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Homing
Kinds of Homing Terms modified by Homing Selected AbstractsHoming in German Cockroaches, Blattella germanica (L.) (Insecta: Dictyoptera): Multi-Channelled Orientation CuesETHOLOGY, Issue 10 2004Colette Rivault Cockroaches use navigational cues to elaborate their return path to the shelter. Our experiments investigated how individuals weighted information to choose where to search for the shelter in situations where path integration, visual and olfactory cues were conflicting. We showed that homing relied on a complex set of environmental stimuli, each playing a particular part. Path integration cues give cockroaches an estimation of the position of their goal, visual landmarks guide them to that position from a distance, while olfactory cues indicate the end of the path. Cockroaches gave the greatest importance to the first cues they encountered along their return path. Nevertheless, visual cues placed beyond aggregation pheromone deposits reduced their arrest efficiency and induced search in the area near the visual cues. [source] Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardiumEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2009H. J. Ankersmit Abstract Background, Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. Methods, Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. Results, The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. Conclusion, These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium. [source] SHORT COMMUNICATION: Development of a Human Model to Study Homing Behavior of Immune Cells into Decidua and Placental Villi Under Ex Vivo ConditionsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009Joana Heinzelmann Problem, Homing of lymphocytes and NK cells into the decidua and its regulation has been very controversially discussed. Therefore, we aimed to establish an in vivo simulation method for analysis of homing behavior, which might be also useful for other cells such as stem or tumor cells. Method of study, A human term placenta has been perfused with medium to elute blood and then with maternal autologous carboxyfluorescein succinimidyl ester (CFSE)-labeled peripheral blood lymphocytes for 3 hr and rinsed for another 2 hr. Tissue was analysed histologically for detection of labeled cells. Labeled lymphocytes and beads in perfusate have been identified and counted by flow cytometry. Results, At the moment of tissue fixation for histology, the perfusate was free of labeled cells. Labeled perfused lymphocytes have been found adhered and integrated in vessel wall structures, in decidual stroma and as colonies in individual villi. Conclusion, Placenta perfusion with a lymphocyte suspension is feasible without plugging the tube system. Time is sufficient for cells to adhere and to migrate into the stroma. Also some villi have been infiltrated which might be caused by inflammatory stimuli. The perfusion system might be useful to test substances for their capacity to influence homing of lymphocytes or other cells. [source] Immunity, Homing and Efficacy of Allogeneic Adoptive Immunotherapy for Posttransplant Lymphoproliferative DisordersAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2007M. K. Gandhi Adoptive immunotherapy using autologous Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (auto-CTL) can regress posttransplant lymphoproliferative disorders (PTLD). Widespread applicability of auto-CTL remains constrained. Generation is time-consuming, and auto-CTL cannot be established in patients treated with the B-cell depleting antibody rituximab. By contrast, pregenerated allogeneic CTL (allo-CTL) offers immediate accessibility. Allo-CTL has previously shown efficacy in "early" polyclonal- PTLD. We treated three patients with aggressive, advanced monoclonal-PTLD following solid-organ transplantation. All were refractory to at least three prior therapies. Despite HLA disparity, there was negligible toxicity, with early in vivo antiviral efficacy and reconstitution of EBV peptide-specific immunity. Two patients attained complete remission (CR). One remains in CR 17 months following therapy, coincident with persistence of donor-derived tumor targeted EBV-specific CTL; the other died of non-PTLD related pathology. In the third patient, autopsy demonstrated homing of allo-CTL at the tumor site. Larger prospective studies of EBV-specific allo-CTL in PTLD are warranted. [source] Homing of transplanted bone marrow cells in livers of Schistosoma mansoni -infected miceAPMIS, Issue 4 2010NAGWA ELKHAFIF Elkhafif N, Voss B, Hammam O, Yehia H, Mansy S, Akl M, Boehm S, Mahmoud S, El Bendary O, El Fandy G. Homing of transplanted bone marrow cells in livers of Schistosoma mansoni -infected mice. APMIS 2010; 118: 277,87. The efficiency of differentiation of bone marrow cells (BMCs) into hepatocytes in vivo and its importance in physiopathological processes is still debated. Murine schistosomiasis was used as a liver injury model and unfractionated male mice BMCs were transplanted through intrahepatic injection into non-irradiated Schistosoma mansoni -infected female mice on their 16th week post-infection. Two weeks after bone marrow transplantation, mice were sacrificed on a weekly basis until 10 weeks. Tracing of male donor-derived cells in female recipient mice livers was carried out by the detection of Y chromosome expression by fluorescent in situ hybridization (FISH) and also of chromodomain Y-linked (CDYL) protein by indirect immunofluorescence (IF). Their transformation into hepatocytes was studied by double labelling indirect IF using antibodies directed against CDYL and mouse albumin. Histopathological and electron microscopic examinations revealed the presence of small hepatocyte-like cells in the periportal tracts and in between the hepatocytes facing the sinusoids. Donor-derived cells showing Y chromosome by FISH and expressing CDYL protein by IF were recovered in the infected transplanted livers. The initial number of these cells increased with increased post-transplantation time. Cells were mainly localized in the periphery of schistosoma granuloma. Few donor-derived cells appeared within the hepatic parenchymal tissue and showed positivity for albumin secretion by double labelling with IF. We suggest that transplanted bone marrow stem cells can repopulate the Schistosoma -infected liver of immunocompetent mice. Their differentiation is a complex event controlled by many factors and needs to be further characterized extensively. The extent and type of liver injury and the number of transplanted cells are important variables in the process of stem cell engraftment and differentiation into functioning hepatic cells that still need to be defined. [source] Development of Live Cell Chips to Monitor Cell Differentiation ProcessesENGINEERING IN LIFE SCIENCES (ELECTRONIC), Issue 1 2008C. Maercker Abstract A big demand exists for high-throughput functional in vitro assays which can measure cellular phenotypes by molecular methods and therefore improve the resources of primary cells for cell therapy, tissue engineering and high-content screenings in drug development. This approach focuses on cellular adhesion which is an important differentiation process during homing of stem cells. Moreover, it is a promising method especially for adherent cells which are not accessible by classical cell sorting methods. The chip design includes a housing with electrodes to measure electric field densities and impedance, respectively. Moreover, specific coatings of the wells permit a perfect growth of the selected cell types. In parallel, protein biomarkers can be followed by light microscopy. So far, experiments have been started to discriminate between different cell densities and cell types. In addition, after stimulating human cardiac fibroblasts and human umbilical vein endothelial cells, concentrations of proteins involved in adhesion had been increased, and proteins were translocated within the cells. In ongoing experiments, different human cell lines and fibroblastoid mesenchymal stem cells isolated from fat tissue, umbilical cord, or bone marrow are tested in the chip. To optimize the adhesion conditions, the surfaces within the vials of the chip were specifically activated. Microscopy was adjusted to be able to measure cellular morphology in parallel. This concept allows to identify the behavior of mesenchymal stem cells, which cannot be described so far by standard biomarkers. In addition, simulation of the homing process of the cells within its stem cell niche in an in vitro assay is a promising setup for large-scale gain-of-function or loss-of-function screenings in functional genomics as well as for generating precursor cells relevant for the therapy of various diseases. [source] Homing in German Cockroaches, Blattella germanica (L.) (Insecta: Dictyoptera): Multi-Channelled Orientation CuesETHOLOGY, Issue 10 2004Colette Rivault Cockroaches use navigational cues to elaborate their return path to the shelter. Our experiments investigated how individuals weighted information to choose where to search for the shelter in situations where path integration, visual and olfactory cues were conflicting. We showed that homing relied on a complex set of environmental stimuli, each playing a particular part. Path integration cues give cockroaches an estimation of the position of their goal, visual landmarks guide them to that position from a distance, while olfactory cues indicate the end of the path. Cockroaches gave the greatest importance to the first cues they encountered along their return path. Nevertheless, visual cues placed beyond aggregation pheromone deposits reduced their arrest efficiency and induced search in the area near the visual cues. [source] Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardiumEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2009H. J. Ankersmit Abstract Background, Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. Methods, Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. Results, The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. Conclusion, These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium. [source] T lymphocyte rolling and recruitment into peripheral lymph nodes is regulated by a saturable density of L-selectin (CD62L)EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007Elena Galkina Dr. Abstract L-selectin mediates tethering and rolling of lymphocytes in high endothelial venules (HEV) of lymph nodes (LN) and of leukocytes at inflammatory sites. We used transgenic mice expressing varying levels of wild-type or a non-cleavable mutant form of L-selectin on T cells to determine the relationship between L-selectin density, tethering and rolling, and migration into LN. T cells expressing supraphysiological levels of either wild-type or non-cleavable L-selectin showed rolling parameters similar to C57BL/6 T cells in hydrodynamic flow assays and during rolling in Peyer's patch HEV. In contrast, PMA- or antigen-activated T cells and L-selectin+/, T cells expressing subphysiological levels of L-selectin showed reduced numbers of rolling cells with increased rolling velocity. Short-term homing studies showed that elevated expression of L-selectin above physiological levels had no effect on T cell migration to LN; however, low L-selectin expression resulted in reduced T cell homing to LN. Thus, T lymphocyte migration into LN is regulated by the density of cell surface L-selectin. In addition, there is a saturable density of L-selectin required for optimal homing to PLN in C57BL/6 mice, the L-selectin level on circulating naive T cells promotes optimal homing, and increased expression above saturating levels promotes no further increase in T cell recruitment. [source] The chemokine receptor CCX-CKR mediates effective scavenging of CCL19 in vitroEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2006Iain Comerford Abstract The chemokines CCL19, CCL21 and CCL25, by signalling through the receptors CCR7 or CCR9, play critical roles in leukocyte homing. They also bind another heptahelical surface protein, CCX-CKR. CCX-CKR cannot couple to typical chemokine receptor signalling pathways or mediate chemotaxis, and its function remains unclear. We have proposed that it controls chemokine bioavailability. Here, using transfected HEK293 cells, we have shown that both CCX-CKR and CCR7 mediate rapid CCL19 internalisation upon initial chemokine exposure. However, internalised CCL19 was more efficiently retained and degraded after uptake via CCX-CKR. More importantly, CCR7 rapidly became refractory for CCL19 uptake, but the sequestration activity of CCX-CKR was enhanced. These properties endowed CCX-CKR with an impressive ability to mediate progressive sequestration and degradation of large quantities of CCL19, and conversely, prevented CCR7-expressing cells from extensively altering their chemokine environment. These differences may be linked to the routes of endocytosis used by these receptors. CCX-CKR, unlike CCR7, was not critically dependent on ,-arrestins or clathrin-coated pits. However, over-expression of caveolin-1, which stabilises caveolae, blocked CCL19 uptake by CCX-CKR while having no impact on other chemokine receptors, including CCR7. These data predict that CCX-CKR scavenges extracellular chemokines in vivo to modify responses through CCR7. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636327 [source] Role of the monomeric GTPase Rho in hematopoietic progenitor cell migration and transplantationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2006Stephan Göttig Abstract To investigate the role of the monomeric guanosine triphosphatase (GTPase) Rho on migration of hematopoietic progenitor cells (HPC), we employed different clostridial toxins which inhibit the Rho family of GTPases. Pretreatment with C2I-C3, a cell-accessible C3 transferase fusion protein that targets Rho, increased chemokinetic migration of the factor-dependent multipotent cell line Factor Dependent Cell Paterson with mixed lineage differentiation potential (FDCP-mix) and of primary lineage marker-depleted HPC in vitro. In contrast, treatment with lethal toxin (LT) from Clostridium sordellii, which predominantly inactivates Rac, and with toxin,B from C.,difficile, which inactivates Rho, Rac and Cdc42, decreased in vitro migration. When HPC pretreated with LT or toxin,B were transplanted into mice, homing to the bone marrow was impaired, whereas C2I-C3 treatment did not alter HPC homing. However, in a competitive hematopoietic repopulation experiment in C57BL/6 mice, pretreatment of bone marrow cells with any of the inhibitors, including the Rho inhibitor C2I-C3, resulted in suppressed donor-type hematopoiesis. Our data indicate that whereas Rac supports HPC cell cycling, migration, short-term homing and hematopoietic regeneration, Rho coordinates down-regulation of HPC migration and is required for hematopoietic regeneration. [source] Mice with neonatally induced inactivation of the vascular cell adhesion molecule-1 fail to control the parasite in Toxoplasma encephalitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2003Martina Deckert Abstract Under various inflammatory conditions, cell adhesion molecules are up-regulated in the central nervous system (CNS) and may contribute to the recruitment of leukocytes to the brain. In the present study, the functional role of vascular cell adhesion molecule (VCAM)-1 in Toxoplasma encephalitis (TE) was addressed using VCAMflox/flox MxCre mice. Neonatal inactivation of the VCAM-1 gene resulted in a lack of induction of VCAM-1 on cerebral blood vessel endothelial cells, whereas the constitutive expression of VCAM-1 on choroid plexus epithelial cells and the ependymawas unaffected; in these animals, resistance to T.,gondii was abolished, and VCAMflox/flox MxCre mice died of chronic TE caused by a failure to control parasites in the CNS. Although leukocyte recruitment to the CNS was unimpaired, the B cell response was significantly reduced as evidenced by reduced serum levels of anti- T.,gondii -specific IgM and IgG antibodies. Furthermore, the frequency and activation state of intracerebral T.,gondii -specific T cells were decreased, and microglial activation was markedly reduced. Taken together, these data demonstrate the crucial requirement of VCAM-1-mediated immune reactions for the control of an intracerebral infectious pathogen, whereas other cell adhesion molecules can efficiently compensate for VCAM-1-mediated homing across cerebral blood vessels. [source] IL-15 and IL-16 overexpression in cutaneous T-cell lymphomas: stage-dependent increase in mycosis fungoides progressionEXPERIMENTAL DERMATOLOGY, Issue 4 2000K. Asadullah Abstract: Cytokines are of major importance for the pathogenesis of cutaneous T-cell lymphomas (CTCL). Recent data suggested that IL-15 and IL-16 are survival/growth factors for the malignant T cells in these entities. To investigate the expression of IL-15 and IL-16 in mycosis fungoides (MF) and CD30+ pleomorphic T-cell lymphoma in vivo, we established a competitive RT-PCR technique. Analyzing skin biopsies from CTCL patients at different stages in comparison to psoriatic and healthy skin, we found IL-15 and IL-16 mRNA overexpression in both CTCL entities. Remarkably, there was some evidence for a stage-dependent increase during MF progression. We found only slight overexpression in early stage MF, when only few tumor cells are detectable within the infiltrates, whereas marked overexpression was found in more advanced lesions, which are characterized by a higher density of malignant cells. These results suggested that CTCL cells themselves might produce the cytokines. To further elucidate this hypothesis, two CTCL cell lines were analyzed but gave conflicting results. Therefore, the cellular origin of the IL-15 and IL-16 overexpression in CTCL remains unclear. Considering the significant overexpression of IL-15 and IL-16 and their biological capacities it is likely that these cytokines contribute to the tumor development. So, they might be involved in growth and skin homing of CTCL cells. [source] VDE-initiated intein homing in Saccharomyces cerevisiae proceeds in a meiotic recombination-like mannerGENES TO CELLS, Issue 7 2003Tomoyuki Fukuda Background: Inteins and group I introns found in prokaryotic and eukaryotic organisms occasionally behave as mobile genetic elements. During meiosis of the yeast Saccharomyces cerevisiae, the site-specific endonuclease encoded by VMA1 intein, VDE, triggers a single double-strand break (DSB) at an inteinless allele, leading to VMA1 intein homing. Besides the accumulating information on the in vitro activity of VDE, very little has been known about the molecular mechanism of intein homing in yeast nucleus. Results: We developed an assay to detect the product of VMA1 intein homing in yeast genome. We analysed mutant phenotypes of RecA homologs, Rad51p and Dmc1p, and their interacting proteins, Rad54p and Tid1p, and found that they all play critical roles in intein inheritance. The absence of DSB end processing proteins, Sae2p and those in the Mre11-Rad50-Xrs2 complex, also causes partial reduction in homing efficiency. As with meiotic recombination, crossover events are frequently observed during intein homing. We also observed that the absence of premeiotic DNA replication caused by hydroxyurea (HU) or clb5, clb6, mutation reduces VDE-mediated DSBs. Conclusion: The repairing system working in intein homing shares molecular machinery with meiotic recombination induced by Spo11p. Moreover, like Spo11p-induced DNA cleavage, premeiotic DNA replication is a prerequisite for a VDE-induced DSB. VMA1 intein thus utilizes several host factors involved in meiotic and recombinational processes to spread its genetic information and guarantee its progeny through establishment of a parasitic relationship with the organism. [source] Chemokine receptor-dependent alloresponsesIMMUNOLOGICAL REVIEWS, Issue 1 2003Wayne W. Hancock Summary:, Immunologists have typically viewed alloreactivity schematically as a function of antigen presentation, expansion of alloreactive T and B cells within regional lymphoid tissues, and cellular infiltration and destruction of an allograft. Actual details of the steps between immune activation and accumulation of effector cells within a graft typically have not received much attention. However, just how cells ,know' to move to and migrate within a graft or not is proving to be of increasing interest, as the chemokine-dependent mechanisms underlying leukocyte recruitment to a transplant are dissected. Experimentally, chemokine receptor targeting can prolong or induce permanent allograft survival, despite preservation of alloresponses within secondary lymphoid tissues, whereas current immunosuppressive protocols have only modest effects on chemokine production and leukocyte homing. Recent knowledge of the chemokine-dependent nature of allograft rejection, acceptance, and tolerance induction are presented as a basis for understanding the rationale for preclinical trials of chemokine receptor-targeted therapies currently underway in primate recipients of solid organ allografts. [source] Multiple myeloma biology: lessons from the 5TMM modelsIMMUNOLOGICAL REVIEWS, Issue 1 2003Karin Vanderkerken Summary:, Multiple myeloma (MM) is a B cell neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, the development of osteolytic lesions and the induction of angiogenesis. These different processes require three-dimensional interactions, with both humoral and cellular contacts. The 5TMM models are suitable models to study these interactions. These murine models originate from spontaneously developed myeloma in elderly mice, which are propagated by in vivo transfer of the myeloma cells into young syngeneic mice. In this review we report on studies performed in the 5TMM models with special emphasis on the homing of the myeloma cells, the characterization of the migrating and proliferating clone and the identification of the isotype switch variants. The bone marrow microenvironment was further targeted with osteoprotegerin (OPG) to block the RANK/RANKL/OPG system and with potent bisphosphonates. Both treatments resulted in a significant protection against myeloma-associated bone disease, and they decreased myeloma disease, as evidenced by a lower tumor load and an increased survival of the mice. These different studies demonstrate the strength of these models, not only in unraveling basic biological processes but also in the testing of potentially new therapeutic targets. [source] T cells developing in fetal thymus of T-cell receptor ,-chain transgenic mice colonize ,, T-cell-specific epithelial niches but lack long-term reconstituting potentialIMMUNOLOGY, Issue 1 2006Karin Leandersson Summary The ,, T cells generated during mouse fetal development are absolutely dependent on their invariant T-cell receptors (TCRs) for their function. However, there is little information on whether the epithelial homing properties of fetal T cells might also be developmentally induced by factors unrelated to TCR specificity. We have previously described TCR ,-chain transgenic (2B4 TCR-, TG) mice, in which the transgenic TCR ,-chain is expressed early, already at embryonic day 14 (E14). These mice have a large population of ,,, T-cell-like' CD4, CD8, (double-negative; DN) ,, T cells, some of which develop during E14,E18 contemporarily to intraepithelial lymphocytes (IELs) expressing invariant TCR-,,. Using the 2B4 TCR-, TG mouse model we have been able to more precisely study the impact of a variant TCR expression on IEL development and homing. In this study we show that TCR-, TG and TCR-, TG crossed to TCR-,-deficient mice (TCR-, TG × TCR-,,/,) carry TG TCR-,+ dendritic epidermal T cells (DETCs) and TCR-, TG+ IELs in the small intestine. The TG+ DETCs develop and seed the epidermis with similar kinetics as V,5+ DETCs of normal mice, in contrast to the TCR-,,+ DETCs found in TCR-,,/, mice. However, whereas the intestinal TCR-, TG+ IELs persist in old mice (> 20 months), the TCR-, TG+ DETCs do not. The data in this study indicate that the timing of TCR expression and thereby development during ontogeny regulates the specific homing potential for fetal T cells but not their subsequent functions and properties. [source] Characterization of CC-chemokine receptor 7 expression on murine T cells in lymphoid tissuesIMMUNOLOGY, Issue 2 2003Olle Bjorkdahl Summary Expression of the lymph node homing and CC-chemokine receptor 7 (CCR7), with L-selectin (CD62L), has been shown to divide human memory T cells into two functionally distinct subsets. We generated a polyclonal antibody against murine CCR7 and used this antibody to study CCR7 expression on murine T-cell subsets. Using flow cytometric staining of T cells for visualisation expression of CCR7 in association with CD62L and CD44, a major population of CD4 or CD8 T cells expressing CCR7 were found to be CD62Lhigh CD44low, which would suggest a naïve cell phenotype. By analogy with human studies, memory cells could be subdivided into CCR7high CD62Lhigh CD44high (central memory) and CCR7low CD62Llow CD44high (effector memory). The proportions of these populations were different in lymph node, blood and spleen. Functional, short-term in vitro polyclonal stimulation of blood, spleen and lymph node cells from naive mice demonstrated that CCR7high CD4 T cells produced predominantly interleukin (IL)-2, whereas CCR7low CD4 T cells produced both IL-2 and interferon-, (IFN-,). However, in contrast to previously published reports, the CCR7high CD8 T-cell subpopulation produced both IFN-, and IL-2. Analysis of effector T cells, induced by immunization in vivo, showed that a proportion of activated naïve CD4 T cells down-regulated CCR7 only after multiple cell divisions, and this coincided with the down-regulation of CD62L and production of IL-4 and IFN-,. Finally, analysis of effector T cells during the phase of maximal clonal expansion of secondary immune responses in vivo indicated that the vast majority of both IL-2- and IFN-,-producing cells are CCR7low, while few cytokine-expressing CCR7high T cells were detected. Our results support the hypothesis, developed from studies with human cells, that CCR7 may separate functionally different murine memory T-cell subpopulations, but indicate additional complexity in that CCR7high CD8 T cells also may produce IFN-,. [source] Intestinal dendritic cells: Their role in bacterial recognition, lymphocyte homing, and intestinal inflammationINFLAMMATORY BOWEL DISEASES, Issue 10 2010S.C. Ng PhD Abstract Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-,. Specialized CD103+ intestinal DC can promote the differentiation of Foxp3+ regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source] Prospective evaluation of intestinal homing memory T cells in ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 5 2004A. L. Hart Abstract Background: Intestinal homing (,7+) memory T cells reflect the mucosal environment in which they were primed. We hypothesized that prospective assessment of cytokine production by intestinal homing (,7+) memory T cells in ulcerative colitis patients followed from remission to early relapse may elucidate shifts in cytokine production relevant to the mucosal environment associated with the early phase of inflammation. Methods: Twelve patients with frequently relapsing ulcerative colitis (,2 relapses in the previous 12 months) were recruited in remission and followed prospectively until relapse. Antibody labeling of whole blood and flow cytometry were used to identify ,7+ cells and ,7, populations within CD3+CD45RA, leukocytes. Production of cytokines (IFN-,, TNF-,, IL-2, IL-10, TGF-,, and IL-4) was determined by intracellular labeling. Results: Early relapse of ulcerative colitis was associated with a shift of T cells from the naive to the memory T cell pool, and further the ratio of ,7+:,7, memory T cells was significantly reduced at relapse (p < 0.01). A greater proportion of intestinal homing ,7+ memory T cells produced IL-4 (p < 0.02) and TNF-, (p < 0.05) at disease relapse compared with remission. Non-intestinal homing ,7,memory T cells also showed a tendency toward an increased production of TH1 and TH2 cytokines. Conclusions: The earliest phase of intestinal inflammation in ulcerative colitis patients is associated with an increase in both TH1 (TNF-, and TH2 (IL-4) cytokines by intestinal homing ,7+ memory T cells. These data support the principles of targeting lymphocyte trafficking as therapies in ulcerative colitis. [source] Antiadhesion molecule therapy in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 4 2002Dr. Gert Van Assche Abstract Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. Some of these molecules such as MadCAM-1 are specific for the gastrointestinal endothelium, but in inflammatory bowel diseases most of the adhesion factors are up-regulated. Adhesion molecules also are involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. Recently, therapeutic compounds directed against trafficking of lymphocytes toward the gut mucosa have been designed, and are being developed as a novel class of drugs in the treatment of Crohn's disease (CD) and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Secondly, the changes in adhesion molecules and T-cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered in trials of biological therapies directed against adhesion molecules. Both antiintercellular adhesion molecule-1 (ICAM-1) and anti-,4 integrin strategies are being developed. Trials with the anti-ICAM-1 antisense oligonucleotide, ISIS-2302, in steroid-refractory CD have provided conflicting efficacy data. The anti-,4 integrin antibodies natalizumab (Antegren) and LDP-02 are in phase III and phase II trials, respectively. In the near future, these novel biological agents may prove valuable therapeutic tools in the management of refractory IBD. [source] Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2INTERNATIONAL JOURNAL OF CANCER, Issue 4 2010Wen Min Lau Abstract Breast cancer metastases develop in the bone more frequently than any other site and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver and lung, closely mimicking the anatomical distribution of metastases in patients with breast cancer. Using an in vivo selection process, we established NT2.5 sublines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sublines revealed both known and novel mediators of bone metastasis and osteolysis, including the transcriptional co-activator CITED2. In further studies, we found that expression of CITED2 was elevated in human primary breast tumors and bone metastasis compared to normal mammary epithelium and was highest in breast cancer cell lines that cause osteolytic bone metastasis in animal models. In addition, reducing CITED2 expression in NT2.5 cells inhibited the establishment of bone metastasis and osteolysis in vivo, suggesting a potential role for CITED2 in promoting breast cancer bone metastasis. [source] Spontaneous splenic haematoma in a multiple myeloma patient receiving pegfilgrastim supportINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 6 2006E. HATZIMICHAEL Summary Growth factors are a significant advance in the supportive care of patients with cancer with a wide range of indications. Frequent side effects of G-CSF include bone pain, headache, fatigue and nausea. We report a case of subcapsular splenic haematoma following pegfilgrastim administration in a 65-year old patient with multiple myeloma. Proposed mechanisms accounting for splenic enlargement include extramedullary haemopoiesis, intrasplenic infiltration by mature and immature myeloid cells and intrasplenic stem cell homing and proliferation. The risk of spontaneous splenic rupture is difficult to quantify. Physicians should be aware of this life-threatening condition and early diagnosis can be difficult since anemia and splenomegaly are common findings in haematologic patients. [source] Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetesIUBMB LIFE, Issue 1 2007Alexei Y. Savinov Abstract Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, ,-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes. IUBMB Life, 59: 6-13, 2007 [source] Restoration of Bone Mass and Strength in Glucocorticoid-Treated Mice by Systemic Transplantation of CXCR4 and Cbfa-1 Co-Expressing Mesenchymal Stem Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2009Chun-Yang Lien Abstract Transplantation of gene-modified mesenchymal stem cells (MSCs) in animals for bone regeneration therapy has been evaluated extensively in recent years. However, increased endosteal bone formation by intravenous injection of MSCs ectopically expressing a foreign gene has not yet been shown. Aside from the clearance by lung and other tissues, the surface compositions of MSCs may not favor their bone marrow (BM) migration and engraftment. To overcome these hurdles, a gene encoding the chemokine receptor largely responsible for stromal-derived factor-1 (SDF-1)-mediated BM homing and engraftment of hematopoietic stem cells (HSCs), CXCR4, was transduced into mouse C3H10T1/2 cells by adenovirus infection. A dose-dependent increase of CXCR4 surface expression with a parallel enhanced chemotaxis toward SDF-1 in these cells after virus infection was clearly observed. Higher BM retention and homing of CXCR4-expressing MSCs were also found after they were transplanted by intramedullary and tail vein injections, respectively, into immunocompetent C3H/HeN mice. Interestingly, a full recovery of bone mass and a partial restoration of bone formation in glucocorticoid-induced osteoporotic mice were observed 4 wk after a single intravenous infusion of one million CXCR4-expressing C3H10T1/2 cells. In the meantime, complete recovery of bone stiffness and strength in these animals was consistently detected only after a systemic transplantation of CXCR4 and Cbfa-1 co-transduced MSCs. To our knowledge, this is the first report to show unequivocally the feasibility of ameliorating glucocorticoid-induced osteoporosis by systemic transplantation of genetically manipulated MSCs. [source] Early homing of adult mesenchymal stem cells in normal and infarcted isolated beating heartsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2008Claudia Penna Abstract Little is known on the early homing features of transplanted mesenchymal stem cells (MSCs). We used the isolated rat heart model to study the homing of MSCs injected in the ventricular wall of a beating heart. In this model all types of cells and matrix elements with their interactions are represented, while external interferences by endothelial/neutrophil interaction and neurohormonal factors are excluded. We studied the morphology and marker expression of MSCs implanted in normal hearts and in the border-zone of infarcted myocardium. Early morphological adaptation of MSC homing differs between normal and infarcted hearts over the first 6 hrs after transplantation. In normal hearts, MSCs migrate very early through the interstitial milieu and begin to show morphological changes. Yet, in infarcted hearts MSCs remain in the site of injection forming clusters of round-shaped cells in the border-zone of the infarcted area. Both in normal and infarcted hearts, immuno-histochemistry and confocal imaging showed that, besides the proliferative marker proliferating cell nuclear agent (PCNA), some transplanted cells early express myoblastic maker GATA-4, and some of them show a VWF immunopositivity. Moreover, a few hours after injection connexin-43 is well evident between cardiomy-ocytes and injected cells. This study indicates for the first time that the isolated beating heart is a good model to study early features of MSC homing without external interferences. The results show (i) that MSCs start to change marker expression few hours after injection into a beating heart and (ii) that infarcted myocardium influences transplanted MSC morphology and mobility within the heart. [source] Origin of cardiac progenitor cells in the developing and postnatal heartJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Elizabeth N. Kuhn The mammalian heart lacks the capacity to replace the large numbers of cardiomyocytes lost due to cardiac injury. Several different cell-based routes to myocardial regeneration have been explored, including transplantation of cardiac progenitors and cardiomyocytes into injured myocardium. As seen with cell-based therapies in other solid organ systems, inherent limitations, such as host immune response, cell death and long-term graft instability have hampered meaningful cardiac regeneration. An understanding of the cell biology of cardiac progenitors, including their developmental origin, lineage markers, renewal pathways, differentiation triggers, microenvironmental niche, and mechanisms of homing and migration to the site of injury, will enable further refinement of therapeutic strategies to enhance clinically meaningful cardiac repair. J. Cell. Physiol. 225: 321,325, 2010. © 2010 Wiley-Liss, Inc. [source] Cadherins in neural crest cell development and transformationJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2001Patrick Pla Cadherins constitute a superfamily of cell adhesion molecules involved in cell-cell interaction, histogenesis and cellular transformation. They have been implicated in the development of various lineages, including derivatives of the neural crest. Neural crest cells (NCC) emerge from the dorsal part of the neural tube after an epithelio-mesenchymal transition (EMT) and migrate through the embryo. After homing and differentiation, NCC give rise to many cell types, such as neurons, Schwann cells and melanocytes. During these steps, the pattern of expression of the various cadherins studied is very dynamic. Cadherins also display plasticity of expression during the transformation of neural crest cell derivatives. Here, we review the pattern of expression and the role of the main cadherins involved in the development and transformation of neural crest cell derivatives. © 2001 Wiley-Liss, Inc. [source] Non-direct homing behaviours by adult Chinook salmon in a large, multi-stock river systemJOURNAL OF FISH BIOLOGY, Issue 1 2008M. L. Keefer Two non-direct homing behaviours, overshoot of natal tributaries and temporary non-natal tributary use, were evaluated for 5150 radio-tagged spring,summer Chinook salmon Oncorhynchus tshawytscha from 40 populations in the large Columbia River system. Over 7 years, 2,44% (mean = 15%) of individuals within each group temporarily entered presumed non-natal tributaries. In addition, many Chinook salmon from lower river tributaries initially travelled 3 to >250 km upstream in the main-stem river beyond confluences with presumed natal tributaries before returning to the natal sites (,overshoot'). Both overshoot and temporary tributary use behaviours declined exponentially with increasing distance from the natal tributary. Non-direct homing also increased later in the season as water temperatures rose and was associated with hatchery origin in some cases. The behaviours may reflect a mix of active searching for olfactory cues from natal sites, behavioural thermoregulation and orientation challenges in a large-river migration corridor transformed by dams and reservoirs. While anadromous salmonid homing is generally accurate and precise, these results indicate that route finding can be non-direct, potentially increasing energetic costs and harvest risks during migration. [source] Changing the pathogenetic roadmap of liver fibrosis?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt1 2008Where did it start; where will it go? Abstract The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes , formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) , the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrix,producing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelial,mesenchymal transition, by influx of bone marrow,derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-,) plays a central role, which is controlled by the bone-morphogenetic protein (BMP)-7, an important antagonist of TGF-, action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials. [source] | ||||||||||||||||||||||||||||||||||