1,721,008 research outputs found
Dosimetria in fantoccio rigido di sorgenti per brachiterapia, con particolare riferimento allo I 125.
No full textno abstrac
PIF* promotes brain re-myelination locally while regulating systemic inflammation-clinically relevant multiple sclerosis M smegmatis model
Full text linkNeurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current studies suggest that it is likely caused by infection(s) triggering a systemic immune response resulting in antigen/non-antigen-related autoimmune response in central nervous system (CNS). New therapeutic approaches are needed. Secreted by viable embryos, PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role. Synthetic PIF (PIF) duplicates endogenous peptide’s protective effect in pre-clinical autoimmune and transplantation models. PIF protects against brain hypoxia-ischemia by directly targeting microglia and neurons. In chronic experimental autoimmune encephalitis (EAE) model PIF reverses paralysis while promoting neural repair. Herein we report that PIF directly promotes brain re-myelination and reverses paralysis in relapsing remitting EAE MS model. PIF crosses the blood-brain barrier targeting microglia. Systemically, PIF decreases proinflammatory IL23/IL17 cytokines, while preserving CNS-specific T-cell repertoire. Global brain gene analysis revealed that PIF regulates critical Na+/K+/Ca++ ions, amino acid and glucose transport genes expression. Further, PIF modulates oxidative stress, DNA methylation, cell cycle regulation, and protein ubiquitination while regulating multiple genes. In cultured astrocytes, PIF promotes BDNF-myelin synthesis promoter and SLC2A1 (glucose transport) while reducing deleterious E2F5, and HSP90ab1 (oxidative stress) genes expression. In cultured microglia, PIF increases antiinflammatory
IL10 while reducing pro-inflammatory IFNγ expression. Collectively, PIF promotes brain re-myelination and neuroprotection in relapsing remitting EAE MS
model. Coupled with ongoing, Fast-Track FDA approved clinical trial, NCT#02239562 (immune disorder), current data supports PIF’s translation for neurodegenerative disorders therapy
TRL2 HAPLOTYPE AND M TUBERCULOSIS IN THE ADJUVANT CO-MODULATE TRAFFICKING OF EFFECTOR T CELLS
No full textTLR2 haplotype and M. Tuberculosis in the adjuvant co-modulate trafficking of CNS-specific effector cells
No full textImpact of infectious agents on trafficking of effector T cells is mediated by a polymorphic site of TLR2.
No full textThe role of infectious agents in the regulation of antigen-specific T cell trafficking is currently unknown. Here we report evidence that the amount of M tuberculosis in the adjuvant modulates rapid relocation of PLP139-151 (p139)-specific T cells carrying the public TCR-beta chain BV1-CASS SGS NTE JB1.1 from draining lymph nodes (LN) to spleen, in the SJL mouse. In fact, T cells of mice immunized in the presence of a low dose of M tuberculosis mostly reached the spleen by day 28 after immunization (“late relocation”), whereas a high dose of M tuberculosis in the adjuvant promoted relocation of T cells to the spleen already by d 14 after immunization (“early relocation”). Modulation of T cell mobilization was strain-dependent with the C57/Bl6 background conferring a dominant “early relocation” phenotype to F1 (SJL x C57/Bl6) mice, allowing early relocation of T cells to the spleen also in the presence of low dose M tuberculosis. T cells from F1 (SJL x C57/Bl6tlr2-) mice that displayed only functional TLR2 of SJL origin did not relocate to the spleen at day 14 post-immunization in the presence of low dose of M tuberculosis, suggesting that TLR2 of C57/Bl6 origin confers the early relocation phenotype to F1 (SJL x C57/Bl6) mice. One non-synonymous polymorphism exists between TLR2 of SJL and of C57/BL6. F1 (SJLxC57/Bl6) mice homozygous for TLR2 of SJL display the same “late relocation” phenotype of F1 (SJL x C57/Bl6tlr2-) heterozygous littermates, formally proving that this polymorphism is responsible for “early/late” relocation phenotype. By transferring T cells from F1 mice obtained crossing SJL mice transgenic for the mentioned TCR-beta chain of the p139-specific, public receptor (SJLBV10) with C57/Bl6wt or C57/Bl6tlr2-, we determined that egress of antigen specific lymphocytes is modulated directly by TLR2 expressed on T cells. To clarify the mechanisms controlling early and late mobilization of T cells we examined the expression of activation markers and adhesion molecules involved in T cell trafficking. We show that early relocation associated with intermediate expression of CD44, a marker of T cell activation as well as adhesion molecule controlling T cell migration under inflammatory conditions. Our results reveal that pathogens engaging TLR2 on activated T cells through a polymorphic site modulate expression of activation/adhesion molecules and regulate effector T cells trafficking in vivo
TLR2 HAPLOTYPE REGULATES SEVERITY AND COURSE OF EAE BY MODULATING THE PROINFLAMMATORY ATTITUDE OF CNS-SPECIFIC T CELLS .
No full textObjective: M. Tuberculosis-derived motives play an essential role in the induction of the experimental model of Multiple Sclerosis, the experimental autoimmune encephalomyelitis (EAE). To examine the role of TLR2 (the main receptor for M tuberculosis) in the development of EAE, we crossed SJL mice with wild type B6 mice (B6wt) or B6129-Tlr2tm1kir/3 that fail to express TLR2 (B6tlr2-). Gene dosage is partially reflected by expression of TLR2, since activated T cells and CDR3- cells from lymph nodes of F1 (SJL x B6tlr2-) mice display a reduced level of TLR2 on their surface with respect to F1 (SJL x B6wt). SJL and B6 strains are both prone to develop EAE following immunization with myelin-derived peptides (PLP139-151 (p139) and MOG35-47, respectively). There are however relevant differences between these two models. First, opposite to B6, SJL mice develop EAE without the need for pertussis toxin (PTx) administration; second, SJL mice develop a relapsing remitting EAE, while B6 undergo a progressive/chronic form of the disease. Methods: SJL and breeding couples for C57/BL6wt and C57/BL6tlr2- mice were bred in the animal housing facility of our University. We used protocols of immunization and immunoscope analysis as described respectively in Nicolò 2006 and Ria 2004. We performed real time PCR with SYBRgreen method (Biorad®) to study IFN, FoxP3, IL17, IL13, IL10, IL12, IL23 expression. The histological examination of CNS were performed in collaboration with the Anathomy Institute of our University.
Results: We show here that both F1 mice develop EAE when immunized with p139. Surprisingly, disease is more severe in F1 (SJL x B6tlr2-) mice than in F1 (SJL x B6wt) mice. F1 (SJL x B6tlr2-) mice also consistently showed a partial remission of EAE symptoms, while F1 (SJL x B6wt) mice did not. Histological examination of CNS shows more frequently rostral infiltrates and demyelination in F1(SJL x B6tlr2-) mice than in F1 (SJL x B6wt) mice, that presented seriously damaged spinal cord.
Conclusions: In these two strains we analyzed the influence of polymorphic site of TLR2 on polarization of T cells by the expression of cytokines. Interestingly we observed that there is a significantly increase of IFNgamma and IL17 in the F1 (SJL x B6tlr2-) group with respect to F1 (SJL x B6wt) providing a mechanistic interpretation for the role of TLR2 haplotype in the modulation of severity of EAE
Analysis of T cells repertoire and clinical course of EAE after pretreatment with CNS antigens with asymmetric liposomes
No full textObjective: Experimental Autoimmune Encephalomyelitis (EAE) is the murine model of Multiple Sclerosis. Phospholipids have been shown to effectively modulate the immune response. We studied the effect of asymmetric liposomes on recruitment of CNS-specific T lymphocytes in EAE and on disease clinical course.
Methods: T cell repertoire analysis: Female SJL mice were pretreated s.c. with liposomes with or without PLP139-151. Mice were immunized s.c. 15 days after pretreatment with PLP139-151 in PBS emulsified 1:1 in CFA. Ten days later T cells from draining lymph nodes were cultured in the presence or absence of PLP139 for 3 days. The analysis of specific TCR-β repertoire were performed using immunoscope technique (Ria et al. 2006).
EAE induction: Female SJL mice were pretreated s.c. with liposomes or with plp139-151 and liposomes and were immunized 15 days after to induce EAE with PLP139-151 emulsified 1:1 with CFA 4x. Clinical score was evaluated following published criteria (Touhy et al. 1988).
Results: The immunoscope analysis of the PLP139-151 specific TR-β repertoire showed some interesting results: mice treated with Liposomes and PLP 139-151 recruited less frequently CD4+ T cells carrying the semiprivate rearrangement VB4-Jb1.6 than mice of the control group; There were no differences in the recruitment of CD4+ T cells carrying the public rearrangement VB10-Jb1.1. Furthermore, administration of Liposomes and PLP139-151 decreased usage of CD8+ cells carrying the public and semi-private rearrangements VB17-Jb1.6 and VB20-Jb2.3. Surprisingly we observed that the pre-immune TCR-β repertoire, which is usually depleted after immunization with PLP (Penitente et al. 2008), was still preserved in the group of mice pretreated with Liposomes and PLP 139-151.
When EAE was induced after pre-treatment with liposomes in the presence or absence of PLP139-151, We observed a significant difference in the clinical score of the disease. In particular the group of mice previously treated with Liposomes + PLP139-151 presented a lower severity of the symptoms at the onset of the disease.
Conclusions: Although the observed differences in the recruitment of T lymphocytes can justify the different clinical course of the disease, further studies are needed to understand the mechanism through which co-administration of antigens with asymmetric liposomes modifies immune responses
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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