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Cebula A.,Georgia Regents University | Seweryn M.,Ohio State University | Seweryn M.,University of Lodz | Rempala G.A.,Ohio State University | And 7 more authors.
Nature | Year: 2013

Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4 + Foxp3 + regulatory T (T reg) cells generated in the thymus or extrathymically by induction of naive CD4 + Foxp3-T cells. Previous studies suggested that the T-cell receptor repertoires of thymic T reg cells and induced T reg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota-and food-derived antigens to which T reg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage and favour tolerogenic presentation of antigens to naive CD4 + T cells, suggesting that intestinal homeostasis depends on microbiota-specific induced T reg cells. Here, to identify the origin and antigen-specificity of intestinal T reg cells, we performed single-cell and high-throughput sequencing of the T-cell receptor repertoires of CD4 + Foxp3 + and CD4 + Foxp3-T cells, and analysed their reactivity against specific commensal species. We show that thymus-derived T reg cells constitute most T reg cells in all lymphoid and intestinal organs, including the colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that thymic T reg cells, and not induced T reg cells, dominantly mediate tolerance to antigens produced by intestinal commensals. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Krol M.,Warsaw University of Life Sciences | Polanska J.,Wroclaw University of Environmental and Life Sciences | Pawlowski K.M.,Warsaw University of Life Sciences | Turowski P.,Justus Liebig University | And 6 more authors.
Journal of Applied Genetics | Year: 2010

Metastasis is a final step in the progression of mammary gland cancer, usually leading to death. Potentially, a molecular signature of metastasis can be defined via comparison of primary tumors with their metastases. Currently, there is no data in the literature regarding the molecular portrait of metastases in dogs and only few reports regarding human cancer. This is the first report describing the transcriptomic signature of canine cancer metastatic cells. Two adenocarcinoma cell lines isolated from the canine mammary gland (CMT-W1 and CMT-W2) were compared with cell lines isolated from their lung metastases (CMT-W1M and CMT-W2M) with regards to the following cytometric parameters: cell cycle, ploidy, Bcl-2 expression, susceptibility to induced apoptosis, and transcriptomic profile. Cytometric analyses revealed significant differences in cell cycle and antiapoptotic potential between the examined cells. Using oligonucleotide microarrays, we found 104 up-regulated genes in the metastatic cell line CMT-W1M and 21 up-regulated genes in the primary CMT-W1 cell line. We also found 83 up-regulated genes in the CMT-W2M cell line and only 21 up-regulated genes in the CMT-W2 cell line. Among the up-regulated genes in both metastatic cell lines, we found 15 common genes. These differently expressed genes are involved mainly in signal transduction, cell structure and motility, nucleic acid metabolism, developmental processing, and apoptosis (GHSR, RASSF1, ARF1GAP, WDR74, SMOC2, SFRP4, DIAPH1, FSCN1, ALX4, SNX15, PLD2, WNT7B, POU6F2, NKG7, and POLR2F). Seven of them are involved in a cellular pathway dependent on ghrelin via growth hormone secretagogue receptor (GHSR). Our results suggest that this pathway may be essential for mammary cancer cells to have a metastatic potential. Source

Pawlak A.,Wroclaw University of Environmental and Life Sciences | Rapak A.,Ludwik Hirszfeld Institute of Immunology and Experimental Therapy | Zbyryt I.,Wroclaw University of Environmental and Life Sciences | Obminska-Mrukowicz B.,Wroclaw University of Environmental and Life Sciences
In Vivo | Year: 2014

Background/Aim: Lymphoma, the most common hematopoietic cancer in dogs is sensitive to chemotherapy which is the dominant treatment method. The aim of the present study was to evaluate the concentration-dependent cytotoxicity and ability to induce apoptosis of the antineoplastic agents cyclophosphamide (CYC), chlorambucil (CBL), cytosine arabinoside (ARA), dexamethasone (DEX), doxorubicin (DOX), etoposide (ETO), lomustine (LOM), prednisone (PRED) and vincristine (VINK) against GL-1, CL-1, CLBL-1 and Jurkat cell lines. Materials and Methods: To determine cell viability and level of apoptosis, three different tests were performed: Thiazolyl Blue Tetrazolium Bromide (MTT), annexin V/propidium iodide (An/PI) staining and flow cytometric DNA fragmentation. Results: All tested substances exhibited concentration-dependent inhibitory effects on the proliferation of the examined cell lines with a different level of apoptosis induction. VINK and DOX strongly decreased the viability of canine cell lines, whereas CYC induced the highest level of apoptosis. Conclusion: Canine lymphoma (CL-1, CLBL-1) and leukemia (GL-1) cell lines are a useful tool for developing new and more effective treatment regimes for canine neoplasia. Source

Wojciech L.,Georgia Regents University | Ignatowicz A.,Georgia Regents University | Seweryn M.,Ohio State University | Rempala G.,Ohio State University | And 4 more authors.
Nature Communications | Year: 2015

The role of the T-cell receptor (TCR) in commitment of thymocytes to regulatory CD4 + Foxp3 + and conventional CD4 + Foxp3- T-cell lineages remains controversial. According to the prevailing view, commitment to the former lineage, in contrast to the latter, requires that high affinity TCRs bind rare class II MHC/peptide complexes presented in thymic niches, which could explain differences between their TCR repertoires. Here we challenge this view and show that the binding of identical TCRs to the same ubiquitously expressed MHC/peptide complex often directs thymocytes to both CD4+ lineages, indicating that the TCR affinity does not play the instructive role, and that restricted presentation of peptides in thymic niches is not necessary for selection of CD4 + Foxp3 + T cells. However, depending on whether immature thymocytes bound the ligand predominantly with low or high affinity, the repertoires of regulatory and conventional CD4+T cells were correspondingly similar or mostly different, suggesting that negative rather than positive selection sets them apart. © 2014 Macmillan Publishers Limited. Source

Nowak B.,Jagiellonian University | Ciszek-Lenda M.,Jagiellonian University | Srottek M.,Jagiellonian University | Gamian A.,Ludwik Hirszfeld Institute of Immunology and Experimental Therapy | And 3 more authors.
Archivum Immunologiae et Therapiae Experimentalis | Year: 2012

Oral administration of some probiotic bacteria (e.g. Lactobacillus rhamnosus) attenuates various types of experimental arthritis, including collagen-induced arthritis (CIA) and inhibits arthritogenic autoantibodies. Much less is known about the possible anti-arthritogenic properties of exopolysaccharide (EPS), the major component of lactic bacteria biofilm. In this study, we asked the question whether systemic administration of EPS derived from L. rhamnosus KL37 depresses the production of anti-collagen IgG and affects the development of CIA in DBA/1 mice. Arthritis was induced employing two models of active CIA, in which mice were immunized with type II collagen (CII) either in the presence of lipopolysaccharide (LPS; mild arthritis with moderate CII-specific IgG production) or with Complete Freund's Adjuvant and LPS (severe arthritis with massive CII-specific IgG production). Passive CIA was induced by intravenous injection of CII-specific monoclonal antibodies and LPS. Disease progression, the incidence and severity of arthritis, were determined. Serum concentration of CII-specific IgG was measured by enzyme-linked immunosorbent assay. Systemic administration of EPS markedly reduced CII-specific antibody production. Moreover, EPS significantly ameliorated arthritis in the active models of CIA, especially, when LPS alone was used as an adjuvant. In contrast, when arthritogenic antibodies were injected to mice in high amounts, the effect of EPS on the development of passive CIA was negligible and transient. These results show that EPS can suppress active CIA by the inhibition of arthritogenic antibodies production. Therefore, we suggest that EPS or EPS-producing probiotics may be promising agents for the supporting therapy of patients with rheumatoid arthritis. © L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012. Source

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