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C Dinarello

Publications and source records attributed to C Dinarello.

12 recordsLinked to original sources
PubMed2001

Interleukin-18 binding protein in acute graft versus host disease and engraftment following allogeneic peripheral blood stem cell transplants.

Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon-gamma (IFN-gamma) production and IFN-gamma and sIFN-gammaR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN-gamma production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day -10 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL-6R, sIFN-gammaR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment (p < 0.05). Accordingly, during rejection, IL-18BP serum levels remained low and similar to pretransplant levels. The mean elevation of IL-18BP detected in association to acute GVHD was significantly higher in comparison to normal engraftment (p < 0.05). A correlation between IL-18BP, sIFNgammaR, and sIL-6R serum levels was found in all patients. No correlation between IL-18 and IL-18BP serum levels was found in patients undergoing uneventful PBSCT and rejection, whereas a marked increase in both IL-18 and IL-18BP levels was detected during acute GVHD (p < 0.01). Our data suggest that the dysregulation of IL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications. Furthermore, because preliminary data from our group show that IL-18 blockage ameliorates GVHD in murine models, it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.

Acute Disease↗
PubMed1997

Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma.

PURPOSE: A randomized, double-blind, placebo-controlled trial was performed to compare the toxicity and biologic effects of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus the recombinant human soluble p75 tumor necrosis factor (TNF) receptor immunoglobulin G (IgG) chimera (rhuTNFR:Fc) with high-dose IL-2 alone in patients with advanced melanoma and renal cell carcinoma. PATIENTS AND METHODS: Twenty patients with advanced melanoma or renal cell carcinoma were randomized to receive IL-2 (Chiron, Emeryville, CA) 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) combined with placebo or the rhuTNFR:Fc fusion protein (Immunex, Seattle, WA) 10 mg/m2 on days 1 and 15 and 5 mg/m2 on days 3, 5, 17, and 19. The impact of rhuTNFR:Fc on IL-2 toxicity and biologic effects was evaluated. RESULTS: No clinically significant difference in toxicity was observed in the two treatment arms. The adjusted median number of IL-2 doses administered during cycle 1 was 24.5 (range, seven to 28) and 21.5 (range, five to 27) for the placebo and rhuTNFR:Fc arms, respectively (P = .544). IL-2-induced TNF bioactivity, neutrophil chemotactic defect, and serum IL-6, IL-8, and IL-1 receptor antagonist (IL-1RA) induction were suppressed by rhuTNFR:Fc. Two of nine assessable patients (22%) on IL-2/placebo and three of 10 patients (30%) on IL-2/rhuTNFR:Fc responded. CONCLUSION: Despite evidence of in vitro neutralization of TNF functional activity and partial inhibition of other secondary biologic effects of IL-2, rhuTNFR:Fc does not reduce the clinical toxicity associated with high-dose IL-2 therapy. These results suggest that the toxicity and antitumor effects of IL-2 treatment are independent of circulating TNF.

Adult↗
PubMed1988

Recombinant human interleukin-1 beta causes histamine release from human basophils.

Histamine releasing factors (HRFs) have been demonstrated to be secreted by human lymphocytes and monocytes (alveolar macrophages); however, none has been purified to date. Because of the similarity of our HRF to the physical chemical properties of interleukin-1 (IL-1) and tumor necrosis factor (TNF), we have assessed the ability of preparations of IL-1 and TNF to cause basophil histamine release (HR). Human recombinant pro-IL-1 beta, recombinant mature IL-1, and, to a lesser extent, human recombinant TNF caused significant HR from a subpopulation of donor basophils. The pro-IL-1 beta elicited a dose response between 40 and 800 ng/ml; higher concentrations were inhibitory. Approximately 30% of subjects tested are responsive to either mature IL-1 or TNF. These share the same responder subset, but the magnitude of the TNF response is considerably less. A response to the pro-IL-1 was restricted to those subjects with prominent HR to anti-IgE; the response to mature IL-1 and TNF was unrelated to the response to anti-IgE. As in other functional assays, the pro-IL-1 is 50- to 100-fold less potent than mature IL-1, and unlike human HRF, it is highly unstable and rapidly loses activity. Mononuclear cell-derived HRF differs in physicochemical properties from IL-1 or TNF; nevertheless, it appears likely that a variety of cytokines may possess histamine-releasing capability.

Antibodies, Anti-Idiotypic↗
PubMed1985

Self-regulation of procoagulant events on the endothelial cell surface.

Interleukin 1 (IL-1) is a potent mediator of inflammatory and immunologic phenomena. In addition, IL-1 may be intimately involved in the regulation of hemostasis, since interaction of IL-1 with endothelial cells has been reported to induce tissue factor activity. We demonstrate that perturbation of the endothelial cell induces augmented IL-1 release. Human umbilical vein endothelial cells perturbed by treatment with lipopolysaccharide produced enhanced amounts of IL-1 activity. IL-1 activity from lipopolysaccharide-treated endothelial cell supernatants could be absorbed by an antibody to IL-1 coupled to Sepharose. Elaboration of IL-1 activity was dependent on the dose of lipopolysaccharide and occurred in a time-dependent manner. Addition of cycloheximide blocked generation of IL-1 activity. A physiological vessel wall perturbant, the coagulation enzyme thrombin, induced comparable amounts of IL-1 activity in endothelial cell cultures. This effect was specific for the enzyme, since active site-blocked thrombin and prothrombin had no effect on IL-1. In addition, IL-1-containing supernatants from thrombin-stimulated endothelial cells induced tissue factor procoagulant activity in fresh endothelial cell cultures. Thus, in contrast to the multiple, known inhibitory mechanisms that block thrombin procoagulant activity, these data suggest a circle of interaction in which thrombin induces endothelial cell elaboration of IL-1, a mediator of endothelial cell procoagulant activity. Endothelial cell production of IL-1 in response to perturbation allows these cells to play an integral role in the regulation of the inflammatory and coagulation systems.

Animals↗
PubMed1985

A histamine-releasing factor from activated human mononuclear cells.

Human mononuclear cells activated by streptokinase-streptodornase have been shown to elaborate a factor capable of releasing histamine from human basophils. We have developed reproducible methods for its production in large quantities by using cells obtained from leukapheresis packs, by detection utilizing donor basophils known to release well with anti IgE, and by quantitation of histamine by the radioenzyme method. Human histamine-releasing factor (HRF) gave a single peak upon gel filtration with an estimated m.w. of 32,000; SDS gel electrophoresis revealed a single major band as seen at m.w. 30,000. HRF can be resolved into at least two forms separable by ion-exchange chromatography on QAE Sephadex, and two peaks of activity were obtained by chromatofocusing or isoelectric focusing in gels at pH 6.9 and between 7.4 and 8.3. This factor represents an important potential link between cellular immunity and immediate hypersensitivity.

Basophils↗
PubMed1985

Intracellular human IL-1: a precursor for the secreted monokine.

An intracellular monocyte derived protein possessing interleukin 1 (IL-1) activity has been compared with the secreted from of IL-1. Our results indicated that this intracellular IL-1 had an apparent size greater than that of extracellular IL-1. Data are presented to show that a rabbit heterotypic antiserum prepared against epitopes on the secreted form of human IL-1 blocked the biologic activity of intracellular IL-1 in a dose dependent manner. Intracellular IL-1 had a mass of 30-40 kDa as determined by gel filtration using sephacryl-200 gel.

Cytoplasm↗
PubMed1984

Comparison of chemical analyses of hollow-fiber dialyzer extracts.

Hollow-fiber hemodialyzers containing cellulose-based membranes have been shown to produce positive results with the Limulus amebocyte lysate (LAL) test. This study was undertaken to determine whether endotoxin was causing the reaction. Rinses from 45 parallel-plate and hollow-fiber dialyzers from eight different manufacturers were tested using three lysates and four LAL methods. In addition, four in vitro cellular methods--human leukocytic pyrogen, lymphocytic activating factor, peritoneal macrophage, and arginase release--were used to evaluate endotoxin activity. The substance causing the reaction was identified using chromatographic methods. Results indicate that the LAL-reactive material is cellulose derived and is not pyrogenic.

Arginase↗
PubMed1984

Characterization of Limulus amoebocyte lysate-reactive material from hollow-fiber dialyzers.

Hollow-fiber hemodialyzers containing cellulose-based membranes have been shown to produce positive results with the Limulus amoebocyte lysate test. This study was undertaken to determine whether endotoxin was causing the reaction. Rinses from 45 parallel-plate and hollow-fiber dialyzers from eight different manufacturers were tested before and after treatment with cellulase, using three lysates and four Limulus amoebocyte lysate methods. In addition, four in vitro cellular methods--human leukocytic pyrogen, lymphocytic activating factor, peritoneal macrophage, and arginase release--were used to evaluate endotoxin activity. The substance causing the reaction was identified by chromatographic methods. Results indicate that the Limulus amoebocyte lysate reactive material is cellulose derived and not pyrogenic.

Cellulose↗
PubMed1984

Control of protein degradation in muscle by prostaglandins, Ca2+, and leukocytic pyrogen (interleukin 1).

Protein degradation in skeletal muscle increases with fever and sepsis. Our studies indicate that prostaglandin E2 (PGE2) is an important regulator of muscle proteolysis that seems to signal this increase in fever. When rat skeletal or cardiac muscles were incubated with arachidonate, rates of protein breakdown rose and protein balance became more negative. Aspirin or indomethacin, which prevented synthesis of PGE2, markedly reduced this effect. By itself PGE2 stimulated proteolysis without altering protein synthesis. PGE2 seems to increase proteolysis in the lysosomes, inasmuch as leupeptin and Ep-475 inhibit this response. These inhibitors inactivate lysosomal thiol proteases in the muscles without affecting the Ca2+-activated protease. (In fact, complete inactivation of the latter enzyme with mersalyl did not reduce overall proteolysis in the muscles). When muscles from feverish rats were incubated in vitro, they showed greater protein breakdown and PGE2 synthesis than muscles from normal animals. Addition of indomethacin eliminated this difference. Leukocytic pyrogen (interleukin 1), a protein released by monocytes that signals the onset of fever, also seems to signal increased muscle PGE2 synthesis and muscle proteolysis. This protein enhanced both processes dramatically in the isolated muscles. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of patients showing excessive protein breakdown.

Animals↗
PubMedDate not supplied

Interleukin-1 beta in human colostrum.

The two forms of interleukin-1, IL-1 alpha and IL-1 beta respectively, and tumour necrosis factor (TNF) are polypeptides sharing different biological activities which are often associated with host defence mechanisms. Because of the well-recognized benefits of breast feeding for newborns, colostrum from 9 healthy lactating women was analysed for the presence of these 3 cytokines. Specific radioimmunoassay revealed that colostrum contains a significant amount of IL-1 beta (mean +/- SEM values of 1,130 +/- 259 pg/ml). The concentrations of IL-1 alpha and TNF were negligible. Colostral leukocytes are able to produce IL-1 since high activity was found after stimulation with Staphylococcus epidermidis. In addition, these cells produced IL-1 spontaneously in vitro, in contrast to resting maternal blood monocytes. As IL-1 increases resistance to infection, the presence of this cytokine represent a beneficial aspect of breast feeding.

Adult↗