0 per 100 patients discharged). We conclude that altering the house staff work schedule affects patient care and can lead to a decrease in utilization of health care resources.

Continuity of Patient Care↗
PubMed1990

Immunity against Pseudomonas aeruginosa adoptively transferred to bone marrow transplant recipients.

Infection is a common problem for bone marrow transplant (BMT) recipients during the period of neutropenia that immediately follows the procedure. Gram-negative infections present a particular hazard in these immunocompromised hosts. To augment host defenses against one such pathogen, Pseudomonas aeruginosa, we immunized bone marrow transplant donors and/or recipients with a polyvalent O-polysaccharide-toxin A conjugate vaccine. When either donor or recipient alone was vaccinated before transplant, no increase in specific antibody titers to any of the vaccine components was observed in the recipient. However, when both donor and recipient were vaccinated before transplant, increases in antibody titers to all polysaccharide components occurred to levels shown to be protective in animal models of gram-negative sepsis. Specific antibodies were primarily of the IgG1 and IgG2 subclass even though IgG2 subclass deficiency is common after BMT. The requirement for both donor and recipient immunization reflects the need for primed donor B lymphocytes in the marrow inoculum to be transferred into an antigen-containing environment so that maximum B-cell proliferation and antibody secretion can occur. Adoptive transfer of antibody responses to Pseudomonas aeruginosa and other common bacterial pathogens has the potential to reduce infection-related morbidity and mortality after allogeneic bone marrow transplantation.

Adolescent↗
PubMed1990

Malignant plasma cells are sensitive to LAK cell lysis: pre-clinical and clinical studies of interleukin 2 in the treatment of multiple myeloma.

To assess the role of the cytokine interleukin 2 (IL2) in the treatment of patients with multiple myeloma, we examined the sensitivity of plasma cell lines and malignant plasma cells from multiple myeloma (MM) patients to cell and cytokine-mediated killing induced by IL2. Unstimulated peripheral blood mononuclear cells (PBM) from normal donors produced little killing (mean lysis 1.0 +/- 1.0%, effector:target (ET) ratio 50:1), but cytotoxicity was modestly increased when PBM were incubated with IL2 prior to assay (8.0 +/- 2.9%). Unstimulated PBM from patients with MM also failed to kill autologous malignant plasma cells (mean 0.6 +/- 0.6%), but after exposure to IL2 they induced substantial lysis of autologous malignant cells (mean 55.3 +/- 22.1%). In addition, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma), two cytokines released from mononuclear cells in response to IL2, also reduced the survival and thymidine uptake of malignant plasma cells in culture. To determine whether these potentially beneficial immunomodulatory effects could be reproduced by in vivo administration of IL2, we have administered seven courses of IL2 to four patients with MM after autologous bone marrow transplant (ABMT). No serious adverse effects were noted. Increases in natural killer (NK) and lymphokine-activated killer (LAK) activity of PBM occurred during IL2 infusion, although cells capable of killing autologous MM cells did not circulate. However, IL2 infusions also induced substantial increases in the production of the cytokines TNF and IFN-gamma from peripheral blood lymphocytes. These results suggest that the in vivo administration of IL2 in MM deserves further evaluation, particularly for its potential to control minimal residual disease.

Adult↗
PubMed1989

Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy.

Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.

Antigens, CD↗
PubMed1989

A phase I clinical trial of recombinant interleukin 2 following high dose chemo-radiotherapy for haematological malignancy: applicability to the elimination of minimal residual disease.

Biological response modifiers such as interleukin 2 (IL2) may be most effective in the setting of minimal residual disease. In a phase I-II clinical trial, IL2 was administered to 10 patients in remission of acute myeloid leukaemia and three with multiple myeloma 1-4 weeks after treatment with ablative chemotherapy or chemotherapy and autologous bone marrow transplantation. The aim was to assess the capacity of these patients to tolerate IL2 after intensive therapy and to determine whether regenerating lymphocytes were capable of responding to IL2 with the generation of anti-leukaemic effector cells. Toxicity was severe in two patients treated with escalating doses of IL2 and 19 subsequent infusions administered to 11 patients on a fixed dose schedule for periods of 3-5 days were well tolerated. Major toxicity was confined to hypotension (two courses) which responded rapidly to treatment cessation. No patients required intensive care unit support. IL2 infusions produced no significant adverse effects on marrow regeneration; while there were transient falls in platelet counts there were no episodes of clinical bleeding and neutrophil counts increased from a mean of 1.1 pre-infusion to 2.5 x 10(9)l-1 during the infusion (P = 0.004). A significant biochemical abnormality was hypokalaemia which responded rapidly to correction. Cells with activity against leukaemic progenitor cells appeared in peripheral blood within 48 h of beginning treatment. We conclude that IL2 may be used in minimal residual haematological malignancy, and by producing anti-neoplastic effector cells has the potential, as yet unproven, to prolong disease-free survival of patients entering remission.

Adolescent↗
PubMed1989

Spontaneous and interleukin 2 induced secretion of tumour necrosis factor and gamma interferon following autologous marrow transplantation or chemotherapy.

Culture of lymphocytes from allograft recipients or from normal donors with Interleukin 2 (IL2) induces high levels of gamma-interferon (gamma IFN) and tumour necrosis factor (TNF) secretion. We now show that production of these two cytokines can also be increased after autologous bone marrow transplantation (BMT) and induced following chemotherapy for haematological malignancy. These effects occur even though the regenerating IL2 responsive lymphocytes in this context have previously been extensively exposed to cytotoxic agents. IL2 induced secretion of gamma-IFN and TNF is higher in autograft recipients than in patients treated by chemotherapy alone. This effect may be related to differences in the phenotypic profile between recovering lymphocytes in the two groups and to an increased degree of prior in vivo lymphocyte activation in the autologous bone marrow transplant recipients. In both groups of patients, IL2 acts on CD3+ T cells and on CD16+ NK cells so that depletion of either subset incompletely abrogates IL2 dependent gamma-IFN secretion. As both TNF and gamma-IFN possess anti-leukaemic and anti-infective activity, enhancement of their secretion by IL2 infusion after autologous bone marrow transplant and induction after chemotherapy may be of therapeutic benefit.

Adolescent↗
PubMed1989

In vivo induction of gamma interferon and tumor necrosis factor by interleukin-2 infusion following intensive chemotherapy or autologous marrow transplantation.

Interleukin-2 (IL-2) therapy may improve immune reconstitution and reduce the risk of leukemic relapse in the setting of minimal residual disease by augmenting cytotoxic effector mechanisms directed at residual malignant cells. In addition, IL-2 in vitro promotes the release of cytokines including gamma-interferon (gamma-IFN) and tumor necrosis factor (TNF), which also possess antileukemic activity and can enhance granulocyte function. To determine if IL-2 infusion induces release of gamma-IFN and TNF in vivo in sufficient quantity to mediate these effects, we have measured serum levels of these cytokines and secretion by lymphocytes obtained from patients receiving this cytokine in a phase 1 trial. Serum gamma-IFN was undetectable pre-IL-2 and increased to 1.5 to 17 U/mL during IL-2 infusion (P less than .05). Culture of patient lymphocytes for 48 hours produced 1.2 U gamma-IFN/2 x 10(6) cells/mL pre-IL-2 rising to 50 U/2 x 10(6) cells/mL when the lymphocytes were obtained during therapy (P less than .05). Lymphocyte subset analysis showed that both CD3+ and CD16+ cells secreted gamma-IFN in response to IL-2. TNF secretion by lymphocytes also rose during IL-2 infusion from a mean of 5 U/mL to 14.4 U/mL (P less than .01) although no rise was seen in serum levels. The material secreted by IL-2-stimulated lymphocytes is bioactive as addition of supernatants from lymphocytes obtained during IL-2 therapy to cultures of myeloid blasts significantly inhibited clonogenic growth. IL-2-induced secretion of these cytokines mediated this inhibition as it could be partially blocked by either anti-gamma-IFN or anti-TNF antibodies. Preincubation of granulocytes with the same supernatants produced enhanced oxidative metabolism, measured by chemiluminescence in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP). This effect also could be partially abrogated by anti-gamma-IFN and anti-TNF antibodies. Therefore, secondary cytokine secretion may boost granulocyte function and contribute to the antileukemic effects of IL-2 infusion in patients following bone marrow transplantation or chemotherapy.

Adolescent↗
PubMed1976

Mutators in Saccharomyces cerevisiae: MUT1-1, MUT1-2 and MUT2-1.

The purpose of this study was to characterize two mutator stocks of yeast which were induced and selected on the basis of high spontaneous reversion rates of the suppressible "ochre" nonsense allele lys1-1. In the mutator stock VA-3, a single mutation, designated mut1-1, is responsible for the increase in the reversion rate of the ochre alleles lys1-1 and arg4-17. In stock VA-105, there are two separate mutator mutations. Tetrad analysis data showed these two loci are loosely linked. Based on complementation data, one of these mutations is at the same locus as mut1-1 and designated mut1-2. The second mutator of stock VA-105 was designated mut2-1. All three mutators are recessive. Both mut1-1 and mut1-2 give a high mutation rate for ochre nonsense suppressor (SUP) loci, but not for the ochre nonsense alleles. On the contrary, the mutation rates of the ochre alleles are greatly reduced. With the mutant mut2-1 there were mutations at both the lys1-1 site and its suppressors; mut2-1 is as effective as mut1-2 but not as effective as mut1-1 in inducing reversions of a missense mutant, his1-7. Neither mut1-1, mut1-2 nor mut2-1 were effective in inducing reversions of a putative frameshift mutation, hom3-10, or in inducing forward mutations to canavanine resistance.

Alleles↗