Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of IL-1 alpha, IL-2, IL-6 and TNF-alpha were measured immunoradiometrically in the sera of 82 myelodysplastic (MDS) patients at diagnosis in an attempt to identify possible relationships between serum cytokine levels and clinical and laboratory parameters of the patients. We found that serum IL-6 and TNF-alpha concentrations were significantly higher in the group of MDS patients than in the normal controls (p < 0.03 and p < 0.001, respectively), while serum IL-1 alpha and IL-2 levels did not differ statistically between patients and control subjects. Elevated serum IL-6 and TNF-alpha concentrations were mainly seen in patients with high-risk myelodysplasia (MDS), i.e. patients with chronic myelomonocytic leukemia (CMML) (p < 0.05 and p < 0.001, respectively), refractor anemia with excess of blasts (RAEB) (p < 0.01 and p < 0.001, respectively), or refrochopy anemia with excess of blasts in transformation to acute leukemia (RAEB-t) (p < 0.001 and p < 0.001, respectively). Patients with low-risk disease, i.e. patients with refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS), had serum cytokine levels comparable to those of controls. Patients' serum IL-6 and TNF-alpha correlated inversely with the hemoglobin concentration (p < 0.01 and p < 0.05, respectively) and positively with the absolute number of circulating myeloblasts (p < 0.01 and p < 0.001, respectively) and the proportion of bone marrow (p < 0.001 and p < 0.001, respectively) myeloblasts. A negative correlation was also noted between serum TNF-alpha concentrations and patients' survival in high-risk MDS (p < 0.02). We concluded that elevated serum IL-6 and TNF-alpha values are seen mainly in patients with high-risk disease, and that high serum TNF-alpha concentrations are predictive of shortened survival in this group of patients.
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PMID:Elevated serum TNF-alpha concentrations are predictive of shortened survival in patients with high-risk myelodysplastic syndromes. 970 53

Hemophagocytic lymphohistiocytosis (HLH), also referred to as familial erythrophagocytic lymphohistiocytosis, is a rare disorder of infancy associated with proliferation of activated histiocytes and T cells, anemia, thrombocytopenia, and fevers. This disorder appears to be due to the uncontrolled activation of T cells producing IL-2, tumor necrosis factor-alpha, and interferon-gamma. Untreated, the disorder is universally fatal. Various deficits in immune function have been described during acute disease activity including impaired T cell function, impaired monocyte-mediated antibody-dependent cytotoxicity, impaired natural killer cell function, and impaired IL-1 production. We examined natural killer cell function in familial HLH patients to determine whether this finding was consistently associated with the disease. We also examined natural killer cell function in asymptomatic parents and siblings of patients. Impaired natural killer cell function was identified in all patients and in some family members, including obligate carrier parents. This implies that one potential genetic defect in HLH may result in depressed natural killer function, but that this may not be sufficient to reliably predict eventual progression to disease.
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PMID:Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. 977 32

Interleukin 6 (IL-6) has antitumor activity comparable to IL-2 in murine models with less toxicity. Because the biological effects of intermittent and continuous infusions may differ, we conducted two concurrent Phase I trials of daily x5, 1-h, and continuous 120-h i.v. infusions to determine the toxicity, biological effects, and maximum tolerated dose of i.v. IL-6. Cohorts of six patients with advanced cancer received escalating doses (1, 3, 10, 30, 100, and 150 microgram/kg/day) of recombinant human IL-6 on days 1-5 and 8-12 of each 28-day course (1-h trial) or on days 1-5 of each 21-day course (120-h trial). Treatment was administered in regular inpatient wards and in outpatient clinics and was withheld in the event of grade 3 toxicity. Sixty-nine patients (1-h trial, n = 40; 120-h trial, n = 29) were enrolled, including 27 with renal cancer and 16 with melanoma. All were ambulatory, and 40 were asymptomatic. Fever (97%), anemia (78%), fatigue (56%), nausea or vomiting (49%), and elevated serum transaminase levels (42%) were the most frequent toxicities. Transient hypotension developed in 23 patients (33%). There were three deaths during the study due to progressive disease and/or infection. There were no objective responses. Dose-related increases in platelet counts and C-reactive protein levels were detected in most patients. Principal dose-limiting toxicities included atrial fibrillation (1 episode in the 1-h trial and 4 episodes in the 120-h trial) and neurological toxicities (3 episodes in the 1-h trial and 4 episodes in the 120-h trial). The neurological toxicities included confusion, slurred speech, blurred vision, proximal leg weakness, paraparesis, and ataxia. These effects were transient and reversed when IL-6 was discontinued. IL-6 can be given by i.v. infusion at biologically active doses with acceptable toxicity. Dose-limiting toxicities consisted mainly of a spectrum of severe but transient neurological toxicities and occasional episodes of atrial fibrillation. The maximum tolerated doses recommended for use with these i.v. schedules in Phase II trials are 100 microgram/kg/day by daily x5 1-h infusion and 30 microgram/kg/day by 120-h infusion. Phase II trials will be performed to determine the antitumor activity of IL-6 and better define its toxicity. Patients in these and other IL-6 studies should be monitored closely for neurological and cardiac effects.
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PMID:Concurrent phase I trials of intravenous interleukin 6 in solid tumor patients: reversible dose-limiting neurological toxicity. 981 35

We report a case of granular lymphocyte proliferative disorder accompanied with hemolytic anemia and neutropenia. Phenotypes of the cells were T cell receptor gammadelta+ CD3+ CD4- CD8+ CD16+ CD56- CD57-. Southern blot analysis of T cell receptor beta and gamma chains demonstrated rearranged bands in both. Chromosomal analysis after IL-2 stimulation showed deletion of chromosome 6. Sorted gammadelta+ T cells showed an increase in Fas ligand expression compared with the levels in sorted alphabeta+ T cells. The expression of Fas ligand on these gammadelta+ T cells increased after IL-2 stimulation. The patient's anemia improved along with a decrease in granular lymphocyte count and disappearance of the abnormal karyotype without treatment. The expression of Fas ligand may be involved in spontaneous regression of granular lymphocyte proliferation with hemolytic anemia.
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PMID:Abnormal proliferation of CD4- CD8+ gammadelta+ T cells with chromosome 6 anomaly: role of Fas ligand expression in spontaneous regression of the cells. 1020 5

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

Flaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that causes severe anaemia, forestomach papillomatosis and a papulosquamous skin disease that resembles psoriasis in humans. In the present paper, it is reported that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of adult mutant (fsn/fsn) mice were found to contain almost 10-fold more leucocytes than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that this predominantly lymphoid hyperplasia was characterized by approximately equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However, expansion within the T cell compartment was non-random, because fsn/fsn PLN had a considerably reduced ratio of CD4+ to CD8+ T cells (1.08 +/- 0.37) compared to +/? PLN (2.47 +/- 0.44, P < 0.0001). In vitro assays of cellular proliferation in response to T and B cell growth factors showed that fsn/fsn PLN cells were hyperresponsive to IL-2, IL-4 and IL-7 when compared with PLN cells from +/? mice. Studies using mesenteric lymph node and peripheral blood cells showed that hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in newborn mice showed that the lymphoid disturbances caused by fsn are established at least as early as 2 weeks of age, a time that precedes the onset of the earliest clinical skin lesions. These data implicate a role for the fsn gene product in regulating the size and content of the peripheral lymphoid compartment.
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PMID:The peripheral lymphoid compartment is disrupted in flaky skin mice. 1065 23

Despite considerable progress in recent years in the understanding of the biology of multiple myeloma (MM), this disease remains incurable, although many new therapeutic approaches are under evaluation. The rapid development of recombinant technologies has permitted the production of large amounts of cytokines and growth factors, favoring the use of biotherapies also in this disease. Among these products, the interferons have been the most extensively used in clinical trials, giving the most promising results especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies, or to high dose chemotherapies followed by bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation. However, more recently, a large number of cytokines and growth factors have been introduced in the clinical practice. Data of the use of erythropoietin have consistently demonstrated the role of this growth factor in ameliorating the grade of anemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Using hematopoietic growth factor in the mobilization of PBSC, the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of chemotherapy could be reduced. Despite the large amount of experimental data indicating a role for interleukins, as IL-2 and IL-6, in controlling tumor growth, there are only few clinical studies dealing with their use in MM. Results show that they arrest tumor progression rather than aid tumor regression, for this reason it appears that IL-2 and anti IL-6 antibodies should be investigated as maintenance therapy, in MM patients responding to chemotherapy. In the future it will be necessary to clarify for MM patients the role of other cytokines such as IL-1 beta and TNF alpha. A possible strategy to improve the clinical outcome of MM patients is to prevent the regrowth of residual tumor cells by establishing adoptive immunity at the stages of minimal residual disease previous obtained using chemotherapy. To this end a possible strategy is to induce an immune response against residual tumor cells by passive (using monoclonal antibodies) or active (using the idiotype expressed by malignant cells) immunotherapy.
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PMID:[The role of biotherapy in multiple myeloma]. 1107 35

Idiopathic CD4+ T cell lymphocytopenia was unexpectedly detected in a 33-year-old, otherwise healthy young woman with no HIV or other viral infection, autoimmune, or neoplastic disease or increased susceptibility to infection. CD4+ T cell levels were 60-140/microl over a 3.5-year period. Following an uneventful pregnancy, the patient developed anemia and interstitial nephritis associated with a plasma cell dyscrasia with a monoclonal IgA gammopathy and a shifting immunoglobulin pattern that included IgG and IgA monoclonal proteins and increased urinary light chains. Osteolytic lesions were never detected and bone marrow aspirations revealed up to 10% atypical plasma cells. Various therapies often used in treating multiple myeloma only temporarily controlled the increasing renal damage. IL-2 therapy of 600,000 to 1 million units subcutaneously daily resulted in increased CD4+ T cells to normal levels, a decrease in the gammopathy, a return of renal function, energy, and weight gain, and apparently normal health status sustained for 2 years. The findings are compatible with a potentially fatal but nonmalignant immunoregulatory disorder that can be controlled by IL-2 administration.
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PMID:Idiopathic CD4+ T cell lymphocytopenia evolving to monoclonal immunoglobulins and progressive renal damage responsive to IL-2 therapy. 1131 2

Hepatitis B (HB) in haemodialysis patients results in morbidity and mortality, through chronicity, which leads to cirrhosis and liver carcinoma, even after renal transplantation. Hepatitis B vaccination is protective against HB virus infection. Suppressed immunity in renal failure leads to low HB vaccination success rates. Uremia, inadequate dialysis, use of low biocompatibility dialysis material, hyperparathyroidism, anemia, iron overload and malnutrition are all factors contributing to depressed immunity. Renal failure, associated with chronic inflammation, leads to impaired monokine production which results in decreased immunity. This impairment could result from defective HLA-DR B7-2 expression on monocytes. Hepatitis B vaccination non-responders express increased levels of HLA class II alleles (T-cell immune response modulators) DRB1 01 (DR1) and DRB1 15 (DR15). Various methods have been used to enhance the immune response to HB vaccination such as recombinant adjuvants, thymopentine, IL-2, levamisole and GM-CSF: they have produced variable results. Better dialysis biocompatibility and adequacy have also been conducted to overcome this low immune response. Response to conventional intramuscular HB vaccination is considered an index of adequate dialysis and low inflammatory state, both associated with better cardiovascular outcome and survival. HB vaccination reinforcement techniques evolved from an initial intramuscular double/multiple-dosing regimen to more frequent intradermal smaller dose injection. This newer regimen achieves a higher and almost complete seroconversion rate, although frequent boosters shots are necessary to maintain protective levels. Experience with pre-S1/S2, third generation, vaccines is limited and they have not been proven to be more effective than intradermally administered S antigens. Recombinant HB vaccines, intradermally administered, have been shown to elicit an immune response in all renal failure patients. Additionally the use of recombinant erythropoietin treatment to correct anemia contributes to this success.
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PMID:Recombinant hepatitis B vaccination in renal failure patients. 1267 88

Infection with chicken anaemia virus (CAV), a circovirus, can result in immunosuppression and subsequent increased susceptibility to secondary infections. This is the first report of impairment of pathogen-specific cytotoxic T lymphocytes (CTL) after natural and experimental infection of chickens with CAV and Marek's disease virus (MDV) or reticuloendotheliosis virus (REV). MDV- and REV-specific CTL were generated at 7 days post infection by 9-30-day-old-chickens that were positive for maternal antibodies to CAV at 9-17 days of age. Replication of CAV could not be demonstrated in these chickens using quantitative real-time polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR assays. In contrast, REV-specific CTL failed to develop when chickens negative for maternal antibodies at 9-17 days of age were infected. Infection with CAV at 45 days of age after CAV maternal antibodies had waned also caused a decreased REV-specific CTL response. In these chickens increased levels of CAV DNA of up to 107 copy numbers per micro g DNA and increased relative transcript levels of CAV by up to a factor of 106 were detected by quantitative real-time PCR and RT-PCR. Interleukin (IL)-1beta and IL-2 mRNA levels were not significantly affected by CAV infection at 7 or 14 days p.i. Similar assays for interferon-gamma (IFN-gamma) transcripts demonstrated a 10-fold increase in IFN-gamma mRNA levels at 7 days post infection following REV or REV + CAV infection, while CAV alone caused a two- to fourfold increase. These results show a strong link between CAV antibody status, CAV replication, and the ability to generate REV-specific CTL. It is likely that the immunosuppressive effects of subclinical infection have previously been underestimated.
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PMID:Infection with chicken anaemia virus impairs the generation of pathogen-specific cytotoxic T lymphocytes. 1275 24


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