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)

We describe an unusual example of cellular immunodeficiency associated with interleukin-2 deficiency in an otherwise healthy 15-year-old boy who had isolated cryptococcal osteomyelitis of the scapula at 10 years of age. His previous medical history was remarkable only for prolonged, severe varicella infection at 6 years of age. He had persistent moderate lymphopenia, anergy, and absent lymphocyte blastogenic responses to mitogens, antigens, or monoclonal T cell antibodies. Subnormal blastogenic responses were seen after exposure to high concentrations of phorbol esters. Immunoglobulin levels and specific antibodies were normal. The patient has been in good health since treatment of his osteomyelitis. However, his lymphocyte blastogenic responses to mitogens have remained absent during 4 years of observation; investigation of the cause revealed a specific interleukin-2 deficiency resulting from defective generation of interleukin-2 messenger ribonucleic acid. Secretion of interleukin-1 by monocytes was normal, suggesting that the abnormal blastogenic response and interleukin-2 production were due to a problem intrinsic to T lymphocytes. The generation of messenger ribonucleic acid for interleukin-4 was not affected. Interferon-gamma was produced at subnormal levels. The addition of recombinant interleukin-2 restored lymphocyte blastogenic responses and increased the expression of interleukin-2 receptors. The clinical findings and immunologic abnormalities present in this patient differ from other primary and secondary immunodeficiencies associated with interleukin-2 deficiency. Thus our observations in this patient extend the spectrum of immunodeficiencies associated with abnormalities in the production of this important cytokine.
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PMID:Cryptococcal osteomyelitis and cellular immunodeficiency associated with interleukin-2 deficiency. 144 48

Leukemia inhibitory factor (LIF) is a multi-potential cytokine which has been implicated in the hematopoietic regulatory machinery. For example, we have found that LIF is constitutively expressed in marrow stroma. Other investigators have reported that LIF affects remodeling of bone, and that, in concert with other growth factors, it stimulates hematopoietic stem cell proliferation. Moreover, in vivo animal trials reveal that, at high doses, administration of LIF induces myelosclerosis whereas, at lower doses, megakaryocytosis and thrombocytosis with reduced bone marrow cellularity and marrow lymphopenia are observed. Therefore, the role of LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and sclerosis merits investigation. Further, its megakaryocytic stimulatory properties suggest that LIF may be exploitable in the clinic to enhance platelet production.
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PMID:The modulatory hematopoietic activities of leukemia inhibitory factor. 149 63

This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma, Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers. Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets. Hematologic changes were cell-type- and cytokine-specific: transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection. Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia. Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.
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PMID:Acute hematologic effects of interferon alpha, interferon gamma, tumor necrosis factor alpha and interleukin 2. 190 9

The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS from Salmonella abortus equi was administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C-reactive protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor-alpha (TNF) and interleukin-1 beta serum levels were measured by enzyme-linked immunosorbent assay and interleukin-6 (IL-6) by bioassay. Dose-limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels greater than 8.0 ng/kg of body weight (MTD-2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL-6 serum concentrations increased from less than 4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above-mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15-10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL-6 increased in a dose-dependent manner although the constitutional symptoms are completely attenuated.
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PMID:Biological response to intravenously administered endotoxin in patients with advanced cancer. 225 60

Recombinant human IL-3 administered intravenously to rats as a single injection induced peripheral neutrophilia and monocytosis beginning at 4 to 6 hours after injection, peaking at 8 hours, and subsiding to normal by 12 to 24 hours. IL-3 did not induce an initial neutropenia such as accompanies endotoxin-, G-CSF-, and TNF-induced neutrophilia, or lymphopenia such as accompanies endotoxin-, IL-1-, and TNF-induced neutrophilia. The IL-3-induced peripheral neutrophilia was accompanied by a decrease in mature marrow neutrophils, indicating that the mechanism of neutrophilia was through marrow release rather than by demargination, which occurs after the administration of epinephrine or IL-6. The release of mature marrow neutrophils further suggests that IL-3 either has intrinsic neutrophil releasing activity or indirectly causes neutrophil release through the gene expression of a second cytokine. IL-3 induced a striking left-shifted myeloid hyperplasia in the bone marrow at 8 hours that morphologically was very similar to that observed after administration of endotoxin, a finding consistent with the hypothesis of previous investigators that endotoxin may in part act indirectly on hematopoietic cells by eliciting local marrow production of IL-3. Finally, IL-3 induced an increase in marrow pronormoblasts at 8 hours, consistent with the in vitro proliferative effect of IL-3 on erythroid stem cells. The combination of IL-3 and IL-6 induced a synergistic peripheral neutrophilia and monocytosis and a striking synergistic increase in marrow mast cells. The combination of IL-3 and IL-6 also induced an erythroid and left-shifted myeloid hyperplasia such as would be expected given the individual effects of these hematopoietic growth factors.
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PMID:Acute in vivo effects of IL-3 alone and in combination with IL-6 on the blood cells of the circulation and bone marrow. 280 84

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

The Janus tyrosine kinases (Jaks) play a central role in signaling through cytokine receptors. Although Jak1, Jak2, and Tyk2 are widely expressed, Jak3 is predominantly expressed in hematopoietic cells and is known to associate only with the common gamma (gamma c) chain of the interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 receptors. Homozygous mutant mice in which the Jak3 gene had been disrupted were generated by gene targeting. Jak3-deficient mice had profound reductions in thymocytes and severe B cell and T cell lymphopenia similar to severe combined immunodeficiency disease (SCID), and the residual T cells and B cells were functionally deficient. Thus, Jak3 plays a critical role in gamma c signaling and lymphoid development.
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PMID:Defective lymphoid development in mice lacking Jak3. 748 69

More immunosuppressive drugs than ever have recently graduated from the laboratory to extensive clinical trials of their safety and efficacy in patients undergoing transplantation. Although none of these drugs is perfect, they control different forms of rejection in stringent animal models more effectively than other immunosuppressants; yet these novel molecules suppress the immune system far more specifically than steroids and regimens that cause lymphopenia. Cyclosporin G and IMM 125 (analogues of cyclosporine) and FK506 are the only drugs that selectively inhibit T-cell proliferation by blocking cytokine synthesis. The primary action of rapamycin and leflunomide appears to be an inhibition of the actions of cytokines and growth factors on T, B, and some nonimmune cells. T and B cells are more sensitive than nonimmune cells to the depletion of purines and pyrimidines caused by mizoribine, mycophenolic acid, and brequinar sodium. Nucleotide depletion causes interruption of DNA synthesis and glycosylation of adhesion molecules in immune cells. Further differentiation of T and B cells after proliferation into fully functional immune cells is inhibited by unknown mechanisms by brequinar and deoxyspergualin. On the basis of preclinical studies, these drugs may effectively suppress clinical rejection that is (1) acute (all drugs), (2) chronic (rapamycin, leflunomide, and mycophenolic acid), or (3) antibody-mediated (brequinar, deoxyspergualin, mycophenolic acid, and rapamycin). Some drugs (FK506, deoxyspergualin, mycophenolic acid, rapamycin, and leflunomide) may reverse acute rejection refractory to conventional immunosuppression. These new drugs not only block different biochemical steps that normally lead to fully functional T and B cells after stimulation by alloantigen, but their toxicity profiles also differ. Results from preclinical studies predict that use of selected combinations of these drugs in patients will be more effective, less nephrotoxic, less myelotoxic, and less broadly immunosuppressive than current regimens based on cyclosporine, T-cell depletion, steroids, and azathioprine ... at least, that's the idea! Or as former Vice President Dan Quayle said, "It's a question of whether we're going to go forward into the future, or past to the back."
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PMID:New small molecule immunosuppressants for transplantation: review of essential concepts. 750 52

Substantial in vitro evidence suggests that nitric oxide may be a major mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibition and destruction in the initial events leading to insulin-dependent diabetes mellitus. Using NG-nitro-L-arginine methyl ester, an inhibitor of both the constitutive and the cytokine inducible forms of nitric oxide synthase, and aminoguanidine, a preferential inhibitor of the inducible form of nitric oxide synthase, we investigated the impact of inhibiting nitric oxide production on food-intake, body weight and temperature, blood glucose, plasma insulin, glucagon, corticosterone and leukocyte- and differential-counts in normal rats injected once daily for 5 days with interleukin 1 beta (IL-1 beta) (0.8 microgram/rat = 4.0 micrograms/kg). Inhibition of both the constitutive and the inducible forms of nitric oxide synthase prevented IL-1 beta-induced fever, hyperglycaemia, hypoinsulinemia, and hyperglucagonemia, and partially prevented lymphopenia and neutrophilia, but had no effect on IL-1 beta-induced anorexia and changes in plasma corticosterone. Preferential inhibition of the inducible form of nitric oxide synthase using two daily injections of 5 mg/rat of aminoguanidine prevented IL-1 beta-induced hyperglycaemia and hypoinsulinaemia, and slightly reduced the pyrogenicity of IL-1 on 3 out of 5 days. Higher doses of aminoguanidine (100 mg/rat) prevented lymphopenia and neutrophilia. We conclude that nitric oxide produced by the inducible form of nitric oxide synthase, mediates the IL-1 beta-induced inhibition of insulin release and that the effect of IL-1 beta on temperature, pancreatic alpha-cells, and leukocyte differential counts seems to be mediated by nitric oxide produced by the constitutive form of nitric oxide synthase.
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PMID:Interleukin 1 beta induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases. 753 59

Endothelial cells express adhesion molecules and release free forms (e.g., sELAM-1, sGMP-140, sICAM-1 and sVCAM-1). Compared with controls, the serum levels of these soluble adhesion molecules (SAM) were significantly increased in patients with rheumatoid arthritis. We investigated whether this was associated with the circulating cytokines and changes in peripheral blood T-lymphocyte (T-PBL) subsets. In healthy subjects, sELAM-1 correlated with the serum levels of Il-1 beta, Il-1 receptor antagonist (Il-1RA) and Il-6, while sGMP-140 was associated with Il-8, and sVCAM-1 was related to Il-7 and Il-8. Thus, already in controls, relations exist between the levels of SAM and circulating cytokines. The rheumatoid arthritis patients with low and high serum levels of IgA- and/or IgM-rheumatoid factors (RF) were separately analyzed. They have different cytokine profiles and showed distinct correlations. In patients with low RF, sGMP-140 and sVCAM-1 correlated with Il-1 beta, while sICAM-1 was associated with Il-7 and TNF-alpha. In patients with high RF, sELAM-1 correlated with Il-1RA, and sGMP-140 was associated with many cytokines (e.g., GM-CSF, MIP-1 alpha and TNF-alpha). In addition, lymphopenia (less than 1000 lymphocytes/microliters) was shown in 30% of the patients, and 20% (mostly with low RF levels) had reduced levels of "primed" CD45RO+ cells among T-PBL. In controls, cytokines (Il-7, Il-8 and GM-CSF), but not SAM, were associated with less CD45RO+ T-PBL. In patients with low RF only, sGMP-140 and sELAM-1 correlated with the depletion of "primed" CD4+ and CD8+ T-PBL respectively. In such patients, Il-1 beta and GM-CSF also correlated with less CD8+, CD45RO+ T-PBL. Thus, particularly in patients with low RF, increased SAM, possibly released by the endothelial cells, might reflect the cytokine-induced activation of the vascular endothelium and the extravasation of some CD45RO+ T-PBL.
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PMID:Increased soluble endothelial adhesion molecules in rheumatoid arthritis correlate with circulating cytokines and depletion of CD45RO+ T-lymphocytes from blood stream. 753 32


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