Volume 46 (2000) No. 6

Volume 46 (2000) No. 6



Dedication to Professor Jan Bubenik, M.D., D.Sc.
J. SVOBODA.................................................205
Full text. 205


Reviews
Immunological Therapy of Human Tumors by Gene-Modified Cellular Vaccines
G. PARMIANI............................................207
Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milan, Italy
Corresponding author: Giorgio Parmiani, Unit of Immunotherapy of Human Tumors, Istituto Nazionale
Tumori, Via G. Venezian 1, 20133 Milan, Italy.
No abstract available.
Full text. 207-209


Malaria Blood-Stage Infection and Its Control by the Immune System
P. PERLMANN, M. TROYE-BLOMBERG..................................210
Department of Immunology, Stockholm University, Stockholm, Sweden
Corresponding author: Peter Perlmann, Department of Immunology, Stockholm University, Arrhenius Laboratories F5, S10691, Stockholm, Sweden. Tel.: 468164172; fax: 468157356; e-mail: peter.perlmann@imun.su.se.
Abstract.
Full text. 210-211 212-213 214-215 216-218


Cancer: Is There Involved a Bunch of Culprits, One Culprit, or Something in between?
J. SVOBODA..............................219
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Corresponding author: Jan Svoboda, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 37 Praha 6, Czech Republic. Fax: 420 (2) 24310955, e-mail: svoboda@img.cas.cz.
No abstract available.
Full text. 219-220 221-222 223-225


Mechanisms of Retrovirus-Induced Oncogenesis
G. SOURVINOS1, C. TSATSANIS2, D. A. SPANDIDOS1.........................226
1Laboratory of Virology, and 2Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, Crete, Greece
Corresponding author: D. A. Spandidos, Medical School, University of Crete, Heraklion, Crete, Greece. Tel.: +3 (01) 7227809; Fax: +3 (01) 7252922; e-mail: spandido@hol.gr.
Abstract.
Full text. 226-227 228-229 223-225


Genetic Analysis of Cardiovascular Risk Factor Clustering in Spontaneous Hypertension
M. PRAVENEC1,2, V. ZÍDEK1, V. LANDA3, V. KOSTKA1, A. MUSILOVÁ1, L. KAZDOVÁ4, A. FUČÍKOVÁ5, D. KŘENOVÁ2, V. BÍLÁ2, V. KŘEN1,2................................233
1Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
2Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, 
Czech Republic
3Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
4Institute of Clinical and Experimental Medicine, Prague, Czech Republic
5Czech Agricultural University, Prague, Czech Republic
Corresponding author: Michal Pravenec, Institute of Physiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic. Tel/Fax: 420 (2) 475 2297; e-mail: pravenec@biomed.cas.cz.
Abstract.
Full text. 233-234 235-236 237-238 239-240


Articles
A Comparison of Systemic Versus Inhaled Recombinant IL-2 Administration for the Treatment 
of Metastatic Renal Cell Carcinoma
E. HULAND, H. HEINZER, H. HULAND.....................................241
Department of Urology, University Hospital Hamburg-Eppendorf, Germany
Corresponding author: Edith Huland, Head, Transplantation- and Tumorimmunology, Urologische Klinik 
und Poliklinik, Universitäts-Krankenhaus Eppendorf, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany. Tel.: 49 (40) 42803-4424; Fax: 49 (40) 42803-4662; e-mail: huland@uke.uni-hamburg.de.
Abstract.
Full text. 241-242 243-244 245-246 247-248 249-250


Interferon-alpha Treated Patients with Chronic Myelogenous Leukemia Show BCR/ABL-Positive
Peripheral Blood Progenitor Cells Surviving Long-Term Culture
B. SCHULTHEIS, B. HEISSIG, G. PASTERNAK, S. HÖRNER, R. HEHLMANN...................251
III. Medizinische Universitätsklinik, Klinikum Mannheim, Fakultät für Klinische Medizin der Universität Heidelberg, Mannheim, Germany
Corresponding author: Beate Schultheis, III. Medizinische Klinik, Klinikum Mannheim der Universität Heidelberg, Wiesbadener Str. 7--1l, D-68305 Mannheim, Germany.
Abstract.
Full text. 251-252 253-254 255


BCR/ABL-Negative Clonogenic Hematopoietic Cells Do Not Accumulate in the Plastic-Adherent 
Fraction of Peripheral Blood Mononuclear Cells from Patients with Chronic Myeloid Leukemia in Stable Chronic Phase
B. SCHULTHEIS, G. PASTERNAK, R. HEHLMANN...........................256
III. Medizinische Klinik, Fakultät für Klinische Medizin der Universität Heidelberg, Mannheim, Germany
Corresponding author: Beate Schultheis, III. Medizinische Klinik Mannheim, Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany.
Abstract.
Full text. 256-257 258-259 260-261 262-263


The Influence of the Genetic Background on the Interaction of Retinoic Acid with Lx Mutation of the Rat
V. BÍLÁ1, V. KŘEN1,2, F. LIŠKA2...................................264
1Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague
2Institute of Physiology, Academy of Sciences of the Czech Republic, Prague
Corresponding author: Vlasta Bílá, Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Albertov 4, 128 00 Prague 2, Czech Republic. Tel.: + 420 (2) 24 91 49 58.
Abstract.
Full text. 264 265 266 267-268 269-270 271 272

Reviews
Malaria Blood-Stage Infection and Its Control by the Immune System
P. PERLMANN, M. TROYE-BLOMBERG

Malaria is caused by the protozoon Plasmodium, transmitted to humans by Anopheles mosquitoes. The most dangerous of the plasmodia infecting humans is Plasmodium falciparum. The disease is caused by those parasite stages which multiply asexually in red blood cells. In non-immune individuals, P. falciparum may cause severe and life-threatening disease. Another risk group are pregnant women, particularly during their first pregnancies.
Immunity to malaria usually requires repeated exposure to the parasite to become long lasting. One reason for this is the capacity of the parasite to vary the antigens which are major targets for protective antibodies. Antibody-dependent protection is primarily mediated by cytophilic IgG antibodies activating cytotoxic and phagocytic effector functions of neutrophils and monocytes. Malaria infection also involves elevated production of IgE antibodies. However, IgE-containing immune complexes are pathogenic rather than protective by cross-linking IgE receptors (CD23) on monocytes, leading to local overproduction of tumour necrosis factor (TNF), a major pathogenic factor in this disease.
T cells are essential for both acquisition and regulation of malaria immunity. The major T cells controlling blood stage infections are CD4+ of both the Th1 and Th2 subsets. However, T cells carrying the gamma delta receptor also contribute to this control. The balance between the cytokines produced by different cell types is
critical for the course of infection, with interferon gamma (IFN-gamma) having a key role in anti-malaria defence. Blood-stage infections are also under complex genetic control. Among the regulatory genes, those involved in elevated production of TNF are associated with increased risk of severe disease and death due to P. falciparum infection.
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Mechanisms of Retrovirus-Induced Oncogenesis
G. SOURVINOS, C. TSATSANIS, D. A. SPANDIDOS

Retroviruses are implicated in a series of human and animal tumours such as leukaemias, mammary tumours 
or skin cancer. The mechanism that they use to induce tumour formation varies. Insertional mutagenesis is a common mechanism in rodent, feline and avian retroviruses, where the retrovirus integrates into the host genome and affects the transcription of the neighbouring genes. Cloning of these affected genes led to identification of a series of oncogenes that play a significant role in the induction of human neoplasms. Retrovirus insertion also serves as a model to identify collaborating oncogenes. Human retroviruses use different, more complex mechanisms contributing to oncogenesis. Studies of the propagation and induction mechanisms used by retroviruses have given insight to the understanding of oncogenesis.
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Genetic Analysis of Cardiovascular Risk Factor Clustering in Spontaneous Hypertension
M. PRAVENEC, V. ZÍDEK, V. LANDA, V. KOSTKA, A. MUSILOVÁ, L. KAZDOVÁ, A. FUČÍKOVÁ, D. KŘENOVÁ, V. BÍLÁ, V. KŘEN

The SHR is the most widely studied animal model of hypertension. In this strain, as in many humans with essential hypertension, increased blood pressure has been reported to cluster with other risk factors for cardiovascular disease, including insulin resistance and dyslipidemia. However, the genetic mechanisms that mediate this clustering of risk factors for cardiovascular disease or the hypertension "metabolic syndrome" remain poorly understood. In the current studies, we have demonstrated (1) that a gene or genes responsible
for a whole spectrum of cardiovascular risk factors mapped to a limited segment of the centromeric region of rat chromosome 4, (2) that a spontaneous deletion in the gene for Cd36 that encodes a fatty acid transporter
and is located directly at the peak of QTL linkages on chromosome 4 has been indirectly linked to the transmission of insulin resistance, defective fatty acid metabolism, and increased blood pressure, and (3) based on complementation analysis in two transgenic lines expressing wild-type Cd36 on the genetic background of the SHR strain harboring the deletion variant of Cd36, we have established that defective Cd36 can be a determinant of disordered fatty acid metabolism, glucose intolerance, and insulin resistance in spontaneous hypertension.
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Articles
A Comparison of Systemic Versus Inhaled Recombinant IL-2 Administration for the Treatment 
of Metastatic Renal Cell Carcinoma
E. HULAND, H. HEINZER, H. HULAND

The aim of the current study was to compare the objective response and survival rates of patients with mRCC treated with IL-2 administered either systemically (SYST, subcutaneously) or via inhalation (INH), using relatively large sample sizes to afford a more meaningful comparison. We used univariate and multivariate analyses to retrospectively evaluate the data from two different databases generated from 277 patients treated with IL-2 during the 1993-1997 period, one developed at the University Hospital Hamburg-Eppendorf, and the other at Chiron-Amsterdam. Patients treated with INH IL-2 tended to have a poorer ECOG performance status than patients receiving SYST IL-2. Of 75 patients receiving INH IL-2, eight (10.7%) achieved an objective response; of 202 patients administered SYST IL-2, 45 (22.2%) achieved an objective response. The median survival time was 13.8 months for patients receiving INH IL-2 and 13.1 months for patients treated with SYST IL-2. One- and two-year survival rates were also comparable for the two treatment modalities (one-year: INH, 55%; SYST, 56%; two-year: INH, 28%; SYST, 26%). There was no significant difference in the likelihood of survival for patients receiving INH IL-2 versus SYST IL-2 (risk ratio = 0.82, P = 0.27). Patients administered INH IL-2 experienced considerably less toxicity and complications than patients administered SYST IL-2. We conclude that INH IL-2 treatment is at least as effective as SYST IL-2 treatment in promoting the survival of patients with mRCC. Given that INH IL-2 treatment of patients with a poorer ECOG performance status elicited a survival rate comparable to that seen with SYST IL-2 treatment of patients with a superior performance status, the potential exists for INH IL-2 treatment to be even more effective for patients having a better performance status. Additionally, INH IL-2 treatment is considerably less toxic and associated with fewer complications than SYST IL-2 treatment, thus providing a therapeutic option for otherwise untreatable patients, offering patients a relatively good quality of life, and requiring fewer co-medications. Nonetheless, selection of an IL-2 treatment modality should be based on several patient-related considerations. Moreover, these two IL-2 treatment modalities need not be mutually exclusive. 
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Interferon-alpha Treated Patients with Chronic Myelogenous Leukemia Show BCR/ABL-Positive
Peripheral Blood Progenitor Cells Surviving Long-Term Culture
B. SCHULTHEIS, B. HEISSIG, G. PASTERNAK, S. HÖRNER, R. HEHLMANN

Several groups have shown that Ph- progenitors reappear in LTC of CML bone marrow or PBMNC when the cell preparations were derived from newly diagnosed Ph--positive patients or after induction chemotherapy.
We have tested the hypothesis whether LTC may further decrease CML progenitors if the cells to be cultured were from IFN-treated patients. In our experiments, PBMNC were cultured from 7 IFN- and 5 HU-treated patients in stable chronic phase of the disease, and from 9 patients at diagnosis. Progenitor cells in PBMNC were quantitatively analyzed before and after 35 days of LTC by combining the clonogenic assay in semisolid medium with dual-color interphase FISH for identification of the BCR/ABL status of colony-forming 
progenitor cells. A median of 22 colonies (range 7-88) before and 30 colonies (5-71) after LTC were analyzed per patient. Our results show that the number of BCR/ABL-positive CFC before and after LTC was approximately the same. This was independent of IFN or HU therapy. In the IFN group there were 58% (median) BCR/ABL-positive CFC before and 54% (median) after LTC of PBMNC. In the HU group, 80% of CFC were BCR/ABL-positive before and 85% after LTC. A complete elimination of BCR/ABL-positive cells was not achieved. We conclude that CML early progenitors in PBMNC of IFN-treated CML patients may survive LTC.
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BCR/ABL-Negative Clonogenic Hematopoietic Cells Do Not Accumulate in the Plastic-Adherent 
Fraction of Peripheral Blood Mononuclear Cells from Patients with Chronic Myeloid Leukemia in Stable Chronic Phase
B. SCHULTHEIS, G. PASTERNAK, R. HEHLMANN

PBMNC from patients with CML and healthy control persons were separated into plastic-adherent and nonadherent cell fractions. A colony assay in semisolid medium was used to estimate the number and lineage commitment of CFC in each of the fractions. The CML blood-derived colonies were isolated and analyzed by FISH for BCR/ABL sequences. Thus, we were able to test the hypothesis whether a selective enrichment is possible of normal progenitor cells in the blood of CML patients in stable chronic phase after HU and/or IFN. Although the number of leukocytes differed considerably between patients at diagnosis and in stable chronic phase, the proportion of adherent and nonadherent cells was about the same in all preparations tested. There were also only minor differences of adherence between MNC of CML and normal origin. Furthermore, BCR/ABL-positive and negative colonies were equally distributed among unseparated, adherent, and nonadherent PBMNC fractions. In conclusion, an accumulation of BCR/ABL-negative CFC was not found in any of the PBMNC fractions. CFC from PBMNC of the same lineage commitment were simultaneously present in plastic-adherent and nonadherent cell fractions, indicating that their surface charges might be different and, on the other hand, that different lineage commitment precursors can be present in either of the fractions irrespective of CML or blood origin.
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The Influence of the Genetic Background on the Interaction of Retinoic Acid with Lx Mutation of the Rat
V. BÍLÁ, V. KŘEN, F. LIŠKA

The teratogenic effect of RA was found to be significantly influenced both by genetic background and by the genotype of malformation mutation Lx. The presence of the Lx mutation and BN genetic background strongly increases the teratogenic effect of RA. On the contrary, the SHR genetic background was shown to protect foetuses from RA teratogenic affliction. Recombinant inbred strain BXH2 is endowed with a specific combination of BN and SHR genes, and following RA administration it exhibits the same embryolethal effect as the BN genetic background alone.
Without the Lx mutation there was no effect of RA on hind limbs in SHR/SHR or SHR/BN progeny
whilst there was a significantly higher occurence of oligodactyly in SHR/BN on forelimbs as compared to SHR/SHR (92.2% vs 11.5%). In +/Lx progeny, forelimbs were significantly more afflicted with oligodactyly in SHR/BN +/Lx in comparison with both SHR/SHR and SHR/BXH2 foetuses, which indicates that BN modifiers responsible for oligodactyly were not passed to the BXH2 strain. On the contrary, hind limbs of SHR/BXH2, +/Lx progeny exhibited the highest affliction (62% of polydactyly and/or oligodactyly). In homozygous Lx/Lx progeny, polydactyly prevailed in forelimbs of SHR/BXH2 following RA administration, whilst in BN/BN progeny oligodactyly was the most frequent affliction. On the hind limbs, the highest reduction of toe number after RA treatment was connected with BN modifiers.
The polymorphism of normal morphogenetic factors was shown to be responsible not only for Lx phenotypic manifestation, but also for the variability in the response to RA teratogenic action.
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