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

A major hurdle to lipoplex-based systemic gene delivery is acute inflammatory toxicity. In this study, a safe, simple, and effective alternative to lipoplex administration, specifically, sequential injection of cationic liposome and plasmid DNA, was evaluated. When plasmid DNA was injected into the tail vein of mice 2-5 min after the injection of cationic liposomes, 50-80% lower levels of proinflammatory cytokines, including TNF-alpha, IL-12, and IFN-gamma, were observed compared to lipoplex injection. The sequential injection technique yielded a two- to fivefold higher level of transgene expression in the lung and was more effective in repeated dosing than lipoplex. Other types of lipoplex-associated toxicities, such as neutropenia, lymphopenia, thrombocytopenia, and complement depletion, were also significantly reduced with sequential injection. The reduction in cytokine release was observed with several different liposome formulations and appeared to be a general phenomenon.
Mol Ther 2001 May
PMID:Sequential injection of cationic liposome and plasmid DNA effectively transfects the lung with minimal inflammatory toxicity. 1135 72

The innate immune response to intraportally infused adenoviral vector was evaluated in rhesus monkeys. A first-generation adenovirus-expressing lacZ (Ad-lacZ) was administered at a dose just below that which causes severe morbidity. The response to vector was evaluated for the initial 24 h following infusion. Clinical findings during this time were primarily limited to petechiae, consistent with the development of thrombocytopenia and biochemical evidence of disseminated intravascular coagulation. Serum transaminases were elevated and a lymphopenia developed. Tracking of fluorescent-labeled vector demonstrated distribution to macrophages and dendritic cells of the spleen and Kupffer cells of the liver. A systemic release of the cytokine IL-6 occurred soon after vector infusion. Analysis of splenic cells revealed acute activation of macrophages and dendritic cells followed by massive apoptosis. Bone marrow cultures demonstrated normal erythroid and primitive progenitors with a significant decrease in myeloid progenitors. Similar findings, except the abnormality in bone marrow cultures, were observed in monkeys who received an identical dose of Ad-lacZ in which vector genes were inactivated with psoralen and UV irradiation. These data suggest that inadvertent targeting of antigen-presenting cells following intraportal infusion of vector leads to a systemic cytokine syndrome which may be triggered by the viral capsid proteins.
Mol Ther 2001 May
PMID:Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. 1135 76

Integrins link the cell's cytoskeleton to the extracellular matrix, as well as to receptors on other cells. These links occur not only at focal contacts but also at smaller integrin-containing protein complexes outside of focal contacts. We previously demonstrated the importance of focal contact-independent integrin-cytoskeleton interactions of beta(2) integrins: activation of adhesion resulted from a release of integrins from cytoskeletal constraints. To determine whether changes in integrin-cytoskeleton interactions were related to activation of the integrin, we used single particle tracking to examine focal contact-independent cytoskeletal associations of alpha(IIb)beta(3)-integrin, in which activation results in a large conformational change. Direct activation of alpha(IIb)beta(3) by mutation did not mimic activation of lymphocytes with phorbol ester, because it enhanced integrin-cytoskeleton interactions, whereas activation of lymphocytes decreased them. Using additional integrin mutants, we found that both alpha- and beta-cytoplasmic domains were required for these links. This suggests that 1) both beta(2)- and beta(3)-integrins interact with the cytoskeleton outside of focal contacts; 2) activation of a cell and activation of an integrin are distinct processes, and both can affect integrin-cytoskeleton interactions; and 3) the role of the alpha-subunit in integrin-cytoskeleton interactions in at least some circumstances is more direct than generally supposed.
Mol Biol Cell 2001 May
PMID:Activation-enhanced alpha(IIb)beta(3)-integrin-cytoskeleton interactions outside of focal contacts require the alpha-subunit. 1135 39

Lymphocytes are important components of the immune system. Dietary lipids affect the functioning of the immune system. Changes in the lipid composition of the lymphocyte membrane is a case in point. Membrane structural changes are reflected in the altered function of the cell. Lymphocyte proliferation and lymphocyte rosetting are membrane associated phenomena. Ghee, is a clarified butter product, commonly used in the Indian diet. It is rich in saturated fatty acids and also contain oxysterols which are generated on prolonged heating of ghee. Male weanling rats were fed 2.5% (of the total fat levels) of fresh or thermally oxidized ghee for a period of 8 weeks. The control rats were fed groundnut oil. Lipid composition of lymphocytes in ghee fed rats showed changes. In vitro lipid peroxidation of lymphocyte membranes increased by 26% in oxidized ghee fed rats. Na+K+ ATPase activity was decreased in oxidized ghee fed rats (18%). Lymphocyte proliferation was reduced in ghee fed rats (32%), compared to the controls, irrespective of the mitogens used (Con-A or PHA), or the tissue (splenocytes or peripheral blood lymphocytes). Oxysterols present in oxidized ghee are the likely agents inhibiting lymphoproliferation. Rosetting of lymphocytes decreased in the fresh ghee fed rats by 16% and in oxidized ghee fed rats by 25%. Membrane fluidity declined in the oxidized ghee fed rats. It is concluded that feeding ghee results in decreased proliferation of lymphocytes. Also, feeding oxidised ghee results in decreased proliferation of lymphocytes through alterations in the structure of the lymphocyte membranes in the rat.
Mol Cell Biochem 2001 Oct
PMID:Effect of dietary ghee--the anhydrous milk fat on lymphocytes in rats. 1176 37

The serologic and clinical features of patients from pedigrees multiplex for systemic lupus erythematosus (SLE) were evaluated among three ethnic groups: Hispanics, African-Americans and European-Americans. Data were obtained from a registry of 123 pedigrees, composed of 4 Hispanic, 40 African-American and 79 European-American pedigrees. All patients met at least four criteria for the diagnosis of SLE per the American College of Rheumatology. Clinical information was obtained through review of the medical records and questionnaires completed by the participants. Ethnicity by self-identification was found to be an important factor influencing the prevalence of serologic results and clinical features. Anti-nRNP occurred more frequently in African-Americans (45.7%) than in European-Americans (7.5%) or Hispanics (0%) (p<0.0000001), as did anti-Sm (18.5% vs 1.6% and 0%, respectively) (p<0.000001). Malar rash, photosensitivity and oral ulcers were most frequent in the Hispanic population while proteinuria and leukopenia predominated in the African-American population. Arthritis and lymphopenia were present in a similar proportion in all ethnic groups. These results show that many of the ethnic differences known for isolated cases of SLE are also present in familial cases of SLE.
Cell Mol Biol (Noisy-le-grand) 2001 Nov
PMID:Familial systemic lupus erythematosus: a comparison of clinical manifestations and antibody presentation in three ethnic groups. 1183 71

Acute measles, a well known disease usually contracted during early childhood, is still the major cause of vaccine-preventable infant deaths worldwide. There are about 40 million cases of acute measles per year, with more than one million cases of infant death as a consequence of measles. These are mainly due to opportunistic infections which develop on the basis of a generalized suppression of the cellular immunity in the course and after the acute disease. Lymphopenia, a general proliferative unresponsiveness of T cells ex vivo and cytokine imbalance, are considered as major hallmarks of measles virus (MV) induced immunosuppression. These findings are compatible with modulation of T cell responses by viral interference with professional antigen-presenting cells such as dendritic cells or direct effects on T cells by suppression of survival or proliferation signals. In vitro, MV interaction causes a variety of effects on dendritic cells, including maturation and loss of their allostimulatory functions. Whether there is an additional impact on the quality of T cell responses is unknown as yet. It is clear, however, that surface interaction of lymphocytes with the MV glycoprotein complex is necessary and sufficient to induce a state of proliferative unresponsiveness in T cells. This surface contact mediated signal essentially interferes with the propagation of the interleukin 2 receptor signal by blocking the activation of the protein kinase B, also called Akt kinase, both in vitro and after experimental infection.
J Mol Med (Berl) 2002 Feb
PMID:Regulation of gene expression in lymphocytes and antigen-presenting cells by measles virus: consequences for immunomodulation. 1190 44

Diabetes in the biobreeding (BB) rat results from autoimmune destruction of pancreatic beta cells and thereby it is sharing many features with human type 1 diabetes. Independent crossing studies have demonstrated that diabetes in the BB rat is explained by at least three recessively acting genes termed Iddm1 (major histocompatibility complex), Iddm2 (lymphopenia), Iddm3 (unknown). About 50% of Iddm1 and Iddm2 homozygous first backcross hybrids (BC1) usually develop diabetes. However, 75% of these homozygotes become diabetic when using diabetic BB/HRI and diabetes-resistant BN/Mol rats. That prompted us to carry out a cross between BB/OK and BN/Crl rats in order to localise diabetogenic gene(s) of BB and/or BN rats. Fifty nine Iddm1 and Iddm2 homozygous [(BNxBB)F1xBB] BC1 hybrids (35 M, 24 F) were observed for diabetes occurrence up to an age of 30 weeks. All hybrids were used in a genome-wide scan carried out with 238 microsatellite markers covering about 92% of the genome. Significantly more Iddm1 and Iddm2 homozygous BC1 hybrids became diabetic (69 vs. 50%, p<0.003) with an age at onset of 91+/-31 days. Significant deviations from expected allele distribution between diabetic and non-diabetic BC1 hybrids were found at loci on chromosomes 1, 2, 3, 9, 10, 15, 16 and 19, with the strongest effect observed at locus D10Mgh2, where more heterozygous (91%) than homozygous diabetics (44%) were found. We conclude that BN rats possess more than one gene contributing to type 1 diabetes development.
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PMID:Alleles of diabetes-resistant BN rats contribute to insulin-dependent type 1 diabetes mellitus. 1265 25

Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.
Mol Cell Biol 2003 Apr
PMID:Mammalian twisted gastrulation is essential for skeleto-lymphogenesis. 1266 93

Epinephrine (Epi) increases lymphocyte traffic to lung. We investigated whether Epi also modulates pulmonary cell-mediated immune responses in vivo. C57BL/6 mice were immunized with hen-egg lysozyme (HEL) on day 0, challenged with HEL intratracheally at day 12, and killed at day 15. Mice received Epi (0.5 mg/kg) subcutaneously during the sensitization phase, days 1-7 (Epi-SP), or the effector phase, days 12-14 (Epi-EP); controls received saline subcutaneously. Epi-SP mice showed increased airway inflammation (P < 0.03) and pulmonary angiitis (P < 0.04) characterized by endothelialitis and subendothelial fibrin deposition. Macrophages and granulocytes were increased in perivascular cuffs in situ (P < 0.001). CD3+ lymphocytes increased in the bronchoalveolar lavage fluid, whereas NK1.1+ and CD4+CD25+ lymphocytes decreased (all P < 0.05). Atenolol, a selective beta1-adrenoreceptor (AR) antagonist, inhibited the increased vascular and airway inflammation and the reduction in CD4+CD25+ lymphocytes (all P < 0.05) yielded by Epi, whereas all alpha/beta-AR blockers inhibited airway inflammation. We conclude that Epi-EP selectively promotes vascular inflammation in vivo via a beta1-receptor-mediated mechanism.
Am J Physiol Lung Cell Mol Physiol 2003 Jul
PMID:Epinephrine promotes pulmonary angiitis: evidence for a beta1-adrenoreceptor-mediated mechanism. 1273 78

The BH3-only members of the Bcl-2 protein family are essential for initiation of programmed cell death and stress-induced apoptosis. We have determined the expression pattern in mice of the BH3-only protein Bik, also called Blk or Nbk, and examined its physiological function by gene targeting. We found that Bik is expressed widely in the hematopoietic compartment and in endothelial cells of the venous but not arterial lineages. Nevertheless, its loss did not increase the numbers of such cells in mice or protect hematopoietic cells in vitro from apoptosis induced by cytokine withdrawal or diverse other cytotoxic stimuli. Moreover, whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia, loss of Bik did not. These results indicate that any function of Bik in programmed cell death and stress-induced apoptosis must overlap that of other BH3-only proteins.
Mol Cell Biol 2004 Feb
PMID:Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. 1474 73


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