bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenine analogs as potential differentiation therapy agents for acute myeloid leukemia
Authors: Honma Yoshio 
Published: May 2003

AbstractAlthough the frequency of complete remission in acute myeloid leukemia (AML) has increased, the median duration of such remission is only 9–15 months, even when remission is achieved by treatment with conventional cytotoxic antileukemic drugs. These results clearly call for improved therapies. AML is characterized by a differentiation block leading to the accumulation of immature cells. This maturation arrest can be reversed by certain agents. Several adenine analogs effectively induce the morphologic and functional differentiation of leukemia cells. Thus, adenine analogs, alone or in combination with other differentiation‐inducing agents, may be effective for the therapy of AML. However, the antileukemic analog that is the most suitable for the treatment of AML may depend on the leukemia subtype, since the sensitivity of leukemia cells to these analogs varied greatly among leukemia subtypes. The clinical usefulness of these adenine analogs is discussed. Drug Dev. Res. 59:14–22, 2003. © 2003 Wiley‐Liss, Inc.
Adenosine receptors and human melanoma
Authors: Merighi Stefania , Baraldi Pier Giovanni , Gessi Stefania , Iannotta Valeria , Klotz Karl‐Norbert , Leung Edward , Mirandola Prisco , Tabrizi Mojgan Aghazadeh , Varani Katia , Borea Pier Andrea 
Published: May 2003

AbstractIncreased concentrations of extracellular adenosine are reached in ischemic or inflamed tissues but have also been detected inside tumoral masses. This latter finding may account for an important role of adenosine in the pathogenesis of tumors and its contradictory effects on cell survival and proliferation remain to be reconciled with the presence of specific adenosine receptor subtypes. This article reviews the pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line and the functional significance of their presence in a tumor cell type. We show that adenosine improves cell proliferation via A2A receptors while it arrests the cells at G1/G0 cell cycle phase through A3 stimulation. Furthermore, adenosine triggers a survival signal via A3 receptor stimulation while it simultaneously promotes cell death via A2A receptor activation, inducing a signaling pathway that involves protein kinase C (PKC) and mitogen‐activated protein kinases (MAPKs). Drug Dev. Res. 58:377–385, 2003. © 2003 Wiley‐Liss, Inc.
Extracellular ATP, P2 receptors, and inflammation
Authors: Virgilio Francesco Di , Ferrari Davide , Idzko Marco , Panther Elisabeth , Norgauer Johannes , Sala Andrea la , Girolomoni Giampiero 
Published: May 2003

AbstractOver the past few years, P2 receptors have emerged as new potential players in the early phases of inflammation in their function of chemotactic receptors, triggers of proinflammatory cytokine release, and cytotoxic molecules. However, more recent data suggest that the role of P2 receptors in immunity is much more widespread and touches the very heart of the initiation of the immune response, i.e., antigen presentation by dendritic cells. Drug Dev. Res. 59:171–174, 2003. © 2003 Wiley‐Liss, Inc.
Critical ATP parameters associated with blood and mammalian cells: Relevant measurement techniques
Authors: Abraham Edward H. , Salikhova Anna Y. , Hug Eugen B. 
Published: May 2003

AbstractWe have developed an integrated package that includes software programs and algorithms for measuring in vivo total blood ATP, extracellular blood ATP, blood ATP release rates, and plasma ATP breakdown rates. This clinically tested methodology improves upon existing luciferin/luciferase and high‐performance liquid chromatography assay techniques in that it involves the multidetector luminometric system for determination of blood ATP parameters with simultaneous monitoring of ATP standards and standard curve generations with r2 > 0.99 and increased speed of preparation and assay time (time necessarily for 96‐well plate preparation, assay itself, and analysis). The system and associated software program permits analysis blood ATP parameters in mol, mol/L, or mol/red blood cell (RBC) and has been extensively tested with samples measured in clinics and with samples obtained and measured at the patient bedside. The mobility of the system and ability to perform measurements on location is an important consideration and feature because of the fact that ATP blood levels are rapidly hydrolyzed and hence extremely sensitive to any perturbations associated with any vigorous manipulations during the processing and analysis. EDTA inhibition of extracellular ATP hydrolysis permits determination of extracellular ATP (plasma) and ATP release rates levels performed by iterative measurements performed on sequentially diluted blood aliquots. Back‐extrapolation permits close approximation of the in vivo blood ATP parameters. The assay system is capable of detecting RBC ATP release rates as low as 10,000 ATP molecules·RBC−1min−1. Drug Dev. Res. 59:152–160, 2003. © 2003 Wiley‐Liss, Inc.
Robert Berne: His place in the history of purine research
Authors: Olsson Ray A. 
Published: May 2003

AbstractLast year the purine community lost one of its leaders, Prof. Robert Berne of the University of Virginia. There is little that I can add to the eulogies that appeared at the time of his passing. Rather, I thought I would use this article to place his work in the perspective of over 200 years of research on purines that led up to and then resulted from his work. The story involves scientific notables, many of them Nobel laureates (indicated with an asterisk). Drug Dev. Res. 58:296–301, 2003. © 2003 Wiley‐Liss, Inc.
Allosteric enhancers for adenosine receptors
Authors: Olsson Ray A. 
Published: May 2003

AbstractAgonist allosteric enhancers stabilize the adenosine‐A1 adenosine receptor‐G protein ternary complex, thereby potentiating and prolonging the action of adenosine. Because they act only on the ternary complex their action is event‐ and site‐specific. The 2‐Amino‐3‐aroyl‐4,5‐alkylthiophenes prolong conduction through the cardiac AV node and potentiate the cardioprotective effect of brief coronary occlusions, proof of principle that they could be useful drugs. However, they are unstable, are arylamines and thus have carcinogenic potential and some have antagonist activity, a possible cause of side effects. The recently described 2‐aminothiazole allosteric enhancers might avoid those drawbacks. Two kinds of quinoline derivatives have agonist allosteric enhancer activity at the A3 adenosine receptor. Drug Dev. Res. 58:493–495, 2003. © 2003 Wiley‐Liss, Inc.
Members of the acid blue 129 family as potent and selective P2Y‐receptor antagonists
Authors: Glänzel Markus , Bültmann Ralph , Starke Klaus , Frahm August Wilhelm 
Published: May 2003

AbstractWe previously reported a structure–activity study which identified Acid blue 129 (1‐amino‐4‐(2,4,6‐trimethylphenylamino)‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) as a highly selective antagonist at the P2Y‐receptor of the guinea pig taenia coli. In contrast to the less selective P2Y‐receptor antagonist Acid blue 25 (1‐amino‐4‐phenylamino‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) with its unsubstituted phenyl ring, Acid blue 129 does not show any effect at the P2X‐receptor of the rat vas deferens. It was hypothesized that the nonplanar orientation of the substituted phenyl ring vs. the anthraquinone core, caused by the buttressing methyl groups in 2′,6′‐position, prevents binding of Acid blue 129 to the P2X‐receptor. To prove this assumption we synthesized new compounds structurally related to Acid blue 129. The effects of all compounds were studied on contractions of the rat vas deferens elicited by α,β‐methylene ATP (α,β‐MeATP; mediated by P2X‐receptors) and relaxations of the carbachol‐precontracted guinea pig taenia coli elicited by adenosine 5′‐O‐(2‐thiodiphosphate) (ADPβS; mediated by P2Y‐receptors). All compounds were more or less P2Y‐ vs. P2X‐selective. In contrast to our assumption, it is the 4′‐methyl group of Acid blue 129 and of its new analog MG 32 (1‐amino‐4‐(4‐methylphenylamino)‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) which completely prevents binding to the P2X‐receptor up to 100 μM antagonist concentration, whereas the P2X‐receptor is blocked by related compounds lacking the 4′‐methyl group. Acid blue 129 and MG 32 were the most interesting compounds. Both turned out to be potent P2Y‐receptor antagonists with IC50‐values of approximately 3 μM. They are highly selective vs. both P2X‐receptor and non‐P2‐receptor effects. Drug Dev. Res. 59:64–71, 2003. © 2003 Wiley‐Liss, Inc.
The immunodominant epitope of lipocalin allergen Bos d 2 is suboptimal for human T cells
Authors: Kinnunen Tuure , Buhot Cecile , Närvänen Ale , Rytkönen‐Nissinen Marja , Saarelainen Soili , Pouvelle‐Moratille Sandra , Rautiainen Jaakko , Taivainen Antti , Maillère Bernard , Mäntyjärvi Rauno , Virtanen Tuomas 
Published: May 2003

AbstractWe have proposed earlier that the poor capacity of the lipocalin allergen Bos d 2 to stimulate highly allergic subjects' peripheral blood mononuclear cells could be ascribed to endogenouslipocalins and could be related to the allergenic potential of the molecule. Here, we have characterized the proliferative and cytokine responses of human T cell clones against the immunodominant epitope of Bos d 2. We observed, for clone F1‐9, that a substitution of aspartic acid for asparagine in the core region of the epitope increased the stimulatory capacity of the peptide about 100‐foldin comparison with the natural peptide. For clone K3‐2, from a different patient, the substitution of lysine for glutamine or isoleucine for leucine in the core region resulted in about 30‐fold and10‐fold increases in the stimulatory capacity of the peptides, respectively. The clones also recognized self‐protein‐derived peptides but not the peptides derived from other lipocalins. We suggest that the poor recognition of the immunodominant epitope of Bos d 2 can be a factor accounting for Bos d 2‐allergic subjects' weak cellular responses. Suboptimal recognition of self and allergen epitopesby T cells may be of significance for the allergenicity of proteins.
Prevention of allergen‐specific IgE production and suppression of an established Th2‐type response by immunization with DNA encoding hypoallergenic allergen derivatives of Bet v 1, the major birch‐pollen allergen
Authors: Hochreiter Romana , Stepanoska Tatjana , Ferreira Fatima , Valenta Rudolf , Vrtala Susanne , Thalhamer Josef , Hartl Arnulf 
Published: May 2003

AbstractIn atopic patients, programming towards a preferential Th2 immunity leads to IgE antibody production and cellular Th2 immunity against otherwise harmless antigens. We report the development ofprophylactic and therapeutic DNA vaccines for the major birch‐pollen allergen, Bet v 1. We constructed three DNA vaccines, coding for the complete cDNA, coding for two hypoallergenic fragments or coding for a hypoallergenic Bet v 1 mutant. The protective effect was studied in mice pretreated by intradermal DNA injections, then sensitized with Bet v 1 protein. Mice pretreated with any of the three Bet v 1‐specific DNA vaccines were protected against allergic sensitization to Bet v 1. Protection was characterized by a lack of Bet v 1‐specific IgE production, a lack of basophil activation and an enhanced IFN‐γ expression. DNA vaccines with wild‐type Bet v 1 induced strong Bet v 1‐specific antibody responses whereas DNA vaccines with hypoallergenic Bet v 1 derivatives induced no (fragments) or only transient (mutant) Bet v 1‐specific antibody responses. A therapeutic approach with the fragment‐DNA vaccine reduced IgE production and stimulated a sustained Th1 cytokine milieu. Our results demonstrate that DNA vaccines with hypoallergenic forms of the allergen specifically protect against sensitization and suppress established Th2‐type responses. This concept may be applied for the development of safe and specific DNA vaccines for the prophylaxis and therapy of allergic diseases.
Human cytomegalovirus impairs dendritic cell function: a novel mechanism of human cytomegalovirus immune escape
Authors: Beck Kerstin , Meyer‐König Ursula , Weidmann Manfred , Nern Christian , Hufert Frank T. 
Published: May 2003

AbstractHuman cytomegalovirus (HCMV) employs multiple mechanisms to evade the immune system and succeeds to persist lifelong in the host. Human dendritic cells (DC) are the main antigen‐presenting cells and play the key role in inducing and maintaining immune responses. Here, we studied the interaction of HCMV with DC. We found that DC, irrespectively of their stage of maturation, were fully permissive for HCMV when endothelial cell‐adapted HCMV strains were applied. When fibroblast‐adapted strains were used, viral replication was abrogated at the level of immediate early (IE) and/or early (E) gene expression. Irrespective of the HCMV strain used, infection of DC prevented the signal delivery essential for T cell activation in a multistep manner. Furthermore, we observed an altered expression of adhesion molecules. This might contribute to an impairment of DC migration. Our data indicate that a soluble factor induced by IE and/or E genes is involved in these processes. The impairment of DC function upon HCMV infection may contribute to virus‐mediated immunosuppression and help the virus to establish persistence in the host.
The generalized endotoxic principle
Authors: Seydel Ulrich , Hawkins Lynn , Schromm Andra B. , Heine Holger , Scheel Olaf , Koch Michel H. J. , Brandenburg Klaus 
Published: May 2003

AbstractBacterial lipopolysaccharides (endotoxins, LPS) belong to the most potent immunostimulators in mammals. The endotoxic principle of LPS is located in its lipid A moiety, which for Escherichia coli‐type LPS consists of a hexaacylated diphosphoryl diglucosamine backbone. This lipid A adopts a cubic inverted aggregate structure from which a conical shape of the molecule can be deduced, whereas the tetraacyl lipid A precursor IVa adopts a cylindrical shape and is endotoxically inactive, but antagonizes active LPS. We hypothesize that non‐lipid A amphiphiles with similar physicochemical properties of amphiphilicity, charge, and shape, might mimic the respective lipid A. To test this hypothesis, phospholipid‐like amphiphiles with six acyl chains attached to a bisphosphorylated serine‐like backbone of varying length replacing the diglucosamine backbone were synthesized. The compound with a short backbone fulfills all criteria of an endotoxic agonist, and that with longbackbone fulfills those of an antagonist. This holds true for the human as well as for the murine system. Interestingly, these compounds are inactive in the Limulus amebocyte lysate test which is specific for LPS diglucosamine backbone. These results define a general endotoxic principle and, furthermore, provide new insights into an understanding of early steps of endotoxin action.
Skin‐versus gut‐skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4+CD25+ suppressor T cells
Authors: Iellem Andrea , Colantonio Lucia , D'Ambrosio Daniele 
Published: May 2003

AbstractIn humans and rodents a population of naturally occurring CD4+CD25+ T cells are suppressor T (CD25+ Ts) cells, which are considered to maintain peripheral immunological tolerance. Recently, we have described a unique chemotactic response profile for human CD25+ Ts cells, but their homing potential remains poorly defined. Here, we document a heterogeneous homing potential of human peripheral blood CD25+ Ts cells consistent with their ability to mediate immunosuppression at distinct locations. Surprisingly, CD25+Ts cells are depleted of gut‐homing integrin α4+β7+ T cells, while being enriched in skin‐homing cutaneous lymphocyte antigen (CLA)+ T cells. These findings document heterogeneous homing potential of peripheral blood‐borne CD25+ Ts cells with marked skewing for skin‐ versus gut‐homing. Expression of CCR4 associates with both CD25 and CLA cell surface markers, being highest on CD4+CLA+CD25+ T cells. Importantly, CD4+CD25+ Ts cells isolated from human cord blood lack expressionof CLA while expressing CCR4, suggesting intrinsic expression of CCR4 on CD25+ Ts cells. These observations indicate that the increased expression of CCR4, which is proposed to guide CD25+ Ts cells to DC, is an intrinsic feature of CD25+ Ts cells.
Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec‐7‐dependent and ‐independent mechanisms
Authors: Nicoll Gavin , Avril Tony , Lock Kevin , Furukawa Koichi , Bovin Nicolai , Crocker Paul R. 
Published: May 2003

AbstractSiglec‐7 is a sialic acid binding receptor with inhibitory potential, expressed on human NK cells and monocytes. It has an unusual binding preference for α2,8‐linked disialic acids, such as those displayed by ganglioside GD3. Here we have investigated whether siglec‐7‐GD3 interactions are able to modulate NK cell cytotoxicity. Using synthetic polyacrylamide glycoprobes, siglec‐7 was found to be masked at the NK cell surface but it could be unmasked by sialidase treatment of NK cells. GD3 synthase‐transfected P815 target cells expressed high levels of GD3 and bound strongly to recombinant siglec‐7‐Fc protein. Surprisingly, GD3 synthase‐transfected P815 cells were killed more effectively by untreated cells in a siglec‐7‐independent manner. However, following sialidase treatment of NK cells, a siglec‐7‐dependent inhibition of killing was observed. These findings have important implications for NK cell cytotoxicity against tumor cells like melanoma that express high levels of GD3 ganglioside.
Virus infection expands a biased subset of T cells that bind tetrameric class I peptide complexes
Authors: Coles Richard M. , Jones Claerwen M. , Brooks Andrew G. , Cameron Paul U. , Heath William R. , Carbone Francis R. 
Published: May 2003

AbstractWe have used a TCR β‐chain transgenic mouse to examine the relationship between the ability of a T cell to bind soluble class I‐peptide complexes and its response to antigenic stimulation in vivo. T cells from gBT‐I.3β TCR β‐chain transgenic mice preferentially carried TCR α‐chains bearing the same Vα2 V region as found in the parent receptor specific for an immunodominant HSV‐1 gB‐peptide. Furthermore, CD8+ T cells from these mice bound Kb‐gB tetrameric complexes with relatively high frequency, and most of these cells contained a Vα2 TCR α‐chain. Detailed sequence analysis of the tetramer‐binding peripheral T cells showed that this was a heterogenous population expressing TCR with only partial sequence similarity to the parent receptor, which took the form of preferential inclusion of the parental Jα16 element. Infection with HSV‐1, however, selected a subset of tetramer‐positive T cells. This was based on the emergence of a co‐dominant Jα usage and selection of a restricted CDR3α length. Therefore, the ability to bind soluble MHC‐peptide complexes does not always correlate with the ability of a T cell to respond to its cognate antigen after in vivo stimulation.
Lymphotoxin β receptor‐Ig fusion protein treatment blocks actively induced, but not adoptively transferred, uveitis in Lewis rats
Authors: Shao Hui , Fu Yangxin , Song Lei , Sun Sheher , Kaplan Herry J. , Sun Deming 
Published: May 2003

AbstractPrevious studies have shown that treatment of rodents with a lymphotoxin (LT) β receptor‐Ig fusion protein (LTβR‐Ig), which binds to both LT and LIGHT, prevents the development of autoimmune diseases, but the mechanism involved is unclear. To explore the potential role of LT or LIGHT in the pathogenesis of autoimmune uveitis, uveitis was induced in Lewis rats either by immunization with an uveitogenic peptide, R16, derived from the interphotoreceptor retinoid‐binding protein, or by adoptive transfer of R16‐specific T cells. Interestingly, LTβR‐Ig treatment completely prevented actively induced uveitis, but not the adoptively transferred disease. We also show that LTβR‐Ig‐treated R16‐injected rats had a significantly decreased T cell response to R16 and that herpesvirus entry mediator (HVEM)‐Ig, a fusion protein that blocks LIGHT, also inhibited disease development. Our results suggest that LT or LIGHT plays a critical role in the induction, rather than the effector, phase of the disease.
Vaccination with myelin oligodendrocyte glycoprotein adsorbed to alum effectively protects DBA/1 mice from experimental autoimmune encephalomyelitis
Authors: Wållberg Maja , Wefer Judit , Harris Robert A. 
Published: May 2003

AbstractTo prevent an organism from developing autoimmunity the body limits the number of autoreactive cells through thymic negative selection and regulates their activity through induction of suppressor T cells. Development of antigen‐specific therapies provides an interesting opportunity to imitate the body's own, often effective, method of protection. Our study demonstrates that DBA/1 mice could be protected from experimental autoimmune encephalomyelitis induced through injection of recombinant myelin oligodendrocyte glycoprotein (rMOG) when they were previously immunized intraperitoneally with rMOG adsorbed to aluminium hydroxide. This protection was associated with a decreased IFN‐γ production by rMOG‐specific cells, but not a decreased proliferative response. Protection was long lasting, indicating that MOG‐alum vaccination might be developed as a prophylactic therapy in multiple sclerosis.
Th2 cells shape the differentiation of developing T cell responses during interactions with dendritic cells in vivo
Authors: Schipf Alexander , Heilmann Annette , Boue Laetitia , Mossmann Horst , Brocker Thomas , Röcken Martin 
Published: May 2003

AbstractDuring priming, naive CD4+ Th cells differentiate into cells that produce either IFN‐γ or IL‐4. Even though the cascade of pathways that induces IL‐4‐producing Th2 cells has been determined in vitro, the signals promoting Th2 differentiation under physiological conditions remain enigmatic, especially the natural role of the single most important Th2‐inducing signal,IL‐4. Using Th2 and naive Th cells, each expressing a distinct transgenic TCR, here we show that Th2 cells migrate with the same dynamics as naive Th cells in draining lymph nodes and bind to the same DC, when driven by antigen in complete Freund's adjuvant (CFA). Th2‐cell‐derived IL‐4 deviates CFA‐induced Th1 development toward a Th2 phenotype, if both cell populations co‐localize in the same T cell area, and are activated simultaneously. Thus, intranodal Th2 cells directly influence Th cell differentiation in vivo, but only under restricted conditions. These findings have implications for the design of cytokine‐based therapies and explain the spreading of Th2 responses to multiple aeroallergens in allergic asthma, where naive Th and Th2 cells co‐localize in lung‐draining lymph nodes.