Biomedical subjects

A Wendel

Publications and source records attributed to A Wendel.

At least 19 recordsLinked to original sources

PubMed2005

Quantitative assessment of mouse skin transplant rejection using digital photography.

Mouse skin transplantation is an established in vivo model used to investigate the T-cell-mediated immune response of acute allograft rejection. The critical endpoint of this model is complete rejection of the allograft. However, visual judgement of this end stage of rejection is an arbitrary process and difficult to standardize. To overcome this problem, we established a monitoring method based on digital photography. Serial pictures from skin allografts of individual animals (C57BL/6 on BALB/c) were taken with a digital camera mounted on a microsurgical microscope. Thereby, the description and the correct assessment of early stages of rejection were possible due to the magnification of grafts by the microscope. Rejection scores were introduced to describe different stages from retained to completely rejected grafts. With cyclosporine A as a standard immunosuppressive treatment, we showed that early stages of skin rejection were unambiguously identified. This procedure allows the earlier termination of the experiment and reduction of animal distress, and it can be re-evaluated anywhere and any time after completion.This study demonstrates the suitability of monitoring experimental skin allograft rejection by digital photography, entailing several refinements in animal experimentation, both for the researcher and for the animal.

Animals↗

PubMed2004

GM-CSF counteracts hemorrhage-induced suppression of cytokine-producing capacity.

OBJECTIVE AND DESIGN: To study whether a treatment with the hematopoietic growth factor GM-CSF restores the attenuated ex-vivo cytokine-producing capacity of macrophages after sublethal hemorrhagic shock. SUBJECTS: Male Sprague-Dawley rats. TREATMENT: 20 microg/animal of recombinant murine GM-CSF after shock via arterial line. METHODS: Hemorrhagic shock was established by pressure-controlled bleeding to a mean arterial pressure of 50 mm Hg for 35-40 min and consecutive resuscitation. 24 h after hemorrhage, lipopolysaccharide (LPS)-induced cytokine production of isolated macrophages derived from different compartments was measured. RESULTS: A significant reduction of LPS-induced TNFalpha production was found in whole blood cultures (1.0 +/- 0.7 ng/ml after sham vs. 0.23 +/- 0.08 ng/ml after shock operation), macrophages derived from spleen (0.88 +/- 0.23 ng/ml after sham vs. 0.03 +/- 0.1 ng/ml after shock operation), peritoneum (2.2 +/- 0.7 ng/ml after sham vs. 0.29 +/- 0.4 ng/ml after shock operation) and bronchoalveolar fluid (0.65 +/- 0.13 ng/ml after sham vs. 0.003 +/- 0.027 ng/ml after shock operation, mean +/- S.D.). In cells from animals treated with GM-CSF a significantly enhanced LPS-induced TNFalpha production in splenic, alveolar and peritoneal macrophages was found after shock compared to the cells derived from untreated animals (peritoneum: 289 +/- 366 ng/ml TNFalpha after shock vs. 2066 +/- 94 ng/ml TNFalpha after shock and GM-CSF; lung: 9 +/- 12 ng/ml TNFalpha after shock vs. 64 +/- 17 ng/ml TNFalpha after shock and GM-CSF; spleen: 58 +/- 96 ng/ml TNFalpha after shock vs. 548 +/- 47 ng/ml TNFalpha after shock and GM-CSF). Blood cultures collected from rats after hemorrhagic shock did not show a significant increase of TNFalpha-production after GM-CSF treatment. CONCLUSION: Hemorrhagic shock caused a depression of the TNFalphaa response to LPS which was partly counteracted by treatment with GM-CSF. Therefore, GM-CSF represents a promising approach to normalise trauma- and shock-induced immune dysfunction.

Animals↗

PubMed2001

In vivo and in vitro evidence for extracellular caspase activity released from apoptotic cells.

While caspases play an established role as intracellular executors of apoptosis, little is known about extracellular activities of this ubiquitously expressed family of proteases. We demonstrate here that recombinant caspase-3 retained enzymatic activity in various extracellular fluids. Experiments with cell lines, primary cells, and mice with fulminant CD95-triggered hepatitis showed that significant amounts of DEVD-aminofluoromethylcoumarine-cleaving activity, indicative of active effector caspases, were released into the medium/plasma during apoptosis. Furthermore, caspase activities were detected in liquor samples from human head trauma patients. These findings warrant closer investigation of DEVDase activity as a diagnostic marker, and of potential extracellular substrates for caspases.

Animals↗

PubMed2001

Environmental management of asthma at Massachusetts managed care organizations.

Asthma management staff at eight Massachusetts managed care organizations (MCOs) were interviewed to learn the extent of inclusion of environmental prevention strategies in their asthma disease management policies. Six of the plans had formal asthma disease management programs, all reported to be based on the National Heart Lung and Blood Institute guidelines, but none followed these guidelines in their entirety. Three MCOs provided for home visits that included addressing environmental factors for severe asthmatics. Despite the limited role that MCOs appear to play in environmental prevention of asthma, the authors identify opportunities and encourage efforts to expand these programs.

Adult↗

PubMed2001

Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response.

During infection with gram-negative bacteria, exposure of immune cells to lipopolysaccharide (LPS) from the bacterial cell membrane induces a rapid cytokine response which is essential for the activation of host defenses against the invading pathogens. Administration of LPS to mice induces a state of hyporesponsiveness, or tolerance, characterized by reduced cytokine production upon subsequent LPS challenge. In the model of experimental Salmonella enterica serovar Typhimurium infection of mice, we assessed the question of whether complete LPS tolerance induced by repetitive doses of LPS interfered with cytokine production and host defense against gram-negative bacteria. Although production of various cytokines in response to serovar Typhimurium was attenuated by LPS pretreatment, LPS-tolerant mice showed improved antibacterial activity, evidenced by a prolongation of survival and a continuously lower bacterial load. We attribute this protective effect to three independent mechanisms. (i) Peritoneal accumulation of leukocytes in the course of LPS pretreatment accounted for enhanced defense against serovar Typhimurium during the first 6 h of infection but not for decreased bacterial load in late-stage infection. (ii) LPS-tolerant mice had an increased capacity to recruit neutrophilic granulocytes during infection. (iii) LPS-tolerant mice showed threefold-increased Kupffer cell numbers, enhanced phagocytic activity of the liver, and strongly improved clearance of blood-borne serovar Typhimurium. These results demonstrate that despite attenuated cytokine response, acquired LPS tolerance is associated with enhanced resistance to infections by gram-negative bacteria and that this effect is mainly mediated by improved effector functions of the innate immune system.

Animals↗

PubMed2001

Modulation of cytokine release in ex vivo-stimulated blood from borreliosis patients.

In lipopolysaccharide-stimulated blood from 71 late-stage borreliosis patients, the ex vivo cytokine release capacity of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) was reduced to 28% +/- 5% and to 31% +/- 5% (P < or = 0.001), respectively, compared to that of 24 healthy controls. White blood cell counts were normal in both groups. To investigate direct interactions between the pathogen and the immune cells, blood from healthy controls was exposed in vitro to live or heat-killed Borrelia or to Borrelia lysate. Compared to the pattern induced by bacterial endotoxins, a reduced release of TNF-alpha and IFN-gamma and an enhanced secretion of interleukin-10 and granulocyte colony-stimulating factor was found. In blood from 10 borreliosis patients stimulated with Borrelia lysate, TNF-alpha formation was decreased to 31% +/- 14% and IFN-gamma formation was decreased to 8% +/- 3% (P < or = 0.001) compared to the cytokine response of blood from healthy controls (n = 24). We propose to consider anti-inflammatory changes in the blood cytokine response capacity elicited by Borrelia as a condition that might favor the persistence of the spirochete.

Adolescent↗

PubMed2001

Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used to ameliorate neutropenia in patients after antineoplastic treatment. It has also been suggested as an adjunct treatment in septic patients; however, the recruitment and priming of leukocytes by GM-CSF bears the hazard of a hyperinflammatory response. In particular, the role of GM-CSF in pulmonary functions in septic lungs is still unclear. Therefore, we pretreated rats in vivo with GM-CSF (50 microg/kg, intravenous) and assessed the pulmonary functions of their subsequently prepared isolated perfused lungs when exposed to subtoxic concentrations of lipopolysaccharide (LPS, 2 microg/ml). These lungs showed enhanced expression of cyclooxygenase 2 (COX-2), a significant increase in thromboxane (TX) and tumor necrosis factor (TNF) release into the venous perfusate, and bronchoconstriction. COX-2 inhibition or blocking of the TX receptor abolished the GM-CSF/LPS-induced bronchoconstriction, but not the TNF release. Neutralizing antibodies against TNF did not prevent GM-CSF/LPS-induced bronchoconstriction. After GM-CSF pretreatment, massive neutrophil invasion into the lung occurred. Neutropenic rats were protected against GM-CSF/ LPS-induced lung injury. Similar results were obtained in rats pretreated with G-CSF instead of GM-CSF. We conclude that GM-CSF pretreatment exacerbates pulmonary injury by low-dose LPS via COX-2 expression, TX release, and bronchoconstriction by initiating neutrophil invasion and activation.

Animals↗

PubMed2001

Intravasal peroxynitrite generation causes dysfunction in the isolated perfused rat lung via endothelin.

In septic shock excessive nitric oxide and superoxide are produced, thus generating peroxynitrite. This study investigates whether and how intravasal peroxynitrite causes lung dysfunction. To generate peroxynitrite, isolated and ventilated rat lungs were perfused blood-free in a pressure-constant, recirculating mode with hypoxanthine/xanthine oxidase plus sodium nitroprusside. Airway and vascular resistance, and release of thromboxane A2, prostacyclin, and endothelin-1 were assessed over 200 min. Peroxynitrite generation, as demonstrated by oxidation of the marker 2',7'-dichlorodihydrofluorescein diacetate, caused broncho- and vasoconstriction starting after 100 min. Both reactants alone, i.e., NO. or O2, had no effect. The thromboxane A2/prostaglandin H2 receptor antagonist BM13.177 did not affect peroxynitrite-induced broncho- and vasoconstriction. Combined endothelin(A/B) (ET(A/B)) receptor antagonism (BQ123 plus BQ788) prevented broncho- and vasoconstriction more effectively than the ET(A) receptor antagonist BQ123 alone. In tissue from lungs exposed to peroxynitrite, significantly increased amounts of endothelin-1 were detected. This study identifies endothelin-1 rather than prostanoids as a distal mediator induced by the reaction product of superoxide and nitric oxide, i.e., peroxynitrite. It is concluded that 1) endothelin-1 is a causal mediator of peroxynitrite-induced acute rat lung injury, and 2) peroxynitrite-induced broncho- and vasoconstriction are mediated by both ET(A) and ET(B) receptors.

Animals↗

PubMed2000

The short prodomain influences caspase-3 activation in HeLa cells.

Proteolytic activation of caspases is a key step in the process of apoptosis. According to their primary structure, caspases can be divided into a group with a long prodomain and a group with a short prodomain. Whereas long prodomains play a role in autocatalytic processing, little is known about the function of the short prodomain, for example the prodomain of caspase-3. We constructed caspase-3 variants lacking the prodomain and overexpressed these in HeLa and yeast cells. We found that removal of the caspase-3 prodomain resulted in spontaneous proteolytic activation of the protein when expressed in HeLa cells. This processing was only partially autocatalytic, as demonstrated by a catalytically inactive caspase-3 mutant. Co-expression of the anti-apoptotic protein XIAP (X-chromosome-linked inhibitor of apoptosis protein) completely blocked the observed spontaneous activation, which excluded a direct involvement of caspase-8. Our findings indicate that the short prodomain of caspase-3 serves as a silencing component in mammalian cells by retaining this executioner caspase in an inactive state.

Apoptosis↗

PubMed2000

Metabolic depletion of ATP by fructose inversely controls CD95- and tumor necrosis factor receptor 1-mediated hepatic apoptosis.

Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different models of murine liver injury whether and how metabolically induced alterations of hepatocyte ATP levels control receptor-mediated apoptosis. ATP was depleted either in primary hepatocytes or in vivo by various phosphate-trapping carbohydrates such as fructose. After the activation of the tumor necrosis factor (TNF) receptor or CD95, the extent of hepatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apoptosis mediated by CD95 was enhanced. Similarly, acute TNF-induced liver injury in mice was entirely inhibited by ATP depletion with ketohexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mitochondrial cytochrome c release, loss of mitochondrial membrane potential, activation of type II caspases, DNA fragmentation, and cell lysis after exposure to TNF. The extent of apoptosis inhibition correlated with the severity of ATP depletion, and TNF-induced apoptosis was restored when ATP was repleted by increasing the extracellular phosphate concentration. Our study demonstrates that TNF-induced hepatic apoptosis can be selectively and reversibly blocked upstream of mitochondrial dysfunction by ketohexose-mediated ATP depletion.

Adenosine Triphosphate↗

PubMed2000

Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma.

In a double-blind, placebo-controlled, randomized study, 10 healthy men received either a single dose of 480 microg granulocyte colony-stimulating factor (G-CSF) or saline. Blood taken from the volunteers was stimulated with 10 microg/mL endotoxin and released cytokines were measured by enzyme-linked immunosorbent assay. Expression of G-CSF receptors on leukocytes was examined by flow cytometry and reverse transcriptase-polymerase chain reaction. Functional activity of these receptors was tested by challenging isolated leukocyte populations to release cytokines with endotoxin in the presence of G-CSF. The G-CSF treatment attenuated the release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1beta, and interferon (IFN)-gamma in ex vivo lipopolysaccharide (LPS)-stimulated whole blood. In blood from untreated volunteers the presence of G-CSF in vitro also attenuated the LPS-stimulated release of these cytokines. G-CSF in vitro also attenuated TNF-alpha release from elutriation-purified monocytes. In the presence of 10 ng/mL recombinant TNF-alpha, the attenuation of LPS-inducible IFN-gamma release by G-CSF was blunted in whole blood. However, G-CSF had no such effect on IFN-gamma release from isolated lymphocytes stimulated with anti-CD3 or a combination of TNF-alpha and IL-12. G-CSF receptor expression was detected in human neutrophils and monocytes but not in lymphocytes by means of RT-PCR as well as flow cytometry. These results indicate that G-CSF receptors expressed on monocytes are functional in modulating monokine release. We conclude that the attenuation of IFN-gamma release from lymphocytes is not a direct effect of G-CSF on these cells but is rather due to the inhibition of monocytic IL-12 and TNF-alpha release by G-CSF. (Blood. 2000;95:270-276)

Adult↗

PubMed2000

Blood cytokine response of low-dose molgramostim (rhGM-CSF)-treated patients.

We examined leukocyte counts and ex vivo cytokine response of whole blood to lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in patients under low-dose molgramostim therapy. Patients were injected subcutaneously daily for ten days with 1 microg/kg (n=9) or 2 microg/kg (n=14) molgramostim. Leukocytosis was observed in all patients, but only the eosinophil fraction was significantly increased in relation to other leukocyte populations. Ex vivo IFN-gamma release was decreased and IL-10 and IL-1ra secretion were increased in response to LPS or LTA. Thus, in non-neutropenic patients, leukocytosis can already be initiated by low doses of molgramostim. The ex vivo cytokine data suggest that these doses prime blood towards a systemic anti-inflammatory response.

Adult↗

PubMed2000

Depletion of hepatic glutathione prevents death receptor-dependent apoptotic and necrotic liver injury in mice.

The activation of the death receptors, tumor necrosis factor-receptor-1 (TNF-R1) or CD95, is a hallmark of inflammatory or viral liver disease. In different murine in vivo models, we found that livers depleted of gamma-glutamyl-cysteinyl-glycine (GSH) by endogenous enzymatic conjugation after phorone treatment were resistant against death receptor-elicited injury as assessed by transaminase release and histopathology. In apoptotic models initiated by engagement of CD95, or by injection of TNF or lipopolysaccharide into galactosamine-sensitized mice, hepatic caspase-3-like proteases were not activated in the GSH-depleted state. Under GSH depletion, also caspase-independent, TNF-R1-mediated injury (high-dose actinomycin D or alpha-amanitin), as well as necrotic hepatotoxicity (high-dose lipopolysaccharide) were entirely blocked. In the T-cell-dependent model of concanavalin A-induced hepatotoxicity, GSH depletion resulted in a suppression of interferon-gamma release, delay of systemic TNF release, hepatic nuclear factor-kappaB activation, and an abrogation of sinusoidal endothelial cell detachment as assessed by electron microscopy. When GSH depletion was initiated 3 hours after concanavalin A injection, ie, after the peak of early pro-inflammatory cytokines, livers were still protected. We conclude that sufficient hepatic GSH levels are a prerequisite for the execution of death receptor-mediated hepatocyte demise.

Amanitins↗

PubMed2000

Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis.

TNF-alpha has been implicated as a potentially detrimental cytokine in autoimmune disorders of the nervous system and has been reported to be elevated in antigen-specific therapy of experimental autoimmune neuritis (EAN) in vivo. To investigate the role of TNF-alpha in EAN in rats that had been subjected to antigen-specific therapy with human P2 protein, animals were cotreated with an anti-TNF-alpha neutralizing antibody and the effects of the antibody on disease determined. Using this strategy in adoptive transfer (AT-) EAN, antigen-induced T-cell apoptosis in inflamed sciatic nerve and in liver was reduced to levels observed in control animals indicating that TNF-alpha mediates antigen-induced apoptosis of inflammatory T-cells. Focal liver necrosis, which had been observed in earlier studies after antigen therapy in AT-EAN, was prevented by passive immunization with neutralizing anti-TNF-alpha antibody. Unexpectedly, neutralization of TNF-alpha only partly abolished the protective effect of antigen therapy on the overall disease course. This may indicate that inhibition of TNF-alpha exerts beneficial effects other than through T-cell apoptosis, or that some of the benefit of antigen therapy is mediated by other pathways. These results indicate that secretion of TNF-alpha during antigen therapy has the dual potential to mediate beneficial apoptosis of inflammatory T-cells in the inflammatory lesion and to induce liver damage as a severe side effect.

Animals↗

PubMed1999

Prevention of endotoxin-induced lethality, but not of liver apoptosis in poly(ADP-ribose) polymerase-deficient mice.

Activation of poly-(ADP-ribose) polymerase (PARP) is often associated with cytotoxicity, but its precise role in shock-induced lethality and in different modes of tissue injury is still unknown. We took advantage of the existence of mice with a targeted deletion of the PARP gene (PARP-/-) to examine the differential sensitivity of wild-type (wt) and PARP-/- mice toward endotoxin (LPS)-induced lethality and different forms of liver damage. All PARP-/- animals survived high-dose (20 mg/kg) LPS-mediated shock, which killed 60% of wt animals. Moreover, LPS-induced necrotic liver damage was significantly reduced. In contrast, when apoptotic liver damage was induced via injection of low concentrations of LPS (30 microgram/kg) into D-galactosamine-sensitized mice, or via activation of hepatic cell death receptors, PARP-/- animals were not protected. We conclude that PARP is involved in systemic LPS toxicity, while it plays a minor role in apoptotic liver damage mediated by TNF or CD95.

Animals↗

PubMed1999

CD95-Mediated murine hepatic apoptosis requires an intact glutathione status.

Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo, we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dose-dependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N-acetyl cysteine, alpha-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione.

Acetylcysteine↗

PubMed1999

Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.

Several models of tumor necrosis factor (TNF)/TNF-receptor 1 (TNF-R1)-dependent liver injury in mice were investigated with respect to caspase-3-like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T-cell-activating agents (i.e., agonistic anti-CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-sensitized mice caused TNF/TNF-R1-dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF-mediated hepatotoxicity dependent on both TNF-R1 and TNF-R2. Hepatic caspase-3-like proteases were activated in GalN/TNF, GalN/anti-CD3, or GalN/SEB-treated mice, but not in Con A-treated mice. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-val-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxicity in all GalN-dependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF-R1-dependent, but not TNF-R2-dependent, activation of caspase-3-like proteases, and zVADfmk prevented animals from Con A-mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A- and GalN/Con A-induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase-3-like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driven hepatocyte apoptosis involves activation of caspase-3-like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver.

Amino Acid Chloromethyl Ketones↗

PubMed1999

Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated human dendritic cells (DC) and the influence of PDE inhibitors on DC function.

During differentiation of human monocytes (CD14(+)/CD1a(-)) to CD14(-)/CD1a(+)dendritic cells (DC), a drastic decrease in PDE4 activity was observed, while activities of PDE1 and PDE3 substantially increased. DC released tumour necrosis factor-alpha (TNF) in response to lipopolysaccharide (LPS) challenge, which was abolished both by dexamethasone and the cyclic AMP-elevating drugs db-cAMP and PGE(2). In addition, rolipram, at PDE4-selective concentrations, blocked TNF release by 37 +/- 5% (P<0.05 vs. control). The PDE3 inhibitor motapizone only marginally influenced TNF synthesis, but a synergistic inhibitory effect was noted in combination with rolipram. Qualitatively, similar inhibitory effects were observed in DC-stimulated T cell responses. Motapizone, lacking efficacy when used alone, increased the effect of rolipram in blocking CD4(+)T lymphocyte proliferation in response to antigen (Ag) (tetanus toxoid, TT; keyhole limpet hemocyanin, KLH) presented by DC and in allogeneic mixed leukocyte reactions (MLR). However, in these coculture systems the T cells rather than the DC seem to be the major target cells of PDE-inhibitor action. In summary, PDE inhibitors can affect DC function directly as demonstrated by blocking TNF release and their efficacy reflects the changes in the PDE activity profile during differentiation from their monocyte precursors. These results together with the known efficacy of PDE3/4 inhibitors in T cells support the concept of combined PDE3/4 inhibitors for asthma therapy.

Cell Division↗