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PubMed2005

Recent thymic emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck cancer.

Apoptosis of circulating CD8+ T lymphocytes is a frequent finding in patients with cancer. T-cell output by the thymus or antigen-driven expansion of circulating T cells could compensate for apoptosis and thus normalize their homeostasis. We studied the frequency of recent thymic emigrants (RTE) identified by T-cell receptor excision circles (TREC) and of naive and memory T-cell subsets in peripheral blood samples obtained from 39 patients with head and neck cancer (HNC) and 33 age-matched controls (NC). TREC numbers were determined by real-time quantitative PCR, and CD8+CD45RO-CD27+ or CD4+CD45RO-CD27+ T-cell subsets were quantified by flow cytometry. Age-associated decreases in TREC numbers and proportions of naive CD8+ and CD4+ T-cell subsets were significantly greater in cancer patients than NC. In contrast, the memory compartment was expanded, with increased proportions of CD4+CD45RO+ but not CD8+CD45RO+ T cells, in cancer patients vs. NC. These alterations did not normalize in patients who were NED. The data suggest that lower thymic output combined with rapid turnover of naive CD8+ T cells account for altered lymphocyte homeostasis in HNC patients. The defect persists long after curative treatments and may contribute to immune cell dysregulation in patients with cancer.

Adult↗
PubMed1998

Cohort study on canine emigration and Leishmania infection in an endemic area for American visceral leishmaniasis. Implications for the disease control.

American visceral leishmaniasis is a main public health matter in Brazil. Since dogs have been incriminated as the main urban reservoir of AVL agent Leishmania chagasi, a cohort study aimed at understanding the dynamics of the canine infection was carried out in Jequié--an endemic community in the Northeast of Brazil. The inhabited urban and periurban areas of Jequié were divided into 140 clusters of 0.25 km2. All 1681 dogs domiciled in 34 randomly selected clusters were screened for Leishmania antibodies in an enzyme-linked immunosorbent assay. After the seropositive dogs were painlessly eliminated, a cohort of 1286 seronegative dogs was followed up for 18 months, yielding a total of 1739.7 dog-years. The overall incidence of Leishmania infection, as assessed by the detection of Leishmania antibodies in blood samples collected every six months, was 6.55 cases/100 dog-years (95% confidence interval; CI 6.04-7.26). Two subsets of clusters, with 0.70 and 1.35 relative risks of infection, were identified. The annual emigration rate was 2.26 cases/100 dog-years (95% CI 1.86-2.66). The implications of these findings for the control of American visceral leishmaniasis are discussed.

Animals↗
PubMed2002

Enhanced neutrophil emigration and Porphyromonas gingivalis reduction following PGG-glucan treatment of mice.

Periodontal disease is the consequence of a mixed Gram-negative infection in the gingival sulcus and has been associated with deficits in the neutrophil response. A novel, and heretofore untested, alternative approach to therapy is the use of biological-response modulators that enhance the neutrophil response. Poly-beta1-6-glucotriosyl-beta1-3-glucopyranose glucan (PGG-glucan) is an immunomodulator, derived from yeast, which specifically enhances neutrophil priming, phagocytosis and bacterial killing while failing to induce inflammatory cytokine expression. The hypothesis tested was that PGG-glucan could enhance host resistance to a Gram-negative periodontal pathogen, Porphyromonas gingivalis. Chambers were implanted subcutaneously in the dorsolumbar region of C57BL/6J mice and allowed to heal for 14 days. PGG-glucan was administered subcutaneously to one-half of the animals and saline to the other half. In the first set of experiments the chambers were inoculated with P. gingivalis (A7436) at 4 x 10 (6), 4 x 10 (7), and 4 x 10 (8) colony-forming units (CFU). In the second set of experiments the chambers were inoculated with 5 x 10 (8) CFU of either P. gingivalis or Streptococcus sanguis, a Gram-positive oral microbe that is not periodontopathic. Chambers were sampled over the following 2 weeks. The results demonstrated that: (1). bacterial CFU and neutrophils increased with increasing bacterial inoculum (P<0.02); (2). bacterial CFU were lower in the PGG-glucan-treated animals than in the saline controls (P<0.02); and (3). neutrophil counts were higher in the PGG-glucan-treated animals than in the saline controls (P<0.01). These results indicate that PGG-glucan significantly enhances neutrophil emigration and bacterial killing, thus decreasing the bacterial infection in this model system.

Adjuvants, Immunologic↗
PubMed1998

Vascular endothelium of human dental pulp expresses diverse adhesion molecules for leukocyte emigration.

The expression of adhesion molecules on the vascular endothelium of healthy and inflamed human dental pulp was studied immunohistochemically using antibodies for selectin family and immunoglobulin super-family members. In healthy dental pulp, some vessels reacted very weakly with major histocompatibility complex (MHC) class II, and E- and P-selectin, and many vessels reacted with platelet-endothelial cell adhesion molecule-1 (PECAM-1), but no vessels reacted with intercellular adhesion molecule-1 (ICAM-1), ICAM-3 and vascular cell adhesion molecule-1 (VCAM-1). In inflamed pulp, a large number of vessels reacted strongly with MHC class II, E- and P-selectin, PECAM-1, ICAM-1, ICAM-3, and VCAM-1. This indicates that the vascular endothelium of the inflamed human dental pulp expresses diverse adhesion molecules for leukocyte emigration from the blood stream into tissue. Dental pulp is surrounded by dentin and isolated from other tissue, like an in vitro system, so dental pulp is an attractive model for studying the roles of adhesion molecules on the vascular endothelium in transendothelial migration of leukocytes.

Adolescent↗
PubMed2001

Quasi-stationarity in populations that are subject to large-scale mortality or emigration.

We shall examine a model, first studied by Brockwell et al., which can be used to describe the long-term behaviour of populations that are subject to catastrophic mortality or emigration events. Populations can suffer dramatic declines when disease, such as an introduced virus, affects the population, or when food shortages occur, due to overgrazing or fluctuations in rainfall. However, perhaps surprisingly, such populations can survive for long periods and, although they may eventually become extinct, they can exhibit an apparently stationary regime. It is useful to be able to model this behaviour. This is particularly true of the ecological examples that motivated the present study, since, in order to properly manage these populations, it is necessary to be able to predict persistence times and to estimate the conditional probability distribution of population size. We shall see that although our model predicts eventual extinction, the time till extinction can be long and the stationary exhibited by these populations over any reasonable time scale can be explained using a quasi-stationary distribution.

Animals↗
PubMed2000

Alterations of thymocyte development, thymic emigrants and peripheral T cell population in rats exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts diverse biological effects by activating the cytosolic transcription factor, arylhydrocarbon receptor (AhR), which translocates to nuclei by TCDD binding and induces gene expressions. Among the well known-adverse effects of TCDD is thymus atrophy. In thymus atrophy, TCDD alters the proliferation as well as the differentiation of immature thymocytes. Previous studies on the effects of TCDD on thymocyte development were primarily carried out with high doses of TCDD. The present study investigates the effects of lower doses of TCDD (1 or 2 microg TCDD/kg by gavage) on thymocyte development, and furthermore, their sequential consequences on the peripheral T cell repertoire. Seven days after treatment with 1 or 2 microg TCDD/kg, the expression of CYP1A1 mRNA, one of the sensitive responses caused by the binding of TCDD to AhR, was detected in the thymus of rats. Thymus weights and thymus cell numbers decreased in TCDD-treated rats in a dose-dependent manner. The ratios of CD4 single-positive (SP) cells/CD8 SP cells were significantly reduced by TCDD exposure, indicating that the maturation of CD4(+)CD8(+) double-positive (DP) cells was skewed toward CD8 SP cells. These changes in the thymus were parallel to those previously observed with high doses of TCDD exposure. However, the specific reduction of DP cells reported in previous studies with high doses of TCDD was not detected in the present study. On the other hand, the skewing of mature CD4/CD8 T cell ratio in thymocytes by TCDD was not reflected in mesenteric lymph node (LN) lymphocytes, where the proportion of CD8 T cells was rather lowered by TCDD with a significant difference at 1 microg TCDD/kg. In LN lymphocytes, the percentage of recent thymic emigrants (RTEs), defined by the surface markers of Thy1(+)CD45RC(-), was shown to be significantly reduced by exposure to 1 and 2 microg TCDD/kg. T cell supply from the thymus has a crucial role in keeping the diversity of the T cell repertoire. The results of the present study indicated that lower doses of TCDD affect thymocyte development, especially differentiation, and reduce the proportion of RTE in LN, which may cause immunosuppression by reducing the variety of the T cell receptor repertoire.

Animals↗
PubMed1999

Ventrally emigrating neural tube cells differentiate into vascular smooth muscle cells.

A multipotential cell population originating in the ventral part of the hindbrain neural tube, the ventrally emigrating neural tube cells (VENT cells), has recently been shown to migrate into the craniofacial mesenchyme. Because vascular smooth muscle cells develop from this mesenchyme, we sought to determine if the VENT cells contributed to their differentiation. VENT cells were tagged with replication-deficient retroviral vector with LacZ by microinjection into the lumen of the rostral hindbrain of chick embryos on day 2. Embryos were processed for the detection of LacZ positive cells on day 7. LacZ-positive cells were present in the wall of craniofacial arteries and veins. Immunostaining with the smooth muscle alpha-actin confirmed the labeled cells to be smooth muscle cells. It is concluded that some vascular smooth muscle cells differentiate from neural tube cells. the developmental and functional significance of which remains to be established.

Actins↗
PubMed1998

Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation.

Expression of the avian chT1 thymocyte antigen persists on a subpopulation of peripheral T cells enriched in the DNA deletion circles created by alphabeta and gammadelta TCR gene rearrangements. The chT1+ cells are evenly distributed among all of the peripheral T lymphocyte compartments. The levels of chT1+ T cells in the periphery gradually decline in parallel with age-related thymic involution, and these cells disappear following early thymectomy. Experiments in which variable numbers of the 14 thymic lobes are removed in young chicks indicate a direct correlation between the levels of circulating chT1+ cells and residual thymic mass. Measurement of recent thymic emigrants in the periphery thus provides an accurate indication of thymic function.

Aging↗
PubMed2002

The social and psychological effect of an adult child's emigration on non-immigrant Asian Indian elderly parents.

The impact of immigration on parents left behind has been largely ignored in the literature. This exploratory study uses cultural specificity theory to examine the effect an adult child's emigration has on the familial support system available to the parents left behind, and on the parent's psychological well-being. Twenty-nine parents (age 55+) in India, who had adult children in the United States, were selected using snowball sampling. Qualitative interviews based on a semi-structured interview schedule were conducted during the fall and winter of 1997. Results show that although most parents do not live in an extended family, they receive support from extended family members. However, the biggest source of daily support comes from hired help. Hired help allows parents to live independently and decreases reliance on informal support systems. Since hired help is relatively inexpensive most parents can substitute help for their children. This does not alleviate feelings of loneliness and depression.

Journal Article↗
PubMed2002

Sex differences in emigration and mortality affect optimal management of deer populations.

Populations of red deer that are limited by food, like those of many other ungulates, commonly include more females than males. We assessed the contribution of variation in sex- and age-specific rates of mortality and emigration to density-dependent changes in the adult sex ratio, using long-term observations and demographic experiments involving the red deer population on Rum, Scotland. We incorporated these effects in a stochastic model of local populations under different management regimes to show here that, when female numbers are allowed to increase to more than 60% of the ecological carrying capacity, the sustainable annual harvest of males from local deer populations will fall. Because males are typically culled by fee-paying hunters and generate more income than females, income will decrease as the male harvest falls. Because numbers of female deer throughout much of the Highlands probably exceed the threshold at which male density starts to be affected, many managers might be able to raise income from local deer populations by reducing female numbers, with potential benefits to the vegetation of Scottish Highland environments.

Animals↗
PubMed2006

CD8+ recent thymic emigrants home to and efficiently repopulate the small intestine epithelium.

Prevailing knowledge dictates that naive alphabeta T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8(+) recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and alpha(4)beta(7) integrin were required for gut entry of CD8(+) RTEs. After T cell receptor stimulation, intestinal CD8(+) RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8(+) RTEs efficiently populated the gut of lymphotoxin-alpha-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive alphabeta T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.

Animals↗
PubMed2001

Recent thymic emigrants (CD4+) continuously migrate through lymphoid organs: within the tissue they alter surface molecule expression.

T-cell progenitors migrate from bone marrow (BM) into the thymus. After maturation they are released as recent thymic emigrants (RTE) into the periphery ensuring the diversification of the T-cell repertoire. Both the kinetics with which RTE migrate through the periphery and the surface molecules they express are still unclear. In 1- and 18-month-old Lewis rats CD4+ RTE were identified in blood, spleen, lymph node, and thoracic duct lymph by flow cytometry (CD45RC- and CD90+), were differentiated from CD4+ naive (CD45RC+) and memory T cells (CD45RC-CD90-), and were characterized regarding the expression of surface molecules. Both in 1- and 18-month-old animals the percentage of RTE among the CD4+ population in blood was comparable to that in all other compartments. Surprisingly, RTE expressed alpha4-integrin, LFA-1, and interleukin (IL)-2 receptor at a significantly higher level than naive T cells and more comparable to memory T cells. Within lymphoid tissues RTE, naive, and memory T cells significantly upregulated the expression of CD44 and ICAM-1, and downregulated the expression of L-selectin. These changes were reversed before the cells re-entered the blood. Thus, our data indicate that CD4+ RTE travel through the periphery of young and old rats like mature T cells, continuously modulating their surface molecule expression.

Animals↗
PubMed2001

Age-related changes in CCR9+ circulating lymphocytes: are CCR9+ naive T cells recent thymic emigrants?

The chemokine receptor CCR9 is reported to be predominantly expressed by thymocytes as well as by circulating gut-homing and resident T cells in the small intestinal mucosa. Its ligand thymus-expressed chemokine (TECK) is produced by thymic and small intestinal epithelium. Here we report that the proportion of circulating CCR9+ naive T cells (mostly CD4+) declines with age, from approximately 15% of all T cells at birth to around 1% in adults. The proportion of CCR9+ T cells lacking the classical gut-homing receptor alpha4beta7, was much higher in children than in adults. Therefore, circulating CD3+CCR9+CD45RA+ cells have most likely left the thymus quite recently. This notion was supported by the small number of CCR9+ naive T cells which was present shortly after thymectomy. Establishing a phenotypic marker for recent thymic emigrants might provide a powerful tool in the clinical assessment and follow-up after cancer chemotherapy, hematopoietic stem cell transplantation, and during antiretroviral treatment of human immunodeficiency virus (HIV)-infected patients.

Adolescent↗
PubMed2000

Identification of a human recent thymic emigrant phenotype.

The ability to measure human thymic output would be an invaluable tool for the study of the development of the naive T cell repertoire, as well as naive T cell regeneration after intensive cytotoxic chemotherapy or effective antiretroviral therapy of progressive HIV infection. We and others have demonstrated previously that quantification of T cell receptor rearrangement excision circles (TREC) within peripheral T cell populations provides insight into the frequency of recent thymic emigrants (RTE) and, therefore, into thymic function. However, measurement of RTE by this approach is complicated by the fact that TREC levels also are determined by turnover within the naive T cell compartment. Here, we report a phenotypic approach to RTE measurement. We demonstrate that alphaE integrin (CD103) expression is up-regulated very late in thymic development on a subset of CD8(+)/CD4(-) thymocytes and also defines a distinct subset of naive CD8(+) T cells in the periphery. The latter subset is differentiated from circulating CD103(+) mucosa-associated memory T cells by its naive T cell phenotype (CD45RO(-), CD62L(bright), CD27(bright), CD11a(dim), CD95(dim)) and its high concentration of TREC. Indeed, sorted CD103(+) naive CD8(+) cells display higher levels of TREC than their CD103(-) naive counterparts, and these cells demonstrate an age-related decline in frequency that is enhanced significantly by thymectomy. The thymic dependence of this subset and the cells' relatively evanescent presence in the periphery suggest that these cells are a population of RTE and that quantification of their frequency in peripheral blood provides an estimate of the level of ongoing thymopoiesis.

Adult↗
PubMed1996

T helper cells in murine germinal centers are antigen-specific emigrants that downregulate Thy-1.

After immunization, activated splenic T cells proliferate in periarteriolar lymphoid sheaths (PALS) and subsequently migrate to the lymphoid follicle where they enter nascent germinal centers. Analysis of TCR V(D)J gene rearrangements indicates extensive emigration, frequently involving more than a single white pulp region. These migrants constitute a unique set of T helper cells that express antigen-specific alpha beta TCR, CD3, and CD4, but little or no Thy-1, a differentiation antigen present on the great majority of peripheral murine T lymphocytes. The origin of CD4+ Thy-1 follicular T cells appears to be the Thy+ population in the PALS, as both sets commonly share identical V(D)J rearrangements.

Animals↗
PubMed1998

Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP.

Circulating leukocytes are thought to extravasate from venules through open interendothelial junctions. To test this paradigm, we injected N-formyl-methionyl-leucyl-phenylalanine (FMLP) intradermally in guinea pigs, harvesting tissue at 5-60 min. At FMLP-injected sites, venular endothelium developed increased surface wrinkling and variation in thickness. Marginating neutrophils formed contacts with endothelial cells and with other neutrophils, sometimes forming chains of linked leukocytes. Adherent neutrophils projected cytoplasmic processes into the underlying endothelium, especially at points of endothelial thinning. To determine the pathway by which neutrophils transmigrated endothelium, we prepared 27 sets of serial electron microscopic sections. Eleven of these encompassed in their entirety openings through which individual neutrophils traversed venular endothelium; in 10 of the 11 sets, neutrophils followed an entirely transendothelial cell course unrelated to interendothelial junctions, findings that were confirmed by computer-assisted three-dimensional reconstructions. Having crossed endothelium, neutrophils often paused before crossing the basal lamina and underlying pericytes that they also commonly traversed by a transcellular pathway. Thus, in response to FMLP, neutrophils emigrated from cutaneous venules by a transcellular route through both endothelial cells and pericytes. It remains to be determined whether these results can be extended to other inflammatory cells or stimuli or to other vascular beds.

Animals↗
PubMed1999

Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy.

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

Adolescent↗
PubMed2001

Chemoattractants induce a rapid and transient upregulation of monocyte alpha4 integrin affinity for vascular cell adhesion molecule 1 which mediates arrest: an early step in the process of emigration.

Chemoattractants and chemokines induce arrest of rolling monocytes during emigration from blood into tissues. In this study, we demonstrated that alpha4 integrin affinity for vascular cell adhesion molecule (VCAM)-1 was upregulated rapidly and transiently by chemoattractants and stromal cell-derived factor (SDF)-1alpha and mediated monocyte arrest. alpha4 integrin affinity changes were detected and blocked using soluble VCAM-1/Fc (sVCAM-1/Fc). In a flow cytometry assay, markedly increased sVCAM-1/Fc binding to human blood monocytes or U937 cells transfected with formyl peptide (FP) receptor was detected 30 s after FP or SDF-1alpha treatment and declined after 2 min. In a parallel plate flow chamber assay, FP, C5a, platelet-activating factor, or SDF-1alpha coimmobilized with VCAM-1 induced leukocyte arrest, which was blocked by inclusion of sVCAM-1/Fc but not soluble nonimmune immunoglobulin G in the assay buffer.

Antigens, CD↗