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Biomedical subjects

J Löhler

Publications and source records attributed to J Löhler.

At least 37 records · Page 2Linked to original sources
PubMed1996

Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene.

Interferon consensus sequence binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Mice with a null mutation of ICSBP exhibit two prominent phenotypes related to previously described activities of the IRF family. The first is enhanced susceptibility to virus infections associated with impaired production of IFN(gamma). The second is deregulated hematopoiesis in both ICSBP-/- and ICSBP+/- mice that manifests as a syndrome similar to human chronic myelogenous leukemia. The chronic period of the disease progresses to a fatal blast crisis characterized by a clonal expansion of undifferentiated cells. Normal mice injected with cells from mice in blast crisis developed acute leukemia within 6 weeks of transfer. These results suggest a novel role for ICSBP in regulating the proliferation and differentiation of hematopoietic progenitor cells.

Animals↗
PubMed1996

Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue.

Immune defence against pathogens entering the gut is accomplished by lymphocytes in the gut-associated lymphoid tissue (GALT), a major compartment of the immune system. The GALT, comprising Peyer's patches, lamina propria lymphocytes and intra-epithelial lymphocytes of the intestine, is populated by lymphocytes that migrate there from the vasculature. Here we report that, in mice deficient for the beta7 integrin subfamily of adhesion molecules, the formation of the GALT is severely impaired. This is probably due to a failure of beta7-/- lymphocytes to arrest and adhere to the vasculature at the site of transmigration into the GALT.

Animals↗
PubMed1996

An alternative, nonkinase product of the brain-specifically expressed Ca2+/calmodulin-dependent kinase II alpha isoform gene in skeletal muscle.

The gene for the alpha isoform of Ca2+/calmodulin-dependent kinase II (alpha CaMKII) codes for a multifunctional protein kinase that is found exclusively in the brain. Here we show that in skeletal muscle, an alternative nonkinase product, hereafter referred to as alpha KAP (alpha CaMKII association protein), is expressed from the same gene. alpha KAP consists of a C-terminal region that is identical to the association domain of alpha CaMKII, with the exception of 11 amino acids inserted in the variable region. The N-terminal sequence of alpha KAP is highly hydrophobic and not present in any known CaMKII protein. The catalytic and regulatory domains of alpha CaMKII are missing in alpha KAP. Analysis of the exon-intron structure revealed that the alpha KAP transcript is derived from the alpha CaMKII gene by alternative promoter usage and RNA splicing. The transcriptional start site of alpha KAP mRNA is located within an intron of the alpha CaMKII gene. Therefore, the relationship between alpha KAP and alpha CaMKII is that of a gene within a gene. Immunostaining using anti-alpha KAP antibodies suggests that alpha KAP is associated with sarcomeres of skeletal muscle fibers. On the basis of its primary structure and specific location, the possible function of alpha KAP as an anchoring protein for CaMKII is discussed.

Alternative Splicing↗
PubMed1996

[Pathogenetic models ulcerative colitis and Crohn disease].

Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are thought to be distinct clinical entities. The mechanisms involved in the pathogenesis of the diseases are poorly understood, however, it is thought that dysregulation of the immune system, especially of the mucosal immune reactivity, as well as a genetic susceptibility and environmental factors, e.g. bacterial flora, may each contribute to initiation and/or progression and chronicity of the diseases. Experimental animal models are available to study the different components involved in inflammatory bowel disease and to complement our understanding of chronic inflammatory reactions in these organs ultimately leading to effective alternative therapeutic approaches.

Adoptive Transfer↗
PubMed1996

[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].

Il-2 has been described as a key cytokine regulating the growth, differentiation and function of lymphocytes. To better understand its in vivo function Il-2 deficient mouse mutants were generated on a mixed (129/Ola x C57BL6) genetic background which predominantly develop an ulcerative colitis-like disease (10). To further elucidate the complex disease syndrome of Il-2-/-mice and to study the possible contribution of genetic factors in its pathogenesis we have bred the IL-2-/-mice to various genetic backgrounds. The resulting phenotypes were analyzed clinically and morphologically and the status of their immune system was assessed. Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease, which becomes manifest as hemolytic anemia, follicular hyperplasia of lymphoid organs, inflammatory changes of pancreas, liver, heart, lungs and thoracal blood vessels but not of the colon (11). The mutants all die within 5 weeks of age. The changes of the immune system are dominated by an uncontrolled polyclonal activation and proliferation of T and B cells, associated with an increased production of autoantibodies. Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells. In such treated mice amelioration of hemolytic anemia but not of inflammatory lesions in most of the affected organs could be recognized. The primary immunologic change of Il-2-/-mice is obviously an uncontrolled proliferation of CD4+ T cells. It suggests that the in vivo function of IL-2 which is not compensated by other cytokines is the maintenance of self tolerance.

Animals↗
PubMed1995

Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice.

Hepatocarcinogenesis is deterministic in transgenic mice expressing in the liver gene construct Alb-DS4 that encodes autocrine growth factor IgEGF (D Stern et al. (1987), Science 235: 321-324), causing their death within 7.1 months. Hepatic expression of construct AAT-myc encoding murine c-myc causes liver cancer in 44% of the mice at 14.8 months. Cooperation of these genes was evident in CD2F1 transgenics bearing Alb-DS4 plus AAT-myc, in which accelerated hepatocellular carcinoma (HCC) formation caused death of all mice within 4.4 months. Alb-DS4 also cooperates with the Hcs locus, which in C3H/HeJ mice mediates high susceptibility to spontaneous hepatocarcinogenesis, causing accelerated formation of HCC to which mice succumbed at 5.1 months. Thus, genes that predispose to HCC formation cooperate in transgenic mice and their interaction is a key to understand mechanisms that cause liver cancer.

Animals↗
PubMed1995

Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells.

Interleukin-2-deficient mice (IL-2-/-) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized auto-immune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2-/- mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4- T cells (CD44high, CD69-) represents the first alteration of the immune system in IL-2-/- mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.

Anemia, Hemolytic, Autoimmune↗
PubMed1995

Gliomatosis peritonei combined with mature ovarian teratoma: immunohistochemical observations.

Gliomatosis peritonei (GP) is the metastatic implantation of glial cells within the peritoneal cavity of patients with ovarian teratomas. The case of a young woman is presented, who initially developed a mature teratoma in the left ovary that was surgically removed. Nine years later a mature teratoma in the right ovary was excised, upon which GP was found in the greater omentum. To identify the cellular composition of the ovarian teratoma and of the omental implants, immunostainings were performed using antibodies against glial and neuronal antigens as well as against determinants of hematopoietic cells. In the teratoma the neuroectodermal part was strongly HNK-1-positive and contained GFAP- and vimentin-positive astrocytes and some NSE-positive neuron-like cells. In addition, neuroectodermal tissue was infiltrated by numerous CD68-positive macrophages/histiocytes and CD20-positive B lymphocytes. The omental nodules consisted of astrocytes, which expressed GFAP, vimentin and desmin. The implants also contained macrophages/histiocytes, which exhibited morphologic features reminiscent of microglial cells. In GP, macrophages might release glia-promoting trophic factors, which could allow the neural component of ovarian teratoma to implant in the peritoneal cavity and survive there for many years. Macrophage-derived factors might induce astroglial differentiation, which could explain why the peritoneal implants are mostly mature even when they originate from immature teratomas.

Adolescent↗
PubMed1995

Perturbations of multiple hemopoietic lineages in retrovirus-induced murine malignant histiocytosis.

A fatal systemic proliferation of malignant histiocytes resembling human malignant histiocytosis was induced in susceptible mice following infection with the murine retrovirus malignant histiocytosis sarcoma virus (MHSV). It is shown that MHSV additionally caused profound alterations of erythropoiesis, granulocytopoiesis and thrombocytopoiesis, and in the hemopoietic stem cell compartment. In the erythroid lineage, MHSV induced a normocytic peripheral anemia, which was paralleled by an unphysiologic, multifocal clonal expansion of erythroid blasts in the spleen. These cells were not transformed and appeared to have a maturation defect since blood reticulocytes did not increase above control values. Moreover, MHSV exerted cytopathic effects on neutrophilic granulocytes and megakaryocytes, since their numbers transiently decreased in the spleen, and agranulocytosis and thrombocytopenia was observed in the blood. Nonetheless, regeneration was found in both lineages at later stages of the infection, which was accompanied by a terminal granulocytosis. The number of lineage-committed and multipotential colony-forming cells in the CFU-S assay increased transiently, but decreased to very low levels in the final stages of the disease. Thus, the studies demonstrate that the same etiologic agent, MHSV, had different effects on hemopoietic cells, which included malignant transformation, hyperproliferative and cytopathic effects.

Anemia↗
PubMed1994

MHC class I molecule-restricted presentation of viral antigen in beta 2-microglobulin-deficient mice.

Normally, Ag is presented to CD8+ T lymphocytes as a tripartite complex consisting of peptide epitope, MHC-encoded class I heavy (alpha) chain, and beta 2-microglobulin (beta 2-m) light chain. Although there is agreement about the function of both peptide and alpha-chain, the role of beta 2-m has remained uncertain. In particular, can Ag be presented without its participation? We have sought to obtain an answer by using mice in which the gene for beta 2-m had been disrupted by homologous recombination. As a consequence, no light chains are synthesized and, furthermore, few if any CD8+ T lymphocytes are formed. Elimination of lymphocytic choriomeningitis (LCM) virus from the tissues of acutely infected mice is mediated solely by CD8+ T lymphocytes; hence, in the beta 2-m-lacking mutants the infection cannot be terminated. Here it is shown that infusion of immune spleen cells from syngeneic beta 2-m+/+ mice and from mice compatible in K or D of the MHC resulted in virus clearance. Approximately five times more cells were required to achieve antiviral effects in beta 2-m-deficient than in wild-type mice but attempts to improve elimination by treatment of the former with IFN-gamma or beta 2-m have failed. Depleting the immune splenocytes of CD8+ T lymphocytes but not of CD4+ T lymphocytes abolished the antiviral potential. We conclude that LCM virus-infected murine cells can present viral Ag to CD8+ effector T lymphocytes together with class I MHC molecules K and D, despite the total absence of beta 2-m.

Animals↗
PubMed1994

The carbohydrate epitope 3-fucosyl-N-acetyllactosamine is region-specifically expressed in astrocytes of the rat brain. Light- and electron-microscopical observations.

The carbohydrate epitope 3-fucosyl-N-acetyllactosamine (CD15) is involved in cell-to-cell recognition processes in various tissues. In the CNS of the adult rat, immunoreactivity for CD15 reveals a region-specific distribution pattern by light microscopy. In the present study we investigated the ultrastructural localization of CD15 in the rat brain using preembedding immunocytochemical methods. In addition we studied CD15 expression in cultured astrocytes from optic nerves of 11-day-old rats. In optic nerve sections, immunostaining was found on the surface of astrocytes at various contact sites, i.e. astrocyte-astrocyte, astrocyte-oligodendrocyte, astrocyte-axon myelin, and astrocyte-blood vessel contacts. Oligodendrocyte-oligodendrocyte contacts, however, were always negative. In the telencephalic cortex, CD15 immunoreactivity was found in glial cell processes around synapses and in the cerebellar cortex in Bergmann glial cells. In astrocytes grown in serum-containing medium, CD15 was expressed on the surface of fibroblast-like glial fibrillary acidic protein-positive astrocytes, which were identified as type 1 astrocytes as well as on process-bearing A2B5-positive cells, representing type 2 astrocytes. The present data support the assumption that in the adult rodent brain, CD15 is exclusively expressed by astrocytes. The in vivo distribution of this carbohydrate molecule on distinct astroglial contact sites supports the notion that CD15 could act in cell-to-cell recognition processes.

Animals↗
PubMed1994

Mutants of a multipotent hematopoietic cell line blocked in GM-CSF-induced differentiation are leukemogenic in vivo.

FDCP-Mix cells infected with a retroviral vector expressing the GM-CSF gene (GMV-FDCP-Mix) self-renew in the presence of interleukin-3 (IL-3), are multipotent, and undergo differentiation into granulocytes and macrophages coupled with clonal extinction after removal of IL-3. Mutants of GMV-FDCP-Mix were isolated that escape clonal extinction after differentiation induction by the autocrine secreted GM-CSF. Some of these mutant clones have a blast cell morphology and are blocked in differentiation, whereas others exhibit all stages of granulocyte and macrophage differentiation without clonal extinction. In contrast to the parental GMV-FDCP-Mix cells, all the mutants tested were leukemogenic when injected into syngeneic mice. Depending on the in vitro differentiation capacity of the transplanted mutant cell lines, the animals developed undifferentiated blast cell leukemias or CML-like syndromes. Thus, these mutant cell lines can be used to define the cooperating steps in autocrine myeloid leukemia.

Animals↗
PubMed1994

Murine hepatitis caused by lymphocytic choriomeningitis virus. I. The hepatic lesions.

BACKGROUND: The hepatitis that occurs after adult mice are infected with lymphocytic choriomeningitis (LCM) virus is immune mediated, although the details of the pathogenetic mechanisms are largely unknown. To better understand the sequence of events leading to alterations typical for hepatitides with immunopathogenesis, livers of immunocompetent mice infected with LCM virus were examined. EXPERIMENTAL DESIGN: Virus replication and histopathology in the livers and concentrations of liver enzymes in the sera of C57BL/6 mice were followed from day 3 through day 14 after intraperitoneal infection with 10(6) mouse infectious units of LCM virus. Histologic, histochemical, immunohistologic, and in situ hybridization methods were used to determine the cells involved in the inflammatory process. RESULTS: Infectious virus rose to 10(9) mouse infectious units/g of liver by day 7 and declined thereafter. Viral RNA and antigen were localized in foci of hepatocytes and in Kupffer and endothelial cells of the sinusoids. Disseminated spotty necroses, steatosis, a marked sinusoidal reaction, and lobular and (later) periportal mononuclear infiltrates were observed. In the infiltrates, T cells predominated followed by macrophages and NK cells; the number of B and plasma cells rose moderately. Among T lymphocytes the CD8+ cells increased preferentially, and the CD4/CD8 ratio changed from 1.7 to 0.3. Other features were major histocompatibility complex antigen expression on hepatocytes, enhanced immunocytochemical evidence of fibronectin and ICAM-1 in sinusoids, and deposition of immunoglobulin, complement, and fibrinoid. Changed activities of liver enzymes and bilirubin levels paralleled the pathologic alterations. CONCLUSIONS: Although CD8+ T cells seem to be central in the pathogenesis of LCM hepatitis, probably more than one immunopathologic mechanism is operative.

Animals↗
PubMed1993

Interleukin-10-deficient mice develop chronic enterocolitis.

Interleukin-10 (IL-10) affects the growth and differentiation of many hemopoietic cells in vitro; in particular, it is a potent suppressor of macrophage and T cell functions. In IL-10-deficient mice, generated by gene targeting, lymphocyte development and antibody responses are normal, but most animals are growth retarded and anemic and suffer from chronic enterocolitis. Alterations in intestine include extensive mucosal hyperplasia, inflammatory reactions, and aberrant expression of major histocompatibility complex class II molecules on epithelia. In contrast, mutants kept under specific pathogen-free conditions develop only a local inflammation limited to the proximal colon. These results indicate that the bowel inflammation in the mutants originates from uncontrolled immune responses stimulated by enteric antigens and that IL-10 is an essential immunoregulator in the intestinal tract.

Anemia↗
PubMed1993

Induction of monocytic differentiation and tumorigenicity by v-Ha-ras in differentiation arrested hematopoietic cells.

Activated ras genes are often associated with human myeloid leukemias with a monocytic differentiated phenotype. To investigate the role of the activated ras gene in leukemogenesis, a myeloid nontumorigenic cell line (FDC-P1) was infected with a selectable retroviral vector carrying the v-Ha-ras gene (H1neo). Infected FDC-P1 cells were not only tumorigenic, but also showed increased monocytic differentiation in vitro. Monocytic differentiation and tumorigenicity in vivo were correlated with several-fold increased levels of activated ras gene expression. Tumorigenic cells were arrested with respect to monocytic marker expression at a much later stage of macrophage differentiation than the parental noninfected FDC-P1 cells. These data thus suggest a model of how activated ras genes could be involved in the preferential induction of hematopoietic malignancies with a myelomonocytic phenotype.

Animals↗
PubMed1993

Microenvironmental changes during axonal regrowth in the optic nerve of the myelin deficient rat. Immunocytochemical and ultrastructural observations.

Lesion-induced regenerative sprouting of CNS axons is accompanied by reactions of the supporting glia and vascular and connective tissue which may influence the extent of regeneration. In a previous report, it was shown that after crush injury, the amyelinated optic nerve of the myelin deficient (md) mutant rat contains greater numbers of regrowing axons proximal to the site of crush than that of normally myelinated littermates. The present study was designed to compare the response of the microenvironment, i.e. glial cells and vascular and connective tissue, in md and normally myelinated optic nerves 2, 4 and 6 days after crush injury. In unoperated normal optic nerves monoclonal antibodies to the HNK-1 carbohydrate labelled astrocytic processes at the ultrastructural level whereas in unoperated md mutants HNK-1 staining was restricted to axonal surfaces. Immunoreactivity with monoclonal antibodies to stage-specific embryonic antigen-1 (SSEA-1) was confined to astrocytic surfaces in both md and wildtype animals. After axotomy of md optic nerves regrowing axons were more numerous in the proximal site of the crush and extended further into the lesion than in wildtype animals. In both md and wildtype rats regrowing axons were HNK-1-positive. In md rats strong reaction with antibodies to laminin and fibronectin was only seen in 6-day-old lesions of md rats whereas immunoreactivity was less distinct in operated littermate controls. Immunolabelling was obviously associated with blood vessels, since crush lesions in both md and wildtype rats were Schwann cell-free as assessed by electron microscopy and immunocytochemistry. In both operated md and normal littermates crush lesions contained degenerating astrocytes as well as reactive astrocytes in which the intermediate filaments of the perikarya failed to stain immunocytochemically for GFAP, vimentin, desmin, and a common determinant of intermediate filaments. In contrast, reactive astrocytes in the lesion site of normally myelinated rats expressed the SSEA-1 antigen intracytoplasmically whereas in md mutants astrocytes were completely SSEA-1-negative. Infiltration of crush lesions by macrophages was less extensive in md rats than in normal littermates. However the overall content of macrophages in the peritoneal cavity was also reduced. The present study demonstrates that (1) md optic nerves lack HNK-1-reactive astrocytes; (2) in the axotomized wildtype optic nerve impaired axonal regrowth may be associated with distinct immuno-phenotypes of the supporting glial cells, i.e. SSEA-1-positive astrocytes; (3) laminin and fibronectin seem not to be essential for improved axonal regrowth in md rats.

Animals↗
PubMed1993

Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene.

Mice infected intracerebrally with lymphocytic choriomeningitis virus (LCM virus) develop a characteristic central nervous system disease and usually die. If the intravenous or intraperitoneal route is used, the infection leads to less severe clinical signs and the virus is eliminated. Illness and virus clearance are immunological phenomena, which are assumed to be caused exclusively by CD8+ T lymphocytes. In contrast, of the two phases of a delayed-type hypersensitivity reaction caused by inoculation of the virus into the mouse's foot, only the first is mediated by CD8+ cells, whereas the second is mediated by CD4+ cells. We have examined LCM virus-specific immune responses in mice devoid of CD8+ T lymphocytes as a result of disruption of the beta 2-microglobulin gene. As expected, the virus persisted but footpad swelling did not occur, although intracerebral infection resulted in CD4+ T-lymphocyte-mediated illness and antiviral antibodies were produced. Different results had been obtained by Fung-Leung et al. (W.-P. Fung-Leung, T. M. Kündig, R. M. Zinkernagel, and T. W. Mak, J. Exp. Med. 174:1425-1429, 1991), who, is essentially identical experiments but with mice lacking CD8+ T lymphocytes as a result of disruption of the Lyt-2-encoding gene, recorded control of the infection and development of a local delayed-type hypersensitivity reaction. We consider these differences important, because they provide us with clues that may help to understand the mode of action of the CD8+ T cells in cell-mediated antiviral immunity.

Animals↗