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)

T-lymphotropic retroviruses of cats cause lymphopenia and immunosuppression and represent the major cause of death in that species. Similarly HTLV-I which is T4 tropic is associated with an increased risk for development of infectious disease in regions where the virus is endemic. Since HTLV-I is also believed to be transmitted by blood and by sexual intercourse we considered the possibility that a variant form of HTLV might cause AIDS. The identification of cross-reactive antibodies to HTLV-I-MA in a third or more of the AIDS patients and in suspicious blood donors that donated to transfusion-associated cases of AIDS eventually led to the recognition of HTLV-III, the causative agent of AIDS. The protein most associated with lymphocyte immortalization or transformation in the case of HTLV-I is p42. The proteins of HTLV-I encoded by the amino terminus of the env gene designated gp61 and gp45 are the most immunogenic antigens of this virus. Similarly those encoded by the amino terminus of the env gene HTLV-III designated gp160 and gp120 appear to be the most immunogenic markers for this agent. Almost all AIDS patients, ARC patients, and asymptomatic hemophiliacs have detectable antibodies to gp120 and gp160. HTLV-III related agents designated STLV-III have been found in macaque monkeys that develop simian AIDS and high prevalence rates of antibodies to STLV-III can be found in healthy African green monkeys. We hypothesize that the STLV-III of African green monkeys could represent a recent source of the virus to have infected humans in central Africa where the human epidemic probably began. The recognition that up to one million people may already be infected with HTLV-III in the United States alone indicates the need for development of a vaccine. The availability of primate species infected with the serologically related STLV-III agents that either resist disease development (African green monkeys) or succumb to an AIDS-type syndrome (rhesus) provide models that should aid in our attempts to develop such vaccines.
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PMID:Retroviruses associated with leukemia and ablative syndromes in animals and in human beings. 299 Jun 82

Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1(DeltaVII) (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1(DeltaVII) isoform. Ets1(DeltaVII) homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8(+) and CD8(+)CD4(+) thymocytes were observed. Lymphoid cell (CD19(+), CD4(+), and CD8(+)) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1(DeltaVII) mutants demonstrate lymphocyte maturation defects associated with misregulation of p16(Ink4a), p27(Kip1), and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.
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PMID:Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice. 1733 35

SEW2871 is a potent sphingosine-1-phosphate receptor type-1 (S1P(1))-selective agonist that induces peripheral lymphopenia through sequestration of lymphocytes into secondary lymphoid organs, similar to the non-selective sphingosine-1-phosphate (S1P) receptor agonist FTY720. FTY720 has been reported to interfere with human dendritic cell (DC) effector functions and both FTY720 and SEW2871 have been shown to modulate murine DC trafficking in vivo. Little is known about the possible effects of SEW2871 on human and murine DC functions. Here, we demonstrate that in contrast to FTY720, SEW2871 does not induce down-regulation of S1P(1) in human DCs and thus does not exert a functional antagonism at S1P(1). Notably, the compound was found to impair chemotaxis of immature and mature human DCs in vitro, possibly by interfering with the activation of p44/p42 and p38 mitogen-activated protein kinase signaling pathways. Comparative FACS analyses show that SEW2871 mediates CD18 down-regulation on mature human DCs. The influence on DC migration could be confirmed with in vivo assays using BALB/c mice in which SEW2871 impairs the migration of CD11c+ DC and CD207+ Langerhans cells (LC) to the draining lymph nodes (LNs) under inflammatory conditions. These results suggest that the S1P-S1P(1) axis might not only control lymphocyte trafficking but also play a pivotal role in DC migration from the skin to LN.
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PMID:Sphingosine-1-phosphate receptor type-1 agonism impairs blood dendritic cell chemotaxis and skin dendritic cell migration to lymph nodes under inflammatory conditions. 1849 25

Strong evidence exists for interactions of zwitterionic phosphate and amine groups in sphingosine-1 phosphate (S1P) to conserved Arg and Glu residues present at the extracellular face of the third transmembrane domain of S1P receptors. The contribution of Arg(120) and Glu(121) for high-affinity ligand-receptor interactions is essential, because single-point R(120)A or E(121)A S1P(1) mutants neither bind S1P nor transduce S1P function. Because S1P receptors are therapeutically interesting, identifying potent selective agonists with different binding modes and in vivo efficacy is of pharmacological importance. Here we describe a modestly water-soluble highly selective S1P(1) agonist [2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino) ethanol (CYM-5442)] that does not require Arg(120) or Glu(121) residues for activating S1P(1)-dependent p42/p44 mitogen-activated protein kinase phosphorylation, which defines a new hydrophobic pocket in S1P(1). CYM-5442 is a full agonist in vitro for S1P(1) internalization, phosphorylation, and ubiquitination. It is noteworthy that CYM-5442 was a full agonist for induction and maintenance of S1P(1)-dependent blood lymphopenia, decreasing B lymphocytes by 65% and T lymphocytes by 85% of vehicle. Induction of CYM-5442 lymphopenia was dose- and time-dependent, requiring serum concentrations in the 50 nM range. In vitro measures of S1P(1) activation by CYM-5442 were noncompetitively inhibited by a specific S1P(1) antagonist [(R)-3-amino-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146)], competitive for S1P, 2-amino-2-(4-octylphenethyl)propane-1,3-diol (FTY720-P), and 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2, 4-oxadiazole (SEW2871). In addition, lymphopenia induced by CYM-5442 was reversed by W146 administration or upon pharmacokinetic agonist clearance. Pharmacokinetics in mice also indicated that CYM-5442 partitions significantly in central nervous tissue. These data show that CYM-5442 activates S1P(1)-dependent pathways in vitro and to levels of full efficacy in vivo through a hydrophobic pocket separate from the orthosteric site of S1P binding that is headgroup-dependent.
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PMID:Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. 1870 35