Lymphatic Dissemination and Comparative Pathology of Recombinant Measles Viruses in Genetically Modified Mice

Mrkic, Branka; Odermatt, Bernhard; Klein, Michael A.; Billeter, Martin; Pavlovic, Jovan; Cattaneo, Roberto

doi:10.1128/jvi.74.3.1364-1372.2000

Cited by 90 publications

(72 citation statements)

References 44 publications

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“…Breeding of the CD46 mice into IFNdefective genetic backgrounds was used to overcome these difficulties. In a mouse strain deficient for IFN-␣͞␤ receptor, dissemination of MV to several tissues was observed (6,29). Studies in mice lacking RAG2, which is a gene critical for the proper development of T and B cells, also resulted in more efficient spread of MV (34).…”

Section: Discussionmentioning

confidence: 99%

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Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

Welstead

Iorio

Draker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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A transgenic mouse containing the complete human SLAM (hSLAM͞CD150) gene, including its endogenous promoter for transcription, was generated by using human genomic DNA cloned into a bacterial artificial chromosome. hSLAM, the primary receptor for measles viruses (MV), was expressed on activated B, T, and dendritic cells with an expression profile equivalent to that of humans. We demonstrated that hSLAM ؉ cells obtained from the transgenic mouse, including activated B, T, and dendritic cells, were susceptible to MV infection in a receptor-dependent manner. Evidence was provided for transient infection in the nasal lymph nodes of hSLAM ؉ mice after intranasal inoculation. Virus was rapidly cleared without signs of secondary replication. To improve the efficiency of MV production, the hSLAM ؉ mice were bred with mice having a Stat1-deficient background. These mice were more susceptible to MV infection and produced more virus particles. After intranasal and intraperitoneal inoculation of these mice with MV, infections of the thymus, spleen, nasal, mesenteric, and leg lymph nodes were detected. Upon necropsy, enlarged lymph nodes and spleen were apparent. Flow cytometric analysis showed that abnormally large numbers of mature neutrophils and natural killer cells caused the splenomegaly. The hSLAM transgenic mouse constitutes an improved rodent model for studying the interaction of MV with immune cells that more accurately reflects the infection pattern found in humans.activated lymphocytes ͉ transgenic mouse ͉ dendritic cells M easles viruses (MV) is one of the most contagious diseases known to man and is a major killer of children in the developing countries of Africa and South America. The high mortality rate associated with MV infection results from increased susceptibility to opportunistic infections. Although MV has been studied extensively, the mechanism for the immunosuppressive effects observed during MV infection remains unclear (1).The development of a mouse model may lead to a better understanding of the immune suppression induced by MV. This was previously attempted by expressing CD46, one of the two receptors for MV, in mice (2-6). However, CD46 receptor, a ubiquitously expressed glycoprotein, is only used by vaccine or laboratory adapted strains of MV. Recently, a second receptor for MV was discovered: CD150 or signaling lymphocytic activation molecule (SLAM) (7-9). SLAM is a host cell receptor for both vaccine and WT MV strains of MV. It is a 70-kDa, type

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Section: Discussionmentioning

confidence: 99%

“…Previous work with CD46 transgenic mice identified the innate immune response as a barrier to efficient MV replication in mice (6,29). Therefore, the hSLAM mice were bred into a Stat1-deficient background, which renders mice extremely susceptible to pathogenic infections (15)(16)(17)(18).…”

Section: Stat1 Deficiency Confers a Permissive Environment For Efficientmentioning

confidence: 99%

Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

Welstead

Iorio

Draker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…These mice have already been [21,24,43] and will continue to be a useful tool to further analyse the significance of tissue-specific isoform expression patterns and to generate additional suitable small animal models for infections with pathogens that use MCP Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

Membrane cofactor protein (MCP; CD46) expression in transgenic mice

Kemper

Leung

Stephensen

et al. 2001

Clinical and Experimental Immunology

101

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SUMMARYHuman membrane cofactor protein (MCP; CD46) is a widely distributed complement regulator. In the mouse, expression of MCP is largely restricted to the testis while a related, widely expressed protein (Crry) appears to perform MCP's (CD46) regulatory activity. We have developed two mouse strains transgenic for human MCP (CD46) utilizing an , 400 kb YAC clone carrying the complete gene. A third mouse strain was generated using an overlapping YAC clone isolated from a second library. The expression of human MCP (CD46) in these mouse strains was characterized by immunohistochemistry, FACS, Western blotting and RT-PCR. No differences were detected in the isoform pattern or distribution among the three strains, although the expression level varied according to how many copies of the gene were integrated. The expression profile closely mimicked that observed in humans, including the same pattern of isoform expression as the donor. In addition, tissue-specific isoform expression in the kidney, salivary gland and brain paralleled that observed in man. The transgenic mice expressed low levels of MCP (CD46) on their E, in contrast to humans but in line with most other primates. These mice should be a useful tool to analyse tissue-specific expression, to establish animal models of infections and to characterize the role of MCP (CD46) in reproduction.

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“…Histological and immunohistochemical (IHC) assays were carried out as described previously (Mrkic et al, 2000). Briefly, tissue specimens for IHC analysis were collected and snap frozen.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

et al. 2006

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Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted these phagocytic cells in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to 492%, depending on therapy and schedule. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue. Vascular endothelial growth factor (VEGF) is one of the major inducers of tumour angiogenesis and is also required for macrophage recruitment. The strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Immunohistologic evaluation of the tumours showed significant depletion of F4/80 þ and MOMA-1 þ and a less pronounced depletion of CD11b þ TAMs. Blood vessel staining (CD31) and quantification of the vessels as well as TAMs and tumour-associated dendritic cells (TADCs) in the A673 model showed reduction rates of 85 to 494%, even 9 days after the end of therapy. In addition, CD11c þ TADCs, which have been shown to potentially differentiate into endothelial-like cells upon stimulation by tumour released growth and differentiation factors, were similarly reduced by clodrolip or antibody treatment. These results validate clodrolip therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination and as a tool to study the role of macrophages and dendritic cells in tumorigenesis.

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Lymphatic Dissemination and Comparative Pathology of Recombinant Measles Viruses in Genetically Modified Mice

Cited by 90 publications

References 44 publications

Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

Membrane cofactor protein (MCP; CD46) expression in transgenic mice

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

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