RESUMO
BACKGROUND AND PURPOSE: The ability to assess tumor malignancy and monitor treatment response noninvasively would be of value to both clinicians and animal investigators. This report describes the MR imaging characteristics of a genetically engineered mouse model of choroid plexus carcinoma (CPC) during tumor growth and progression to malignancy. We assess the ability of vessel tortuosity measurements, as calculated from high-resolution MR angiographic (MRA) images, to detect emerging CPC cancers. METHODS: MR images of 9 healthy mice and of 20 CPC mice with precancerous choroid dysplasia or with cancer over a wide range of sizes were analyzed. Two vessel tortuosity measures and a measure of vessel attenuation (vessel count) were calculated from MRA images. Malignancy assessment was based upon a statistical analysis of vessel tortuosity, by using an equation derived from an earlier study of human brain tumor patients. RESULTS: Choroid dysplasia was correctly judged nonmalignant. On the basis of vessel count, neoangiogenesis could not be detected until cancers were full-blown and had reached a volume of approximately 80 mm3. Vessel tortuosity measurements, however, correctly identified emerging malignancy in lesions larger than 0.3 mm3. CONCLUSION: To the best of our knowledge, this report provides the first description of in vivo, MR imaging characteristics of genetically engineered CPC mice during the progression from dysplasia to cancer. Vessel tortuosity measurements offer promise of correctly defining even tiny tumors as malignant.
Assuntos
Carcinoma/irrigação sanguínea , Carcinoma/diagnóstico , Neoplasias do Plexo Corióideo/irrigação sanguínea , Neoplasias do Plexo Corióideo/diagnóstico , Diagnóstico por Computador , Angiografia por Ressonância Magnética , Animais , Animais Geneticamente Modificados , Angiografia por Ressonância Magnética/métodos , Camundongos/genéticaRESUMO
The lpr mutation in mice results in premature termination of transcription of the gene encoding the apoptosis-signaling receptor Fas. As a result, lpr mice develop severe lymphoproliferation and lupus-like autoantibodies. Growing evidence suggests that the lpr mutation is "leaky" and that low levels of Fas are expressed in lpr mice. To determine if Fas expressed in lpr mice is contributing to apoptosis we generated a novel strain of mice (B6/lprgld) which is homozygous for both the lpr mutation and the gld mutation which encodes nonfunctional Fas ligand (FasL) protein. If low levels of Fas in B6/lpr mice contribute to apoptosis and lessen the severity of disease, the B6/lprgld mice, which also lack functional FasL, would be expected to develop a more severe form of disease than B6/lpr mice. Our results revealed no significant increase in either lymphoproliferation or autoimmunity in B6/lprgld mice compared to B6/lpr or B6/gld mice. Additionally, no increase in surface expression of Fas was detected by flow cytometry on B6/lprgld lymphocytes compared to B6/lpr lymphocytes. However, histological examination of B6/lprgld liver revealed a marked increase in lymphocytic infiltration, compared to livers of B6/lpr and B6/gld mice. Our results suggest that, while low levels of Fas in lpr mice may not be contributing to amelioration of lymphoproliferation or autoimmunity, they may be partially protecting the liver from abnormalities which arise in the absence of Fas-mediated apoptosis.
Assuntos
Autoimunidade/imunologia , Doenças Linfáticas/imunologia , Glicoproteínas de Membrana/genética , Mutação , Receptor fas/genética , Animais , Apoptose , Autoanticorpos/imunologia , Cruzamentos Genéticos , Proteína Ligante Fas , Feminino , Genótipo , Fígado/imunologia , Fígado/patologia , Doenças Linfáticas/patologia , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Reação em Cadeia da Polimerase , Receptor fas/biossíntese , Receptor fas/imunologiaRESUMO
The MHC exerts an important influence on systemic autoimmune disease. In C57BL/6-lpr/lpr (B6/lpr) mice, substitution of the H-2d instead of the H-2b MHC haplotype results in a global reduction in autoantibody levels. Since H-2d expresses both I-A and I-E, while H-2b expresses only I-A, general down-regulation of autoimmunity in the d haplotype might be due to I-E expression. This was tested with I-E alpha d transgenic B6/lpr mice, which expressed a functional surface I-E molecule. Five-month-old transgene-positive B6/lpr mice had much lower total IgG, IgG anti-chromatin, anti-DNA, and IgM rheumatoid factor directed against IgG1 and against IgG2b than transgene-negative littermates (p < or = 0.002), as well as significantly lower spleen and lymph node weights (p < or = 0.002). Decreases in autoantibody levels in the transgenic lpr mice were not due to a nonspecific effect of the I-E alpha d transgene, since transgene-positive B6/lpr.H-2d mice had levels of autoantibodies comparable with transgene-negative B6/lpr.H-2d mice. To determine whether autoantibody was preferentially made by I-E-negative B cells, irradiated (B6/lpr.Igha x B6/lpr.I-E alpha d)F1 mice were reconstituted with equal amounts of B6/lpr.Igha and B6/lpr.I-E alpha d bone marrow. Allotype-specific ELISA showed that most autoantibody was produced by the I-E negative B cells (range 97% to 84%). The results show that a functional I-E molecule in lpr mice leads to generalized reduction in autoantibody levels through a direct effect on the B cell. The molecular mechanism of this effect remains to be determined.
Assuntos
Doenças Autoimunes/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Animais , Autoanticorpos/sangue , Feminino , Antígenos H-2/imunologia , Tecido Linfoide/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Quimera por Radiação , Proteínas Recombinantes/metabolismo , Receptor fas/genéticaRESUMO
The lpr gene encodes a defective form of the fas gene that mediates apoptosis, and its expression results in autoantibodies and massive lymphadenopathy. bcl-2, another gene locus that affects programmed cell death, acts to inhibit apoptosis. Since multiple mechanisms controlling programmed cell death may contribute to systemic autoimmunity, the effect of the bcl-2 transgene on the lpr model was examined by crossing bcl-2 transgenic and C57BL/6-lpr mice. Compared with bcl-2-/lpr mice, bcl-2+/lpr showed dramatic increases in lymphadenopathy and T cell accumulation, but not in autoantibodies or B cell numbers. Short term transfer studies demonstrated that double negative T cells normally have a limited lifespan, and their survival is enhanced by the bcl-2 transgene. Thus, defects in separate apoptosis mechanisms may combine to produce enhanced pathologic effects.