M E Rottenberg

Publications (34)97.13 Total impact

• Article: Differential invasion of Trypanosoma brucei brucei and lymphocytes into the brain of C57BL/6 and 129Sv/Ev mice.

  W Masocha, D N Amin, K Kristensson, M E Rottenberg
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  ABSTRACT: Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. In this study, we compared the outcome of infection with T. b. brucei in MHC-matched (H-2b) C57BL/6 (B6) and 129Sv/Ev (Sv-129). Sv-129 showed higher parasitaemia and lower specific IgM (but not IgG) antibody levels than B6 mice. The number of trypanosomes, CD4+ and CD8+ T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality when compared with Sv-129 mice. Higher levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma, ICAM-1 and E-selectin, but low levels of TGF-beta mRNA were present in brains of B6 when compared with Sv-129-infected mice. Thus, host genetics differentially determine the invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitaemia nor by antibody titres.
  Scandinavian Journal of Immunology 10/2008; 68(5):484-91. · 2.23 Impact Factor
• Article: Interferon-gamma mediates neuronal killing of intracellular bacteria.

  Y Jin, G Lundkvist, L Dons, K Kristensson, M E Rottenberg
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  ABSTRACT: Neurons can be targets for microbes, which could kill the neurons. Just in reverse, we, in this study, report that bacteria can be killed when entering a neuron. Primary cultures of foetal mouse hippocampal neurons and a neuronal cell line derived from mouse hypothalamus were infected by Listeria monocytogenes. Treatment with interferon-gamma (IFN-gamma) did not affect bacterial uptake, but resulted in increased killing of intracellular bacteria, whereas the neuronal cell remained intact. The IFN-gamma-mediated bacterial killing was mapped to the neuronal cytosol, before listerial actin tail formation. Treatment with IFN-gamma induced phosphorylation of the transcription factor STAT-1 in neurons and IFN-gamma-mediated listerial killing was not observed in STAT-1(-/-) neurons or neurons treated with IFN regulatory factor-1 antisense oligonucleotides. IFN-gamma-treated neuronal cells showed increased levels of inducible nitric oxide synthase (iNOS) mRNA, and antisense iNOS oligonucleotides hampered the bacterial killing by neurons upon IFN-gamma treatment. This novel neuronal function - i.e., that of a microbe killer - could play a crucial role in the control of infections in the immuno-privileged nervous system.
  Scandinavian Journal of Immunology 11/2004; 60(5):437-48. · 2.23 Impact Factor
• Article: Adjuvant modulation of the immune responses and the outcome of infection with Chlamydia pneumoniae.

  L Bandholtz, M R Kreuger, C Svanholm, H Wigzell, M E Rottenberg
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  ABSTRACT: Immunization with different adjuvants resulted in antithetic outcomes of infection with Chlamydia pneumoniae. Immunization with the outer major protein-2 from C. pneumoniae (OMP-2) emulsified in Freund's complete adjuvant (FCA) thus increased the susceptibility of mice to infection with the bacteria. The detrimental effect was not observed upon inoculation of irrelevant antigens or major outer membrane protein (MOMP) in FCA, but was also observed after immunization with FCA-chlamydial heat shock protein-60 (HSP-60). The harmful effect of FCA-OMP-2 depended on the presence of both CD4+ and CD8+ cells and was mediated by IL-10, as shown using gene-ablated mice. The increased susceptibility to infection caused by FCA-OMP-2 immunization was long-lasting and observed in mice infected 4 months after the last dose of immunogen. In contrast, partial protection against C. pneumoniae was observed when FCA was replaced with oligodeoxynucleotides containing immunostimulatory CpG motifs mixed with Freund's incomplete adjuvant (FIA-IS-CpG). These polar outcomes of infection related to the cytokine pattern: antigen-stimulated spleen cells from FCA-OMP-2-immunized mice showed higher IL-10/IFN-gamma ratios than FIA-IS-CpG-OMP-2-immunized animals. In agreement, sera from FCA-OMP-2 showed higher anti-OMP-2 IgG1/IgG2a ratios than FIA-IS-CpG-OMP-2-immunized animals. Finally, OMP-2 also generated a protective response when delivered by a eukaryotic expression vector in tandem with CTLA4, a procedure that targeted OMP-2 to antigen-presenting cells.
  Clinical & Experimental Immunology 01/2003; 130(3):393-403. · 3.36 Impact Factor
• Article: IFN-alpha beta-dependent, IFN-gamma secretion by bone marrow-derived macrophages controls an intracellular bacterial infection.

  A G Rothfuchs, D Gigliotti, K Palmblad, U Andersson, H Wigzell, M E Rottenberg
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  ABSTRACT: Several reports have indicated that cell lineages apart from NK and T cells can also express IFN-gamma. However, the biological relevance of this finding is uncertain. We show in this study that bone marrow-derived macrophages (BMMs) express IFN-gamma at the mRNA and protein level early after infection with Chlamydia pneumoniae. Increased IFN-gamma mRNA accumulation by infected BMMs is early, transient, and requires both bacterial and host protein synthesis. The induction of IFN-gamma mRNA levels is independent of IL-12 and was dramatically enhanced in IL-10(-/-) BMMs. Such IL-10(-/-) BMMs contained less bacteria than the wild-type controls, whereas IFN-gammaR(-/-) BMMs showed increased C. pneumoniae load. Inducible NO synthase (iNOS) also participates in the control of bacterial load, as shown by the enhanced numbers of C. pneumoniae in iNOS(-/-) BMMs. However, the increased accumulation of iNOS mRNA and NO in C. pneumoniae-infected BMMs depended on the presence of IFN-alphabeta, but was independent of IFN-gamma. Interestingly, IFN-alphabeta are also required for increased IFN-gamma mRNA accumulation in C. pneumoniae-infected BMMs. Accordingly, IFN-alphabetaR(-/-) BMMs showed higher levels of C. pneumoniae than wild-type BMMs. Our findings unravel an autocrine/paracrine macrophage activation pathway by showing an IFN-alphabeta-dependent IFN-gamma and iNOS induction in response to infection, which protects macrophages against intracellular bacterial growth.
  The Journal of Immunology 01/2002; 167(11):6453-61. · 5.79 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Neural route of cerebral Listeria monocytogenes murine infection: role of immune response mechanisms in controlling bacterial neuroinvasion.

  Y Jin, L Dons, K Kristensson, M E Rottenberg
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  ABSTRACT: The pathologic features of cerebral Listeria monocytogenes infection strongly suggest that besides hematogenous spread, bacteria might also spread via a neural route. We propose that after snout infection of recombination activating gene 1 (RAG-1)-deficient mice, L. monocytogenes spreads to the brain via a neural route. The neural route of invasion is suggested by (i) the immunostaining of L. monocytogenes in the trigeminal ganglia (TG) and brain stem but not in other areas of the brain; (ii) the kinetics of bacterial loads in snout, TG, and brain; and (iii) the increased resistance of mice infected with a plcB bacterial mutant (unable to spread from cell to cell). Gamma interferon (IFN-gamma) plays a protective role in neuroinvasion; inducible nitric oxide synthase (iNOS) accounts only partially for the protection, as shown by a comparison of the susceptibilities of IFN-gamma receptor (IFN-gamma R)-deficient, iNOS-deficient, and wild-type mice to snout infection with L. monocytogenes. The dramatically enhanced susceptibility of RAG-1-deficient, IFN-gamma R gene-deficient mice indicated the overall importance of innate immune cells in the release of protective levels of IFN-gamma. The source of IFN-gamma appeared to be NK cells, as shown by use of RAG-1-deficient, gamma-chain receptor gene-deficient mice; NK cells played a relevant protective role in neuroinvasion through a perforin-independent mechanism. In vitro evidence indicated that IFN-gamma can directly induce bacteriostatic mechanisms in neural tissue.
  Infection and Immunity 03/2001; 69(2):1093-100. · 4.16 Impact Factor
• Article: Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae.

  M E Rottenberg, A Gigliotti Rothfuchs, D Gigliotti, M Ceausu, C Une, V Levitsky, H Wigzell
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  ABSTRACT: By using mice genomically lacking IFN-gammaR, IL-12, perforin, and recombination-activating gene-1 (RAG-1), we analyzed the regulation and importance of IFN-gamma in the control of infection with Chlamydia pneumoniae. IL-12 participates in resistance of mice to C. pneumoniae, probably by regulating the protective levels of IFN-gamma mRNA. In turn, IFN-gamma is necessary for the increased IL-12p40 mRNA accumulation that occurs in lungs during infection with C. pneumoniae, suggesting a positive feedback regulation between these two cytokines. In experiments including RAG-1-/-/IFN-gammaR-/- mice we showed that IFN-gamma produced by innate cells controls the bacterial load and is necessary for the increased accumulation of transcripts for enzymes controlling high output NO release (inducible NO synthase), superoxide production (gp-91 NADPH oxidase), and catalysis of tryptophan (indoleamine 2, 3-dioxygenase (IDO)), mechanisms probably related to bacterial killing. Adaptive immune responses diminish the levels of IFN-gamma and IL-12 mRNA and thereby the levels of inducible NO synthase, IDO, and gp91 NADPH oxidase transcripts. By using RAG-1-/-/perforin-/- mice, we excluded the overt participation of NK cell cytotoxicity in the control of C. pneumoniae. However, NK cells and probably other innate immune cells release IFN-gamma during the bacterial infection.
  The Journal of Immunology 06/2000; 164(9):4812-8. · 5.79 Impact Factor
• Article: Protective DNA immunization against Chlamydia pneumoniae.

  C Svanholm, L Bandholtz, E Castaños-Velez, H Wigzell, M E Rottenberg
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  ABSTRACT: We have investigated the efficacy of the DNA vaccination using the heat shock protein 60 (HSP-60) gene of C. pneumoniae, for protection of mice against infection with the bacteria. C57Bl/6 mice had a 5-20-fold reduction of C. pneumoniae numbers in lungs when immunized intranasally (i.n.) with plasmids (p) encoding pHSP-60. The reduction of the bacterial load coincided with a decreased severity of disease. No specific antibodies were detected after protective i. n. immunization. In contrast, mice immunized intradermally (i.d.) were not protected against challenge with C. pneumoniae, although specific humoral Immunoglobulin (Ig)G responses were generated. Co-inoculation i.n. of pHSP-60 with pIL-12 but not with pGM-CSF further increased protection of mice against infection with C. pneumoniae. Lungs from pHSP-60 i.n. immunized and infected mice showed higher levels of interferon (IFN)-gamma mRNA, and spleen cells from these mice co-cultured with r-HSP-60 released higher levels of IFN-gamma and displayed higher proliferative responses than nonimmunized and infected controls. pHSP-60 immunized IFN-gamma receptor (R)-/- mice were not protected against infection with C. pneumoniae. Likewise, i.n. administration of pIFN-gamma alone induced significant protection. DNA vaccine-induced protection was CD4+ and CD8+ T-cell dependent, as shown by DNA-vaccination of MHC class II-/-, CD4-/-, CD8-/- and CD4-/-CD8-/-mice. Interestingly, DNA vaccine induced CD4+ T cells, in the absence of CD8+ T cells, were involved in worsening the outcome of infection. This worsening was linked with a shift towards a Th2 cytokine pattern.
  Scandinavian Journal of Immunology 05/2000; 51(4):345-53. · 2.23 Impact Factor
• Article: Light-dependent regulation and postnatal development of the interferon-gamma receptor in the rat suprachiasmatic nuclei.

  G B Lundkvist, A Andersson, B Robertson, M E Rottenberg, K Kristensson
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  ABSTRACT: The interferon-gamma receptor gene was detected in the rat hypothalamic suprachiasmatic nuclei (SCN), the main pacemaker for circadian rhythms, and the molecular identity of the transcript was confirmed by sequencing. The expression of the receptor protein showed a daily rhythm that was dependent on light. It reached its adult pattern in the SCN between postnatal day 11 and 20, i.e., at a time when capacity for photic entrainment of the pacemaker is established.
  Brain Research 01/2000; 849(1-2):231-4. · 2.73 Impact Factor
• Article: Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice.

  M E Rottenberg, A C Gigliotti Rothfuchs, D Gigliotti, C Svanholm, L Bandholtz, H Wigzell
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  ABSTRACT: Infection with Chlamydia pneumoniae is a common cause of acute respiratory disease in man and is also associated with atherosclerotic cardiovascular disorder. Herein, we have compared bacterial load and immune parameters of C. pneumoniae-infected mice genomically lacking T cell coreceptors, cytokine receptors, or cytotoxic effector molecules. A protective role for CD8+ cells is shown by the enhanced severity of infection of CD8-/- or TAP-1-/-/beta2-microglobulin -/- mice. CD8+ cells hindered a parasite growth-promoting role of CD4+ T cells, as indicated by the higher sensitivity to early infection of CD8-/- than CD4-/-/CD8-/- mice, which was further confirmed in experiments in which SCID mice were reconstituted with either CD4+ or CD4+ plus CD8+ T cells. Interestingly, CD4+ T cells played a dual role, detrimental early (14 and 24 days) after infection but protective at later time points (60 days after infection). The CD8+ T cell protection was perforin independent. The early deleterious role of CD4+ in the absence of CD8+ T cells was associated with enhanced IL-4 and IL-10 mRNA levels and delayed IFN-gamma mRNA accumulation in lungs. In line with this, IFN-gammaR-/- (but not TNFRp55 -/-) mice showed dramatically increased susceptibility to C. pneumoniae, linked to reduced inducible nitric oxide synthase (iNOS) mRNA accumulation, but not to diminished levels of specific Abs. The increased susceptibility of iNOS-/- mice indicates a protective role for iNOS activity during infection with C. pneumoniae. The higher sensitivity of IFN-gammaR-/- mice to C. pneumoniae compared with that of SCID or recombination-activating gene-1-/- mice suggested a relevant protective role of IFN-gamma-dependent innate mechanisms of protection.
  The Journal of Immunology 04/1999; 162(5):2829-36. · 5.79 Impact Factor
• Article: Trypanosoma cruzi infection in tumor necrosis factor receptor p55-deficient mice.

  E Castaños-Velez, S Maerlan, L M Osorio, F Aberg, P Biberfeld, A Orn, M E Rottenberg
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  ABSTRACT: Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55-/- mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-gamma)-activated macrophages from TNFRp55-/- mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55-/- and WT mice were also activated by IFN-gamma in a dose-dependent way. However, IFN-gamma-activated TNFRp55-/- nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1beta (IL-1beta) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55-/- mice and WT mice released similar levels of NO and showed similar levels of IFN-gamma mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55-/- mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55-/- mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice.
  Infection and Immunity 07/1998; 66(6):2960-8. · 4.16 Impact Factor
• Article: Expression of an oscillating interferon-gamma receptor in the suprachiasmatic nuclei.

  G B Lundkvist, B Robertson, J D Mhlanga, M E Rottenberg, K Kristensson
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  ABSTRACT: The suprachiasmatic nuclei serve as the dominant circadian pacemaker in the mammalian brain, regulating daily behavioral, physiological and hormonal rhythms. In the ventrolateral parts of these nuclei, the receptor for the key immunoregulatory molecule interferon-gamma (IFN-gamma) was detected in the rat brain. The cellular localization of the IFN-gamma receptor corresponded to neuronal elements. Expression of the receptor followed a diurnal rhythm with a peak at zeitgeber time 15. This peak coincided with an enhanced expression of janus kinase 1 and 2 as well as the signal transducer and activator of transcription 1, which constitute the main intracellular signaling pathway of IFN-gamma. This is the first study to show expression of the receptor of an immune modulatory molecule in the pacemaker of the biological clock, which, thus, may be influenced by immune system signal molecules.
  Neuroreport 05/1998; 9(6):1059-63. · 1.66 Impact Factor
• Article: Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37.

  J Johansson, G H Gudmundsson, M E Rottenberg, K D Berndt, B Agerberth
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  ABSTRACT: The influence of ion composition, pH, and peptide concentration on the conformation and activity of the 37-residue human antibacterial peptide LL-37 has been studied. At micromolar concentration in water, LL-37 exhibits a circular dichroism spectrum consistent with a disordered structure. The addition of 15 mM HCO3-, SO42-, or CF3CO2- causes the peptide to adopt a helical structure, with approximately equal efficiency, while 160 mM Cl- is less efficient. A cooperative transition from disordered to helical structure is observed as the peptide concentration is increased, consistent with formation of an oligomer. The extent of alpha-helicity correlates with the antibacterial activity of LL-37 against both Gram-positive and Gram-negative bacteria. Two homologous peptides, FF-33 and SK-29, containing 4 and 8 residue deletions at the N terminus, respectively, require higher concentrations of anions for helix formation and are less active than LL-37 against Escherichia coli D21. Below pH 5, the helical content of LL-37 gradually decreases, and at pH 2 it is entirely disordered. In contrast, the helical structure is retained at pH over 13. The minimal inhibitory concentration of LL-37 against E. coli is 5 microM, and at 13-25 microM the peptide is cytotoxic against several eukaryotic cells. In solutions containing the ion compositions of plasma, intracellular fluid, or interstitial fluid, LL-37 is helical, and hence it could pose a danger to human cells upon release. However, in the presence of human serum, the antibacterial and the cytotoxic activities of LL-37 are inhibited.
  Journal of Biological Chemistry 03/1998; 273(6):3718-24. · 4.77 Impact Factor
• Article: Soluble cell adhesion molecules in human Chagas' disease: association with disease severity and stage of infection.

  S Laucella, E H De Titto, E L Segura, A Orn, M E Rottenberg
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  ABSTRACT: Formation of inflammatory lesions, one of the pathologic consequences of infection with Trypanosoma cruzi, involves intricate cell-cell interactions in which cell adhesion molecules (CAMs) are involved. Sera from 56 Chagas' disease patients grouped according to disease severity were studied for the presence of soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble endothelial selectin (s-E-selectin), soluble vascular cell adhesion molecule-1 (s-VCAM-1), soluble platelet selectin (s-P-selectin), and s-CD44 were studied to determine if they could be used alone or in different combinations as markers for specific diagnostic procedures. Comparisons were made between congenitally, acutely, and chronically infected patients and aged-matched, noninfected individuals, as well as between patients with chronic Chagas' disease grouped according to the severity of their heart-related pathology. No differences in levels of s-CAMs were detected between sera from children with congenital T. cruzi infection and sera from noninfected infants born from chagasic mothers. In contrast, titers of s-ICAM-1, s-VCAM-1, s-selectin, and s-CD44 but not s-P-selectin were significantly increased in sera from patients during the acute phase of infection with T. cruzi. Titers of s-VCAM-1 and s-P-selectin were increased in chronically infected patients. A positive association with disease severity in sera from patients with chronic disease was observed for the levels of s-P-selectin. In contrast, we found no association between clinical symptoms and levels of s-VCAM-1. Patients with chronic disease with severe cardiopathy also showed diminished levels of s-CD44 in comparison with healthy controls or patients with mild disease. The results are discussed in the context of pathology of Chagas' disease.
  The American journal of tropical medicine and hygiene 01/1997; 55(6):629-34. · 2.59 Impact Factor
• Article: Intracellular co-localization of Trypanosoma cruzi and inducible nitric oxide synthase (iNOS): evidence for dual pathway of iNOS induction.

  M E Rottenberg, E Castaños-Velez, R de Mesquita, O G Laguardia, P Biberfeld, A Orn
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  ABSTRACT: Evidence is presented from studies in vitro and in vivo for a dual pathway of inducible nitric oxide synthase (iNOS) induction during Trypanosoma cruzi infection, one of which is interferon (IFN)-gamma dependent and the other not. In vitro, the IFN-gamma-dependent iNOS induction decreases parasite multiplication, and is in vivo associated with protection. iNOS induced by this pathway mediated a high NO output and showed a diffuse, cytoplasmic immunostaining in IFN-gamma-activated macrophages in vitro as well as in cell infiltrates or infected tissues. Surprisingly, in such tissues, iNOS co-localized with parasite nests, and by immunoelectromicroscopy, iNOS was demonstrated on the parasite surface. iNOS co-localization with parasites was also seen in tissues from T. cruzi-infected IFN-gamma receptor (R) knockout mice suggesting an IFN-gamma-independent pathway of induction. However, no cytoplasmic iNOS was seen in inflammatory infiltrates of these tissues. IFN-gammaR(-/-) mice displayed a dramatically enhanced susceptibility to infection with T. cruzi, diminished accumulation of iNOS mRNA in skeletal muscle and spleen cells, and reduced release of NO and peroxynitrite. Expression of iNOS around intracellular parasites was also observed after infection of peritoneal macrophages or L-929 fibroblasts in vitro in the absence of other exogenous stimuli. A time-dependent NO release and enhanced accumulation of iNOS mRNA also was observed in infected peritoneal cells and fibroblasts. Cultured T. cruzi amastigotes, trypomastigotes, and epimastigotes were not labeled by the anti-iNOS antibodies and contained no iNOS mRNA, indicating that the iNOS detected actually originated from the mammalian cell. A pathogenic effect of low NO levels is suggested by the arresting effect of NOS inhibitors and the enhancing consequences of low concentrations of NO donors on intracellular parasite multiplication.
  European Journal of Immunology 01/1997; 26(12):3203-13. · 5.10 Impact Factor
• Article: Increased expression and secretion of ICAM-1 during experimental infection with Trypanosoma cruzi.

  S Laucella, R Salcedo, E Castaños-Velez, A Riarte, E H De Titto, M Patarroyo, A Orn, M E Rottenberg
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  ABSTRACT: In the present study we demonstrate that spleens and hearts from BALB/c mice infected with the virulent Tulahuén or the low virulent CA-I strains of Trypanosoma cruzi, contain substantially higher ICAM-1 transcripts than uninfected controls. ICAM-1 expression in heart cells was also increased in the protein level, as measured by flow cytometry, ELISA and immunohistochemistry. The adhesive receptor was observed not only on inflammatory cells but also on sarcolemma of cardiac myocytes from T. cruzi infected mice. ICAM-1 expression was higher during the acute phase than in the chronic phase of infection, and paralleled the density of inflammatory leukocytes. Elevated titres of soluble ICAM-1 (s-ICAM-1) were detected in sera from mice during the acute phase of infection with CA-I or Tulahuén parasites. Cytokines, including IFN-gamma, IL-1 alpha, IL-6 and TNF-alpha have been shown to modulate expression of ICAM-1. Spleens and hearts from mice infected with CA-I or Tulahuen strains showed increased accumulation of mRNAs specific for these cytokines, which peaked during the acute phase of infection. However, IFN-gamma activity was not necessary for ICAM-1 induction, as its levels were also increased during infection in IFN-gamma receptor knock-out (IFN-gamma R- ) mice. Upregulation of ICAM-1 expression might be a direct consequence of parasite infection, since its density on cell lines of different lineages was enhanced after 24 or 48 h of infection with T. cruzi.
  Parasite Immunology 06/1996; 18(5):227-39. · 2.60 Impact Factor
• Article: Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression.

  M Aguilar-Santelises, M E Rottenberg, N Lewin, H Mellstedt, M Jondal
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  ABSTRACT: Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
  International Journal of Cancer 05/1996; 69(2):114-9. · 5.44 Impact Factor
• Article: Cytokine gene expression during infection of mice lacking CD4 and/or CD8 with Trypanosoma cruzi.

  M E Rottenberg, L Sporrong, I Persson, H Wigzell, A Orn
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  ABSTRACT: The expression of lymphokine genes during infection of virulent (Tulahuén) or mild (CA-I) strains of T. cruzi was studied in mice lacking CD4 and/or CD8 molecules. The increased susceptibility of CD4- and CD4-CD8- mice to infection with CA-I or Tulahuén was parallelled by diminished IFN-gamma mRNA levels. Nitric oxide release and inducible nitric oxide synthase mRNA accumulation by cells from Tulahuén infected CD4- mice was also diminished. CD8- (but not CD4-CD8- mice) showed an increased IL-4 and IL-10 mRNA accumulation upon infection with both strains of T. cruzi. A 'Th2-like' response (higher IL-4 and IL-10 mRNA to IFN-gamma mRNA ratio), was also observed when cells from noninfected CD8- mice were stimulated with T cell mitogens.
  Scandinavian Journal of Immunology 03/1995; 41(2):164-70. · 2.23 Impact Factor
• Article: Outcome of infection with different strains of Trypanosoma cruzi in mice lacking CD4 and/or CD8.

  M E Rottenberg, A Riarte, L Sporrong, J Altcheh, P Petray, A M Ruiz, H Wigzell, A Orn
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  ABSTRACT: Mice lacking CD4 and/or CD8 gene expression, generated by embryonic stem-cell technology, were used to study the role of CD4+ and CD8+ cells in the resistance to the acute infection with virulent (Tulahuén and RA) or mild (CA-I) strains of Trypanosoma cruzi. The presence of both CD4+ and CD8+ cells contributed to the survival of mice infected with T. cruzi, and each T-cell subtype was able to sustain protective functions in the absence of the other one. However, in certain host-parasite combinations, CD8+ cell-independent mechanisms were able to control the parasite load. Moreover, CD8- mice chronically infected with a low virulent strain of T. cruzi were protected from an otherwise lethal challenge with the parasite. A different organ distribution of parasite nests was observed when mutant (but not wild type) animals infected with different parasite strains were compared. CD4- mice produced high levels of IgG antibodies against peptide antigens or a whole homogenate from the parasite after infection with CA-I strain. A dramatic enhancement of IgG1- and IgG2a-specific antibodies was observed.
  Immunology Letters 03/1995; 45(1-2):53-60. · 2.53 Impact Factor
• Article: Cytokine Gene Expression During Infeetion of Miee Lacking CD4 and/or CD8 with Trypanosoma cruzi

  M. E. ROTTENBERG, L. SPORRONG, I. PERSSON, H. WIGZELL, A. ÖRN
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  ABSTRACT: The expression of lymphokine genes during infection of virulent (Tulahuén) or mild (CA-I) strains of T. cruzi was studied in mice lacking CD4 and/or CD8 molecules. The increased susceptibility of CD4− and CD4−CD8− mice to infection with CA-I or Tuiahuen was parallelled by diminished IFN-mRNA levels. Nitric oxide release and inducible nitric oxide synthase mRNA accumulation by cells from Tulahuen infected CD4− mice was also diminished. CD8− (but not CD4−CD8− mice) showed an increased IL-4 and IL-10mRNA accumulation upon infection with both strains of T. cruzi. A Th2-like’ response (higher IL-4 and IL-10mRNA to IFN-mRNA ratio), was also observed when cells from non-infected CD8- mice were stimulated with T cell mitogens.
  Scandinavian Journal of Immunology 01/1995; 41(2):164 - 170. · 2.23 Impact Factor
• Article: Release of nitric oxide during the experimental infection with Trypanosoma cruzi.

  P Petray, M E Rottenberg, S Grinstein, A Orn
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  ABSTRACT: We analysed the production of nitric oxide (NO) intermediates by cells from BALB/c mice infected with either virulent (Tulahuén or RA) or avirulent (CA-1) strains of Trypanosoma cruzi. Peritoneal or spleen cells from mice infected with T. cruzi released NO when incubated without further stimuli. Cells from mice during the acute stage of infection accumulated higher levels of inducible NO synthase mRNA and produced both, before and after lypopolysaccharide stimulation, higher amounts of NO than cells from mice chronically infected with T. cruzi. NO synthesis showed similar kinetics in connection with all three strains of T. cruzi, but cells from mice inbred with the Tulahuén or RA strains released higher levels of IFN-gamma, an activator of the NO pathways, than cells from mice infected with the CA-1 strain. In vivo administration of L-Ng-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of NO synthase, increased the susceptibility of mice to T. cruzi. We conclude that infection with T. cruzi induces NO production, and suggest that NO plays a role in the resistance against the parasite.
  Parasite Immunology 05/1994; 16(4):193-9. · 2.60 Impact Factor