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Disease Induction (disease + induction)
Selected AbstractsTCR-, chains derived from peripheral ,, T cells can take part in ,, T-cell developmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008Nabil Bosco Abstract Between 10 and 20% of the peripheral ,, T cells express cytoplasmic TCR-, proteins, but whether such TCR-, chains can partake in ,, T-cell development has never been systematically investigated. Therefore, we reconstituted the T-cell compartment of CD3,-deficient mice with Pax5-TCR-, deficient proB cells expressing, via a retroviral vector, TCR-, chains from either peripheral ,, or ,, T cells. Recipient thymi reconstituted with proB cells containing empty vector were small (<15×106 cells), contained few ,, T but no ,, T cells. In contrast, thymi from mice receiving proB cells containing ,, or ,, T-cell-derived TCR-, chains contained 80,130×106 cells, and showed a normal CD4, CD8 and ,, TCR expression pattern. However, regardless of the source of TCR-, chain, reconstituted mice rapidly showed signs of autoimmunity dying 5,15,wk following reconstitution. Autoimmune disease induction could be prevented by co-transfer of Treg cells thereby allowing the functionality of the generated T cells to be assessed. Results obtained show that TCR-, chains from ,, T cells can efficiently take part in ,, T-cell development. The implications of these findings for ,, T-cell development will be discussed. [source] L-Selectin-deficient SJL and C57BL/6 mice are not resistant to experimental autoimmune encephalomyelitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Chiara Uboldi Abstract L-selectin has been suggested to play a role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we demonstrate that L-selectin,/, SJL mice are susceptible to proteolipid protein (PLP)-induced EAE because the compromised antigen-specific T cell proliferation in peripheral lymph nodes is fully compensated by the T cell response raised in their spleen. Transfer of PLP-specific T cells into syngeneic recipients induced EAE independent of the presence or absence of L-selectin on PLP-specific T cells or in the recipient. Leukocyte infiltration into the central nervous system parenchyma was detectable independent of the mode of disease induction and the presence or absence of L-selectin. In addition, we found L-selectin,/, C57BL/6 mice to be susceptible to myelin oligodendrocyte glycoprotein-induced EAE. Taken together, we demonstrate that in SJL and C57BL/6 mice L-selectin is not required for EAE pathogenesis. The apparent discrepancy of our present observation to previous findings, demonstrating a role of L-selectin in EAE pathogenesis in C57BL/6 mice or myelin-basic protein (MBP)-specific TCR-transgenic B10.PL mice, may be attributed to background genes rather than L-selectin and to a unique role of L-selectin in EAE pathogenesis in MBP-TCR-transgenic mice. [source] Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathyLIVER INTERNATIONAL, Issue 5 2000David E. J. Jones Abstract:Background: Primary biliary cirrhosis (PBC) is characterised by intra-hepatic immune-mediated cholangiopathy (non-suppurative destructive cholangitis (NSDC)). Although auto-reactive immune responses against pyruvate dehydrogenase complex (PDC) have been characterised in PBC, the lack of an animal model of the disease has limited study of the mechanisms of disease induction and the development of novel approaches to therapy. Aims: To develop and validate a mouse model of immune-mediated cholangiopathy relevant for future use in the study of the aetio-pathogenesis and therapy of PBC. Methods: Female SJL/J, C57BL/6, NOD and BALB/c mice were sensitised with PDC, its purified E2/E3BP component, and a PDC-E2 derived peptide p163 (a dominant T-cell epitope in humans) in complete Freund's adjuvant (CFA). Morphological changes were assessed under light microscopy by a hepatic histopathologist blinded to the experimental details. Antibody responses to PDC were studied by ELISA and PDC inhibition assay. Results: An initial series of experiments was performed to survey the susceptibility of female mice of a range of strains to the induction of NSDC by i.p. sensitisation with PDC, PDC-E2/E3BP or p163 in CFA. Although each animal showed a specific antibody response following sensitisation, it was found that NSDC development (assessed at 30 weeks post-sensitisation) was restricted to SJL/J mice following sensitisation with any of the mitochondrial antigen preparations. A subsequent series of experiments was performed to examine the specificity and aetiology of this disease. Significant bile duct lesions were only seen in SJL/J animals following sensitisation with CFA containing PDC, and were absent from CFA only and un-sensitised controls. Kinetic analysis revealed that this pathology developed slowly, but a high incidence of animals with severe lesions was observed after 30 weeks. Conclusions: We have described a model of experimental autoimmune cholangitis (EAC) with immunological (anti-PDC antibodies) and histological (immune-mediated cholangiopathy) features suggestive of PBC. This model may be useful in further defining the role of self-tolerance breakdown in the development of this condition. [source] Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in miceARTHRITIS & RHEUMATISM, Issue 6 2007Manfred Kneilling Objective Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. Methods Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse,derived serum or control serum in wild-type Kit+/Kit+ mice, congenic mast cell,deficient KitW/KitW - v mice, or mast cell,deficient KitW/KitW - v mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated ,v,3 integrin using 18F,galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, ,3, and ,-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. Results Comparing wild-type mice, mast cell,deficient KitW/KitW - v mice, and mast cell,reconstituted KitW/KitW - v mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and ,v,3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented ,v,3 integrin activation, angiogenesis, and joint destruction. Conclusion Mast cell engraftment fully restores susceptibility to ,v,3 integrin activation, angiogenesis, and joint destruction in GPI antibody,induced arthritis. Importantly, selective mast cell stabilization prevents ,v,3 integrin activation, angiogenesis, and joint destruction. [source] Gene transfer of disease regulated promoters during experimental autoimmune uveitisACTA OPHTHALMOLOGICA, Issue 2009V ELMALEH Purpose Adeno-associated virus (AAV) vectors have been successfully used to transfer immunosuppressive genes into the retina to prevent experimental uveitis development. Transgene expression is classically regulated by constitutive or tetracycline inducible promoters. It might be more advantageous that the control of transgene expression depends on the pathological process itself. Inflammation activates transcription factors acting on promoters containing short responsive sequences, responding, for example to nuclear factor kappa B (NF,B-RE). These responsive elements can be used to generate disease regulated promoters. Methods An AAV vector with the GFP gene under the control of a NF-kB-RE containing promoter will be injected subretinally in C57Bl6 mice. Autoimmune uveitis will be induced by adoptive transfer of IRBP specific lymphocytes. Animals will be sacrificed at different time points. GFP expression will be analysed by immunofluorescence. VCAM1, MHC II and CD45 will be analysed by immunofluorescence and used to monitor the level of retinal inflammation. Results One week after disease induction, GFP expression was found in eyes injected with this new vector. Milder GFP expression was also found in mice who did not received adoptive transfer. This background was increased a J14. Conclusion Our preliminary results suggest that disease driven GFP expression can be obtained by the use of AAV vectors containing disease regulated promoters. We still need some more times to improve our model. In the future, we plan to replace the GFP gene by an immunosuppressive gene and test if the system can be use to treat experimental uveitis. [source] | ||||||||||