Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 2 (IL-2) treatment of malignancies is often associated with severe toxicity, and the alterations observed after high dose administration of IL-2 are similar to those induced by recombinant tumor necrosis factor (TNF). We therefore examined the hypothesis that IL-2 induces TNF gene expression in vivo. Purified, recombinant human IL-2 was injected intraperitoneally into mice which had been previously primed with complete Freund's adjuvant (CFA). Biologically-active TNF was detected in the ascites fluid of CD-1 mice; it was detectable 30 minutes after IL-2 and peaked at 1 hour (500 +/- 158 units/ml). Plasma levels of TNF also peaked at 1 hour at 32 +/- 4 units/ml. Similar kinetics were observed in CBA/J mice. TNF specific mRNA was also present in the ascites cells, and peaked 30 minutes after IL-2 injection into CBA/J mice. Injection of vehicle containing 10 times the maximum contaminating dose of endotoxin did not induce TNF above background levels. As a further control for potential endotoxin contamination, IL-2 was injected into endotoxin hyporesponsive C3H/HeJ mice. These mice also demonstrated the rapid upregulation of biologically-active TNF in the ascites, with peak production occurring at 1 hour (125 +/- 47 units/ml). The induction of biologically-active TNF in the C3H/HeJ mice was associated with a peripheral blood neutrophilia and lymphopenia, pathophysiologic alterations that have been attributed to TNF. These data show that a single injection of purified, recombinant IL-2 induces TNF gene expression in vivo.
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PMID:Interleukin 2 induces tumor necrosis factor gene expression in vivo. 193 86

Monokines may contribute to the regulation of hematopoiesis and circulating numbers of leukocytes during chronic inflammation. The hematologic effects of daily intravenous injection of the recombinant monokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and granulocyte-colony stimulating factor (G-CSF) were therefore studied in the bone marrow and circulation of rats over the course of a week. TNF induced daily neutrophilia and lymphopenia with no evidence of tachyphylaxis. TNF also induced a slight decrease in early myeloid forms in the marrow, but, more strikingly, induced a marked erythroid hyperplasia of late normoblasts, although no changes other than a slight reticulocytosis were noted in the peripheral red blood cell compartment. IL-1 also induced daily neutrophilia and lymphopenia with no evidence of tachyphylaxis. IL-1 differed from TNF in the induction of a significant myeloid hyperplasia and in the lack of any effect on the erythroid elements of the marrow. The lack of tachyphylaxis to the chronic administration of both TNF and IL-1 suggests that the mechanism of endotoxin-induced tachyphylaxis is not at the level of the effector cell response to these endogenous cytokines. G-CSF induced a biphasic peripheral neutrophilia first peaking on day one, reaching a nadir on day 4, and then rising progressively again until day 7. The low level of neutrophilia on day 4 is not due to marrow depletion of neutrophils secondary to the neutrophil releasing activity of G-CSF because the marrows of G-CSF-treated rats on both days 3 and 7 contained over twice the number of mature neutrophils as controls. Thus, the trough in the neutrophilia induced by G-CSF is postulated to be due to an as-yet unidentified negative feedback mechanism that inhibits neutrophil release from the marrow.
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PMID:The hematologic effects of chronic administration of the monokines tumor necrosis factor, interleukin-1, and granulocyte-colony stimulating factor on bone marrow and circulation. 246 82

Endotoxin reduces the release among other cytokines of tumor necrosis factor (TNF) and interleukin 1 (IL-1) and causes peripheral lymphopenia and a dose-response-dependent initial neutropenia followed by a monophasic neutrophilia. TNF alone induces lymphopenia and an initial neutropenia followed by a biphasic neutrophilia. IL-1 alone induces lymphopenia and a monophasic neutrophilia. TNF-plus-IL-1 caused a greater lymphopenia than either monokine alone, suggesting that both monokines contribute to LPS-induced lymphopenia. TNF-plus-IL-1 induced neutropenia similar in magnitude to that induced by TNF alone and induced a neutrophilia significantly greater than that induced by either monokine alone, suggesting that LPS-induced neutropenia is caused by TNF, while LPS-induced neutrophilia is due to the combined effects of TNF and II-1. TNF and IL-1 were administered together with LPS to simulate the in vivo condition of endogenous monokine release during gram-negative bacteremia. TNF combined with LPS increased both the duration and magnitude of LPS-induced lymphopenia, LPS-induced neutropenia, and LPS-induced neutrophilia. TNF-plus-LPS treated rats at 2 hours after injection exhibited a striking 93% decrease in bone marrow neutrophils even though no peripheral neutrophilia was yet apparent, suggesting that the subsequent neutrophilia was due to demargination and recirculation of neutrophils sequestered in the peripheral vasculature immediately after their release from the bone marrow. Epinephrine, which causes neutrophilia by demargination but not by release of marrow neutrophils, reversed the initial neutropenia in TNF-plus-LPS-treated rats and increased the neutrophilia. IL-1 combined with LPS increased LPS-induced neutrophilia, suggesting that endogenous IL-1 also contributed to LPS-induced neutrophilia. Corynebacterium parvum-primed rats with hyperplasia of the monocyte-macrophage system and treated with TNF differed from naive rats treated with TNF in that the second peak was as great as the initial peak of neutrophilia, supporting the hypothesis that the second peak of TNF-induced neutrophilia is due to the release of endogenous monokines. In conclusion, exogenous TNF, IL-1, and adrenal hormones affect circulating numbers of lymphocytes and neutrophils in a fashion consistent with their postulated endogenous role in the regulation of leukocyte trafficking during bacterial infection.
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PMID:Hematologic interactions of endotoxin, tumor necrosis factor alpha (TNF alpha), interleukin 1, and adrenal hormones and the hematologic effects of TNF alpha in Corynebacterium parvum-primed rats. 278 48

Human recombinant interleukins 1 alpha and 1 beta (rIL-1 alpha and -1 beta) both induced monophasic peripheral neutrophilia and lymphopenia in Lewis rats 1.5 hr after i.v. injection. The kinetics of rIL-1 alpha- and -1 beta-induced neutrophilia were similar to those induced by human monocyte-derived IL-1, IL-1 alpha, and IL-1 beta, and the peripheral neutrophilia was accompanied by a marked decrease in marrow neutrophils. Arachidonic acid metabolites are implicated as biochemical intermediates in the production of the neutrophilia but not lymphopenia, since indomethacin and dexamethasone both completely abrogated IL-1-induced neutrophilia but did not affect the IL-1-induced lymphopenia. Acetylsalicylic acid, a cyclooxygenase inhibitor, did not inhibit IL-1-induced neutrophilia, suggesting that products of the lipoxygenase rather than the cyclooxygenase pathway of arachidonate metabolism may contribute to the neutrophilia. Human recombinant tumor necrosis factor-alpha (rTNF) administered i.v. to Lewis rats induced peripheral neutropenia, two peaks of neutrophilia, and lymphopenia. A wide range of doses of rTNF resulted in an initial neutropenia at 0.5 hr after injection followed by a first peak of neutrophilia at 1.5 hr and a second peak of neutrophilia at 6 hr. The initial neutropenia and the first peak of neutrophilia were not inhibited by pretreatment of rats with dexamethasone, indomethacin, or aspirin. The second peak of neutrophilia was inhibited by both dexamethasone and indomethacin, but was not at all inhibited by aspirin, suggesting that the second peak of neutrophilia is mediated by the release of endogenous cytokines, especially by IL-1, since exogenous IL-1-induced neutrophilia is also completely inhibited by dexamethasone and indomethacin but not by aspirin. The TNF-induced peripheral neutrophilia is also accompanied by a significant depletion of bone marrow neutrophils, indicating that the source of increased circulating neutrophils is, at least in part, via recruitment of marrow neutrophils. Systemic blood pressure was not affected by IL-1 or rTNF at the dosages employed, showing that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic change-related release of adrenal hormones. Adrenalectomy did not alter the IL-1- or rTNF-induced neutrophilia or lymphopenia, also demonstrating that neither monokine mediates its hematologic effects on peripheral blood leukocytes via the release of adrenal hormones.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. 331 83

15 patients aged between 24 and 66 years with 10 different malignant tumor diseases were treated with a recombinant human tumor necrosis factor preparation PAC-4D in a phase-I trial. The starting dose was 10(5) U PAC-4D as an intravenous short infusion. The maximally tolerable dose is around 18 X 10(5) U/m2. As the main clinical side effects were observed: fever, chills, hypertension with subsequent hypotension, lethargy, transient somnolence, headache, neurological deficiency symptoms, nausea and vomiting. Important laboratory-chemical parameters were the increase in transaminases and, in higher dose levels, leukocytosis with the left shift and lymphopenia in the differential blood picture. As dose-limiting toxicity are estimated hypotension, and neurological side effects and hepatotoxicity. In one female patient who received 27 X 10(5) U PAC-4D there appeared pronounced, histologically verified necroses in the metastases of a malignant fibrous histiocytoma.
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PMID:Human pharmacological investigation of a human recombinant tumor necrosis factor preparation (PAC-4D) a phase-I trial. 337 52

Tumor necrosis factor is a peptide cytokine that induces hemorrhagic necrosis of some tumors and is responsible for the severe cachexia observed in advanced infectious diseases. We evaluated the acute effects of intravenous administration of purified human recombinant tumor necrosis factor in mice. With as little as 0.01 microgram/mouse (0.00045 mg/kg) a peripheral blood lymphopenia and neutrophilia developed as determined by flow cytometric analysis. At 1 microgram/mouse, the lymphopenia was both relative (21 +/- 3% versus 65 +/- 3%; p less than 0.001 treated versus control) and absolute (62 +/- 10 versus 229 +/- 29 X 10(4) cells/ml p less than 0.001). The neutrophilia was also relative (79 +/- 3% versus 34 +/- 3%; p less than 0.001 treated versus control) and absolute (237 +/- 26 versus 110 +/- 13 X 10(4) cell/ml; p less than 0.001). The neutrophilia was due to an increase in both mature and immature cells. At the higher doses the animals developed hypovolemic shock with an increased hematocrit and watery diarrhea occurred. Microscopic examination of the small bowel disclosed necrosis of the villi. Ultrastructural studies of the small bowel confirmed the necrosis and also showed severe endothelial cell damage, pyknotic nuclei, exocytosis of Paneth cell granules, and extravasation of red blood cells and neutrophils into the interstitium. A vascular leak syndrome developed with preferential fluid loss into the small and large bowel. These data demonstrate the potent in vivo effects of purified human recombinant tumor necrosis factor.
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PMID:Acute in vivo effects of human recombinant tumor necrosis factor. 359 6

Tumor necrosis factor is a potent agent possessing diverse biological functions. We investigated the effects of intravenous administration of human recombinant tumor necrosis factor (TNF) on immune cell populations in CBA/J mice. The animals developed a significant lymphopenia and neutrophilia both reaching a maximum at 4 hours post-injection with a trend towards resolution to normal values by 6 hours. The lymphopenia was both relative and absolute. Similarly, the neutrophilia was both relative and absolute and was due to the presence of both immature and mature neutrophils. As the neutrophilia and lymphopenia occurred concomitantly, there was no difference at any time point in the total number of peripheral blood white cells. Extensive controls were done to rule out LPS contamination in the TNF preparation. These data demonstrate the potent effects of intravenous administration of human recombinant tumor necrosis factor on peripheral blood constituents.
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PMID:Tumor necrosis factor-induced alterations in circulating leukocyte populations. 380 Oct 29

Preclinical studies have shown that anti-CD3 antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose interleukin-2 (IL-2) and induce the in vivo rejection of murine tumors. A Phase IA/IB trial combining a murine monoclonal antibody, anti-CD3 antibody (OKT3), with low-dose continuous-infusion IL-2 was conducted in cancer patients to define the toxicity and immunologic effects of this combination. OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the IL-2 course without OKT3 to assess the effects of OKT3 on the IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the OKT3/IL-2 course and 18 completing both OKT3/IL-2 and IL-2 alone courses. OKT3 administration was associated with acute hypotension with fevers of > 40 degrees C and in two patients cerebral vascular infarcts. At 600 micrograms/m2 OKT3, these toxicities were dose limiting. In a dose-dependent manner, OKT3 induced the transient release of tumor necrosis factor (TNF) and IL-6 into the serum and a profound lymphopenia. OKT3 did not significantly enhance the toxicity of this schedule of IL-2 administration. All solid tumor patients treated at 100-600 micrograms/m2 OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with renal cell cancer treated at the 600-micrograms/m2 OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a sarcoma and a melanoma patient treated at 100- and 400-micrograms/m2 OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion IL-2 regimen and will not be pursued further in clinical trials.
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PMID:A phase IA/IB trial of anti-CD3 murine monoclonal antibody plus low-dose continuous-infusion interleukin-2 in advanced cancer patients. 761 43

Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application is restricted by associated toxicities. Previous studies implicate tumor necrosis factor (TNF) as an important mediator of certain IL-2-induced toxicities. We hypothesized that soluble TNF receptor (sTNFr), a TNF antagonist, would alter lymphocyte trafficking into normal tissues and ameliorate IL-2-induced toxicity. Four groups of C57BL/6 mice were treated for 4 days with intraperitoneal injections of 100,000 IU IL-2 alone, 100,000 IU IL-2 and 30 micrograms sTNFr combined, 30 micrograms sTNFr alone, or equal volumes of saline. Animal activity was graded and blood obtained for SGPT and SGOT. At necropsy, organs were harvested for wet:dry ratios as a measurement of organ edema. The lung, liver, and thymus were examined histologically for lymphocytic infiltration and graded on a scale of 1 to 5. IL-2-treated groups had a statistically significant increase in organ edema, lymphocytic infiltration into the lung and liver, liver enzyme elevation, and pancytopenia when compared with controls. Soluble TNFr significantly suppressed IL-2-induced pulmonary lymphocytic infiltration and associated serum lymphopenia without significant alteration of other IL-2-induced effects. These data implicate TNF as a mediator of the pulmonary lymphocytic infiltration and of lymphopenia that accompanies IL-2 therapy and further suggest that alternative mechanisms are involved in other IL-2-induced deleterious effects.
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PMID:Interleukin-2-induced lymphocyte infiltration of multiple organs is differentially suppressed by soluble tumor necrosis factor receptor. 812 Nov 66

Antibody neutralization studies have established interferon gamma (IFN-gamma) as a critical mediator of endotoxic shock. The advent of IFN-gamma receptor negative (IFN gamma R-/-) mutant mice has enabled a more direct assessment of the role of IFN-gamma in endotoxin (lipopolysaccharide [LPS]-induced shock. We report that IFN gamma R-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifesting well before the synthesis and release of LPS-induced IFN-gamma. LPS-induced lymphopenia, thrombocytopenia, and weight loss seen in wild-type mice were attenuated in IFN gamma R-/- mice. IFN gamma R-/- mice tolerated 100-1,000 times more LPS than the minimum lethal dose for wild-type mice in a D-galactosamine (D-GalN)/LPS model. Serum tumor necrosis factor (TNF) levels were 10-fold reduced in mutant mice given LPS or LPS/D-GalN. Bone marrow and splenic macrophages from IFN gamma R-/- mice had a four- to sixfold decreased LPS-binding capacity which correlated with similar reduction in CD14. Serum from mutant mice reduced macrophage LPS binding by a further 50%, although LPS binding protein was only 10% reduced. The expression of TNF receptor I (p55) and II (p75) was identical between wild-type and mutant mice. Thus, depressed TNF synthesis, diminished expression of CD14, and low plasma LPS-binding capacity, in addition to blocked IFN-gamma signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFN gamma R-/- mice to endotoxin.
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PMID:Interferon gamma receptor deficient mice are resistant to endotoxic shock. 816 30


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