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The Department of Immunology is mainly concerned with the immune response against parasites. A major issue is the host response to and the effector mechanisms against filarial infections. In the model of the mouse infection with Litomosoides sigmodontis, the role of interleukin-5 was analysed. The up-regulation of this cytokine apparently has an effect not only on eosinophilic granulocytes but also indirectly on neutrophils that appear to play an important role in the effector phase. This novel mechanism of eosinophil-mediated neutrophil activation probably has a bearing also on other conditions with chronic eosinophilia such as chronic asthma. In this mechanism, other cytokines such as interferon-g and tumour necrosis factor-a also play an important interactive role.
Studies on onchocerciasis patients in a hyperendemic region in Guinea show that the specific hyporesponsiveness of patients with generalized infection is due to production of the immunosuppressive cytokines interleukin-10 and transforming growth factor-b by a special set of regulatory T cells. These cells are absent in putatively immune individuals.
A role of endogenous Wolbachia that are present in many filaria in homoeostasis of the worm was demonstrated by the fact that removal of these bacteria from Litomosoides sigmodontis led to worm infertility and reduced growth. This opens up a novel approach for chemotherapy of filariasis.
T cell activation is an important point of control in the immune response. The T cell surface molecule CTLA-4 (CD152) that is expressed after T cell activation and appears to have an effect in down-regulating T cell responses turned out to be strongly up-regulated in several infections such as HIV-infection and in particular in malaria, in contrast to other activation markers. In malaria, expression of this marker was correlated with parasitemia and with the clinical grade of the disease possibly indicating a role for T cell activation in this condition. This molecule may also be a candidate for enhancing immune responses by blocking its down-regulatory interactions. An activated phenotype is a characteristic feature of T cells transformed by Theileria parva and activating signals play a role in maintaining the transformed phenotype. Alternative pathways besides the T cell receptor can induce activation of the T cell, such as CD26, a multifunctional surface protease and receptor. Another interesting molecule is CD83 that is expressed on T cells as well as on the most potent antigen-presenting cells, the interdigitating dendritic cells. Its ligand is still unknown but soluble CD83 immunoglobulin chimeric molecules have an influence on T cell activation by antigen. This suggests the exciting possibility that this hitherto neglected molecule plays an important role in T cell activation. Also involved in the activation of T cells are certain heat shock proteins (Hsp) that are known to bind antigenic peptides. A role of Hsp in MHC class I-dependent antigen-presentation is likely, and possibly also in the induction of a specific systemic reaction to antigenic peptides. As carriers of specific peptides, Hsp may constitute a novel way to vaccinate against intracellular pathogens, e.g. Trypanosoma cruzi that is used as a model infection. It is interesting that Hsp have an activating effect on T lymphocytes beyond their carrier function for specific peptides.
The Department of Virology concentrated on its research on HIV, hantavirus, Lassa virus and hepatitis B virus. As part of the investigations in the AIDS programme of the German Ministry for Research and Technology (BMBF) the studies on the function and immunogenicity of the V3 loop of HIV-1 were continued. The binding of the V3 loop of different virus isolates to chemokine receptors was measured by infectivity assays. The results show that the CCR5 receptor is preferentially used by the highly pathogenic viruses isolated from serum samples of HIV-infected patients. Moreover, the influence of the glycosylation on the function of the gp 120 molecule was investigated supported by a "Sonderforschungsbereich Glykostrukturen" grant of the Deutsche Forschungsgemeinschaft (DFG). A vaccine candidate against HIV was developed based on a novel principle and consisting of a multitude of different representative gp120 molecules.
The investigations on T cell immunity to Lassa virus have shown that different CD4-cell epitopes can be characterized in the nucleocapsid gene. Several peptides presented by MHC class II molecules were identified and corresponding T cell clones could be established, which showed strain-specific reactivity with the Josiah but not with the Nigeria strain of Lassa virus. After the successful collection of numerous lymphocyte samples of individuals from Guinea the cellular immunity to Lassa virus can now be tested. In the meantime, a laboratory for Lassavirus research was established in Conakry, Guinea, which is supported by the Volkswagen-Stiftung and by the European Community. For this, data on the prevalence of hemorrhagic fever viruses will be collected.
Using a fully automated equipment (TaqMan®), the amplification of viral RNA can now be monitored directly in the sealed tubes measuring a fluorescence signal. In about 90% of the early sera of tourists with acute dengue fever, the presence of the virus could thus be demonstrated and the serotype in question be identified.
In September 1998, the European congress on clinical virology of the European Society of Clinical Virology (ESCV) was organized by Prof. Herbert Schmitz. The congress took place in the Hamburg Congress Center and was attended by scientists from various countries presenting contributions on almost all viruses involved in human diseases.
The Central Diagnostic Unit performs the direct identification of bacteria, parasites and viruses and the serodiagnosis of parasitic, bacterial, rickettsial and viral infections. It serves as a national expert laboratory for amoebiasis, leishmaniasis, trypanosomiasis, filariasis and infections with tropical viruses. Because of its specialization, the unit receives material submitted from all parts of Germany and also from Denmark and Austria. The P4-laboratory is used for diagnostic tests in cases of suspected hemorrhagic fever. This laboratory is part of the European Network on Imported Viral Diseases. New diagnostic methods developed by the research laboratories are evaluated and eventually incorporated into the diagnostic routine, most recently the identification of microsporidia and of trypanosomes by PCR.
Experimental investigations in animals are an essential component of research in tropical medicine. Certain parasites can only be maintained by passage in animals and immunization for producing monoclonal and polyclonal antibodies has to be performed in animals. Studies on defense mechanisms and possible vaccines against Entamoeba histolytica, Trypanosoma cruzi, Leishmania major and a murine filaria (Litomosoides sigmodontis) were carried out in mice. The Laboratory Animal Facility cooperates in a number of these scientific projects and it supports and advises scientists in planning and executing such experimentation in accordance with the regulations of the Animal Protection Law. The health status of the animals is excellent. Parasitological, bacteriological and virological tests for a number of animal pathogens have repeatedly been negative, indicating a high standard of hygiene.
Bernhard Fleischer
| Scientific Staff
Prof. Dr. Bernhard Fleischer,
Prof. Dr. Herbert Schmitz,
Dr. Thomas Schüler,
Dr. Arne von Bonin
Associated Members Dr. Thomas Fenner
Visiting Scientists Dr. Lamine Koivogui, Université de Conacry, Guinée Technical Staff Arshad Ali
Doctoral / Graduate Students Niels Albrechtsen
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Strong T lymphocyte activation in acute malaria.
Doctoral / Graduate Students Andrea Dötze
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