Biomedical subjects

G Alber

Publications and source records attributed to G Alber.

At least 19 recordsLinked to original sources

PubMed2006

Induction of immunity and inflammation by interleukin-12 family members.

The interleukin (IL)-12 family is composed of three heterodimeric cytokines, IL-12 (p40p35), IL-23 (p40p19), and IL-27 (EBI3p28), and of monomeric and homodimeric p40. This review focuses on the three heterodimeric members of the IL-12 family. The p40 and p40-like (EBI3) subunits have homology to the IL-6R, the other subunits (p35, p19, and p28) are homologous to each other and to members of the IL-6 superfamily. On the basis of their structural similarity, it was expected that the members of the IL-12 family have overlapping pro-inflammatory and immunoregulatory functions. However, it was surprising that they also show very distinct activities. IL- 12 has a central role as a Th1-inducing and -maintaining cytokine, which is essential in cell-mediated immunity in nonviral infections and in tumor control. IL-23 recently emerged as an end-stage effector cytokine responsible for autoimmune chronic inflammation through induction of IL-17 and direct activation of macrophages. Very recently, IL-27 was found to exert not only a pro-inflammatory Thl-enhancing but also a significant anti-inflammatory function.

Animals↗

PubMed2005

Controlling quantum systems by embedded dynamical decoupling schemes.

A dynamical decoupling method is presented which is based on embedding a deterministic decoupling scheme into a stochastic one. This way it is possible to combine the advantages of both methods and to increase the suppression of undesired perturbations of quantum systems significantly even for long interaction times. As a first application the stabilization of a quantum memory is discussed which is perturbed by one- and two-qubit interactions.

Journal Article↗

PubMed2001

Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology.

The immunological basis of tuberculin-induced necrosis, known for more than a century as "Koch's phenomenon," remains poorly understood. Aerosol infection in mice with the highly virulent Mycobacterium avium strain TMC724 causes progressive pulmonary pathology strongly resembling caseating necrosis in human patients with tuberculosis. To identify the cellular and molecular mediators causing this pathology, we infected C57BL/6 mice and mice selectively deficient in recombinase activating gene (RAG)-1, alphabeta T cell receptor (TCR), gammadelta TCR, CD4, CD8, beta2-microglobulin, interferon (IFN)-gamma, interleukin (IL)-10, IL-12p35, IL-12p35/p40, or iNOS with M. avium by aerosol and compared bacterial multiplication, histopathology, and respiratory physiology in these mice. The bacterial load in the lung was similarly high in all mouse groups. Pulmonary compliance, as a surrogate marker for granulomatous infiltrations in the lung, deteriorated to a similar extent in all groups of mice, except in alphabeta TCR-knockout (KO) and IL-12-KO mice in which compliance was higher, and in IFN-gamma and inducible nitric oxide synthase-KO mice in which compliance was reduced faster. Progressive caseation of pulmonary granulomas never occurred in alphabeta TCR-KO, IL-12-KO, and IFN-gamma-KO mice and was reduced in CD4-KO mice. In summary, alphabeta TCR(+) cells and IFN-gamma are essential for the development of mycobacteria-induced pulmonary caseous necrosis. In contrast, high mycobacterial load and extensive granulomatous infiltration per se are not sufficient to cause caseation, nor is granuloma necrosis linked to the induction of nitric oxide.

Animals↗

PubMed2001

A protective and agonistic function of IL-12p40 in mycobacterial infection.

IL-12p35(-/-)p40(-/-) mice are highly susceptible to Mycobacterium bovis bacillus Calmette-Guérin (BCG) or Mycobacterium tuberculosis infection. In this study IL-12p35(-/-) mice, which are able to produce endogenous IL-12p40, cleared M. bovis BCG and showed reduced susceptibility to pulmonary M. tuberculosis infection, which was in striking contrast to the outcome of mycobacterial infection in IL-12p35(-/-)p40(-/-) mice. Resistance in wild-type and IL-12p35(-/-) mice was accompanied by protective granuloma formation and Ag-specific delayed-type hypersensitivity responses, which were impaired in susceptible IL-12p35(-/- )p40(-/-) mice. Furthermore, IL-12p35(-/-) mice, but not IL-12p35(-/-)p40(-/-) mice, mounted Ag-specific Th1 and cytotoxic T cell responses. In vivo therapy with rIL-12p40 homodimer restored the impaired delayed-type hypersensitivity responses in M. bovis BCG-infected IL-12p35(-/-)p40(-/-) mice and reverted them to a more resistant phenotype. Together, these results show evidence for a protective and agonistic role of endogenous and exogenous IL-12p40 in mycobacterial infection, which is independent of IL-12p70.

Animals↗

PubMed2001

IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis.

To study a potential IL-12p40-dependent but IL-12p75-independent agonistic activity regulating the immune response against Salmonella Enteritidis, the course of infection in IL-12p35-deficient mice (IL-12p35(-/-), capable of producing IL-12p40) was compared with that of IL-12p40(-/-) mice. Mice lacking IL-12p40 revealed a higher mortality rate and higher bacterial organ burden than mice capable of producing IL-12p40. This phenotype was found in both genetically susceptible (BALB/c, Ity(s)) and resistant mice (129Sv/Ev, Ity(r)) indicating Ity-independent mechanisms. The more effective control of bacteria in the IL-12p35(-/-) mice was associated with elevated serum IFN-gamma and TNF-alpha levels. In contrast, IL-12p40(-/-) mice showed reduced IFN-gamma production, which was associated with significantly elevated serum IgE levels. Early during infection (days 3 and 4 postinfection), as well as late (day 20 postinfection), the number of infected phagocytes was strongly increased in the absence of IL-12p40 indicating impaired bactericidal activity when IL-12p40 was missing. Liver histopathology revealed a decreased number of mononuclear granulomas in IL-12p40(-/-) mice. Depletion of CD4(+) or CD8(+) T lymphocytes in vivo suggested that both T cell subpopulations contribute to the IL-12p40-dependent protective functions. Analysis of IL-12p40 vs IL-23p19 mRNA expression revealed an up-regulation of only IL-12p40 mRNA during Salmonella infection. Together these data indicate that IL-12p40 can induce protective mechanisms during both the innate and the adaptive type 1 immune response in Salmonella infection. This novel activity of IL-12p40 complements the well described dominant and essential role of IL-12p75 in protective immunity to Salmonella infection.

Animals↗

PubMed2001

IL-12-independent IFN-gamma production by T cells in experimental Chagas' disease is mediated by IL-18.

IL-12p35-deficient (IL-12p35(-/-)) mice were highly susceptible to Trypanosoma cruzi infection and succumbed during acute infection, demonstrating the crucial importance of endogenous IL-12 in resistance to experimental Chagas' disease. Delayed immune responses were observed in mutant mice, although comparable IFN-gamma and TNF-alpha blood levels as in wild-type mice were detected 2 wk postinfection. In vivo and in vitro analysis demonstrated that T cells, but not NK cells, were recruited to infected organs. Analysis of mice double deficient in the recombinase-activating gene 2 (RAG2) and IL-12p35, as well as studies involving T cell depletion, identified CD4(+) T cells as the cellular source for IL-12-independent IFN-gamma production. IL-18 was induced in IL-12p35(-/-) mice and was responsible for IFN-gamma production, as demonstrated by in vivo IL-18 neutralization studies. In conclusion, evidence is presented for an IL-12-independent IFN-gamma production in experimental Chagas' disease that is T cell and IL-18 dependent.

Acute Disease↗

PubMed2001

Stabilizing distinguishable qubits against spontaneous decay by detected-jump correcting quantum codes.

A new class of error-correcting quantum codes is introduced capable of stabilizing qubits against spontaneous decay arising from couplings to statistically independent reservoirs. These quantum codes are based on the idea of using an embedded quantum code and exploiting the classical information available about which qubit has been affected by the environment. They are immediately relevant for quantum computation and information processing using arrays of trapped ions or nuclear spins. Interesting relations between these quantum codes and basic notions of design theory are established.

Journal Article↗

PubMed2001

Interleukin-12- and gamma interferon-dependent innate immunity are essential and sufficient for long-term survival of passively immunized mice infected with herpes simplex virus type 1.

Interferon (IFN) type I (alpha/beta IFN [IFN-alpha/beta]) is very important in directly controlling herpes simplex virus type I (HSV-1) replication as well as in guiding and upregulating specific immunity against this virus. By contrast, the roles of IFN type II (IFN-gamma) and antibodies in the defense against HSV-1 are not clear. Mice without a functional IFN system and no mature B and T cells (AGR mice) did not survive HSV-1 infection in the presence or absence of neutralizing antibodies to the virus. Mice without a functional IFN type I system and with no mature B and T cells (AR129 mice) were unable to control infection with as little as 10 PFU of HSV-1 strain F. By contrast, in the presence of passively administered neutralizing murine antibodies to HSV-1, some AR129 mice survived infection with up to 10(4) PFU of HSV-1. This acute immune response was dependent on the presence of interleukin-12 (IL-12) p75. Interestingly, some virus-infected mice stayed healthy for several months, at which time antibody to HSV-1 was no longer detectable. Treatment of these virus-exposed mice with dexamethasone led to death in approximately 40% of the mice. HSV-1 was found in brains of mice that did not survive dexamethasone treatment, whereas HSV-1 was absent in those that survived the treatment. We conclude that in the presence of passively administered HSV-1-specific antibodies, the IL-12-induced IFN-gamma-dependent innate immune response is able to control low doses of virus infection. Surprisingly, in a significant proportion of these mice, HSV-1 appears to persist in the absence of antibodies and specific immunity.

Animals↗

PubMed2000

[A new live Salmonella enteritidis vaccine for chickens--experimental evidence of its safety and efficacy].

Within the works for the registration of a new live Salmonella Enteritidis vaccine for layers, safety and efficacy of the vaccine strain were tested by experimental studies. After oral administration of the single and the tenfold dose, no incompatibility reactions were seen in day-old chicks. The laying performance and the egg weight were not affected by the vaccination of the chickens during the laying period. There was only a limited period in which the excretion of the vaccine strain and its persistency in organs were seen. Even after the threefold oral vaccination the vaccine strain could not be isolated from eggs and internal organs of slaughtered chickens. Moreover, a high safety for non-target animals (cattle, pigs) could be established. Studies with BALB/c mice proved that a cell-mediated immunity and the development of complement-fixing antibodies is induced by the vaccine. Efficacy studies in target animals were carried out by a proved dependable oral challenge system that reproduces a latent infection with marked S. Enteritidis strains and by means of the seeder-bird method. The test results demonstrate that the vaccination is capable to avert or to reduce an infection significantly.

Animals↗

PubMed1999

[Experiences in the diagnosis and therapy of so-called thrombus in transit].

With the increasing use of cross-sectional echocardiography in patients with overt or suspected pulmonary thromboembolism in the emergency rooms, more and more right atrial thrombi are detected. These are so-called "transitthrombi" from the venous system on their way to the pulmonary arteries and they are a severe presentation of thromboembolic disease. They appear as an imminent pulmonary embolism and usually coexists with an already massive embolism. In patients were a right atrial thrombus is associated with a patent foramen ovale, paradoxical arterial embolism has been observed. Right sided heart thrombi have a high mortality rate and need immediate treatment. In our hospital we have seen 14 patients with right atrial thrombi and pulmonary embolism in a period of 6 years. Three patients had cardiac arrest with a massive pulmonary embolism, seven patients presented with a submassive embolism. All patients were treated immediately after echocardiographic diagnosis without pulmonary angiography. In about half of the cases transesophageal echocardiography was done additionally for diagnosis and monitoring. Therapeutic options were thrombectomy, fibrinolysis or anticoagulants. We treated one of our patients with thrombectomy, eleven patients with fibrinolysis and two patients with anticoagulants.

Adult↗

PubMed1999

IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes.

We have studied IL-12p35-deficient (IL-12p35(-/-)) mice to evaluate the role of IL-12 in resistance against Listeria monocytogenes. In the absence of bioactive IL-12p75, mutant mice acquired higher bacterial organ burden than wild-type mice and died during the first week following infection with normally sublethal doses of Listeria. Moreover, blood IFN-gamma levels were strikingly reduced in mutant mice at day 2 post-infection. These results suggest that in IL-12p35-deficient mice impaired production of IFN-gamma which is crucial for activation of listericidal effector functions of macrophages leads to defective innate immunity against Listeria. In contrast to mice deficient for IFN-gamma or IFN-gamma receptor which are unable to resist very low infection doses of Listeria, IL-12p35(-/-) mice resisted up to 1000 c.f.u. and were able to eliminate Listeria. Spleen cells from mutant mice re-stimulated with heat-killed Listeria produced considerable amounts of IFN-gamma, suggesting that at low dose infection sufficient IFN-gamma is produced independently of IL-12. Subsequent challenge of these immunized mice with high doses of L. monocytogenes resulted in sterile elimination demonstrating efficient memory responses. These results demonstrate for the first time that at low doses of Listeria IL-12 is neither critical for innate immunity nor for the development of protective T cell-dependent acquired immunity.

Animals↗

PubMed1998

Mice lacking IL-12 develop polarized Th1 cells during viral infection.

Studies in IL-12-deficient mice established the necessity for IL-12 to generate a Th1 cytokine response that is often required for elimination of intracellular pathogens. In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse hepatitis virus (MHV) infection, similar to wild-type animals. In contrast, MHV-infected IFN-gamma receptor-deficient (IFN-gammaR[-/-]) mice showed an increased susceptibility to coronaviral hepatitis. Surprisingly, MHV-infected mice lacking IL-12 produced a polarized Th1-type cytokine response, as evidenced by high IFN-gamma and nondetectable IL-4 production by CD4+ splenocytes and normal virus-specific serum IgG2a/IgG1 ratios. The virus-induced type 1 cytokine secretion pattern was not reversed in IL-12-deficient mice by in vivo neutralization of IFN-gamma nor in IFN-gammaR(-/-) mice receiving IL-12-neutralizing Abs. In IL-12-deficient mice, Th1-type responses were also generated upon immunization with inactivated MHV. In contrast, following immunization with keyhole limpet hemocyanin, mice lacking IL-12 mounted strongly reduced specific IgG2a and increased IgE responses, indicative of a type 2-dominated cytokine pattern. These findings demonstrate that following a virus infection, IL-12 is not essential for the generation of polarized T cell type 1 cytokine expression and associated immune responses, which is in marked contrast to nonviral systems. Our data suggest that viruses may selectively induce IFN-gamma production and Th1-type immune reactions even in the absence of IL-12.

Animals↗

PubMed1998

Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.

To analyze the roles of interleukin-12 (IL-12) and the IL-12-dependent Th1 response in resistance to Cryptococcus neoformans, we have established a chronic infection model in wild-type mice and in mice with targeted disruptions of the genes for the IL-12p35 and IL-12p40 subunits (IL-12p35(-/-) and IL-12p40(-/-) mice, respectively) as well as in mice with a targeted disruption of the IL-4 gene. Long-term application of exogenous IL-12 prevented death of infected wild-type mice for the entire period of the experiment (up to 180 days) but did not resolve the infection. Infected IL-12p35(-/-) and IL-12p40(-/-) mice died significantly earlier than infected wild-type mice, whereas infection of IL-4-deficient mice led to prolonged survival. Interestingly, infected IL-12p40(-/-) mice died earlier and developed higher organ burdens than IL-12p35(-/-) mice, which, for the first time in an infection model, suggests a protective role of the IL-12p40 subunit independent of the IL-12 heterodimer. The fungal organ burdens of IL-4-deficient mice and IL-12-treated wild-type mice were significantly reduced compared to those of untreated wild-type mice and IL-12-deficient mice. Histopathological analysis revealed reduction of the number of granulomatous lesions following treatment with IL-12. Susceptibility of both IL-12p35(-/-) and IL-12p40(-/-) mice was associated with marginal production of gamma interferon and elevated levels of IL-4 from CD4(+) T cells, which indicates Th2 polarization in the absence of IL-12, whereas wild-type mice developed a Th1 response. Taken together, our data emphasize the essential role of IL-12 for protective Th1 responses against C. neoformans.

Animals↗

PubMed1998

Murine leishmaniosis: a paradigm for the importance of T helper 1 and T helper 2 cells.

The murine model of leishmaniosis is a prototypic example for the critical role played by T helper cells in immunity to pathogens. Cytokines, such as interleukin-12 and interleukin-4, are the major regulatory factors for differentiation of naive T helper cells into T helper 1 and T helper 2 cells, respectively. T helper 1 cells, which are cellular immune mechanisms involving gamma interferon production, are associated with protection against murine leishmaniosis. Loss of T helper 1 activity (i.e., reduced gamma interferon production and lack of macrophage activation) leads to a fatal progressive course of murine leishmaniosis. Knowledge of the murine model of leishmaniosis is now contributing to studies of infectious diseases in humans, livestock and companion animals. Greater insight into the pathogenesis, diagnosis and therapy of infectious diseases will be gained from the analysis of cytokine-dependent regulation of T helper responses during infection. In particular, the development of prophylactic and therapeutic vaccines will benefit significantly from these studies.

Animals↗

PubMed1997

[Transesophageal ultrasound for staging lung tumors].

PURPOSE: The usefulness of transesophageal sonography in staging lung cancer was examined. METHOD: Transoesophageal sonography was performed in 15 patients as a staging examination using either biplane or multiplane technique. The results were compared with other radiological techniques such as computed tomography and, if performed, with the findings in the operation. RESULTS: The neoplastic mass was correctly identified in 12 of the 15 patients. Transoesophageal sonography is a very useful examination, more so than computed tomography, for identification of a tumour infiltration into great vessels or cardiovascular structures. In 8 cases we found paraaortal tumour masses and in 4 cases infiltration of the pulmonary artery. In 2 cases we could show an infiltration of heart chambers. The sensitivity for detecting lymph nodes was 80% in the lower mediastinum and, because of method limitations, only 33% in the upper mediastinum. CONCLUSION: Transoesophageal sonography is an excellent addition to the already well established staging methods in staging lung cancer. This examination clearly has advantages over the conventional methods (CT scan) for the diagnosis of vessel involvement, extrinsic compression of the heart, and for the recognition of lymph node metastases. The limitation of this examination is the restriction to the paraoesophageal area and reduced effectiveness in areas filled with air and other nonconductive structures.

Adult↗

PubMed1997

[Cerebral air embolism after central venous catheter].

Introduction of air into the arterial circulation can cause cerebral air embolism, leading to severe neurological deficits. A case is reported on a patient suffering from fatal cerebral air embolism after a subclavian vein catheter had been inserted. The risks associated with inserting and removing central venous catheters are described. Apart from the pathogenesis of a paradoxical air embolism in a patient with a right-to-left shunt due to a patent foramen ovale, air embolism can occur if a large amount of air traverses the pulmonary circulation. The ability of the pulmonary vasculature to filter air may be exceeded by a bolus injection of more than 30 ml air. Air embolism is suspected if acute neurological symptoms occur after inserting a central venous catheter. Echocardiography, especially transoesophageal echocardiography. Is highly sensitive in detecting air emboli in the ventricles. Treatment is effected with hyperbaric oxygen and standard measures of intensive-care medicine.

Aged↗

PubMed1997

Interleukin-12 is indispensable for protective immunity against Leishmania major.

Interleukin-12 (IL-12)-deficient mice derived from a strain genetically resistant to infection with Leishmania major were recently shown to be susceptible toward this parasite, developing a strong Th2 response after injection of a large number of parasites. We further investigated the role of IL-12 in L. major infection by studying the responses of mutant mice against smaller numbers of parasites. IL-12-deficient mice infected with only small numbers of parasites showed the progressive lesion development and high parasite burden associated with a polarized Th2 response. Our data show that IL-12 is indispensable for protective immunity against L. major. Even at low inocula, no salvage pathway appears to compensate for the lack of IL-12. However, genetically susceptible BALB/c mice infected with small numbers of parasites were able to resolve lesions and restrict the parasite burden to levels which were 10(5)-fold lower than those in IL-12-deficient mice. In contrast to mutant mice, BALB/c mice mounted a type 1 response against low inocula of L. major. IL-12-deficient BALB/c mice, however, developed a type 2 response. These data emphasize the essential role of IL-12 in resistance against L. major. In addition, this study suggests that in the absence of IL-12, susceptibility to L. major is determined by the inability to induce a Th1 response rather than the development of a Th2 response. Our results are relevant for potential vaccination strategies that use low inocula of infective microorganisms which fail to induce a protective type 1 response at higher inocula.

Animals↗

PubMed1997

Treatment with homodimeric interleukin-12 (IL-12) p40 protects mice from IL-12-dependent shock but not from tumor necrosis factor alpha-dependent shock.

The role of interleukin-12 (IL-12) was investigated in different shock models using anti-IL-12 reagents. IL-12 is composed of two disulfide-bonded subunits, p35 and p40. The IL-12 p40 homodimer (p40)2 has been shown to be a potent IL-12 antagonist in vitro. We investigated its in vivo inhibitory capacity in different shock models of mice. We could demonstrate that (p40)2 is able to protect mice from septic shock in primarily IL-12-dependent models such as the Shwartzman reaction and lipopolysaccharide (LPS)-induced shock, whereas (p40)2 has no effect in the tumor necrosis factor alpha-dependent LPS/D-GalN shock model. In IL-12-dependent shock models, (p40)2 inhibits IL-12-induced gamma interferon production and thereby interferes with the cascade of cytokine release, finally leading to death.

Animals↗