Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human ...T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector, and memory subsets conserved between diverse individuals. Effector memory CD4+ T cells producing IL-2 predominated in mucosal tissues and accumulated as central memory subsets in lymphoid tissue, whereas CD8+ T cells were maintained as naive subsets in lymphoid tissues and IFN-γ-producing effector memory CD8+ T cells in mucosal sites. The T cell activation marker CD69 was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity.
► Human memory CD4+ and CD8+ T cell subsets exhibit tissue-specific compartmentalization ► CD69 is constitutively upregulated by all tissue-resident but not circulating T cells ► Memory CD4+ T cells producing IL-2 are the majority subset throughout the human body
It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are ...integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.
Background: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries.
Methods: Sixty‐three patients with acute ...lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow‐up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement.
Results: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function.
Conclusion: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer‐related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.
Abstract
BACKGROUND AND AIMS
Filters currently used for hemodiafiltration (HF) can remove sufficiently low to middle molecular weight solutes, like urea to β2 microglobulin (molecular weight: ...11.800). Therefore, the removal rate of α1 microglobulin (α1-MG; molecular weight: 33.000) and albumin leakage are used as a guide to select a filter and to set appropriate operating conditions. Since α1-MG is very expensive, in vitro performance evaluation of the filters using α1-MG is not practical. In the present study, we aimed to investigate whether β-lactoglobulin (β-LG), which has a molecular weight of 18.400 and forms dimer (molecular weight: 36.800) under physiological conditions, can be used as a marker solute in the 30.000 molecular weight region.
METHOD
HF experiments were performed using 1.8 L of porcine whole blood (hematocrit: 30 ± 3%, total protein concentration: 6.5 ± 0.5 g/dL). The sieving coefficients of β-LG, separated from milk by membrane separation (untreated), made whey containing β-LG by acid treatment of milk and pH adjusted (acid-treated) and powdered reagent, were measured in porcine blood. In addition, HF experiments with permeate recycle were performed using three filters with different pore sizes (MFX-S, MFX-E and MFX-M; Nipro) at a blood flow rate of 250 mL/min and filtration flow rate of 42 mL/min for 240 min. The concentration of β-LG was measured by an enzyme-linked immunosorbent assay.
RESULTS
The sieving coefficient of acid-treated or powdered reagent β-LG added to the blood was almost equal to that of untreated β-LG. When the powdered reagent β-LG was treated with mercaptoethanol, the sieving coefficient became larger, meaning that the β-LG is tightly bound by disulfide bonds to form a stable dimer. In HF experiments using three filters with different pore sizes, the filter with a larger pore size resulted in lower transmembrane pressure. The sieving coefficients of β-LG decreased with time and were 0.15 ± 0.024, 0.39 ± 0.023, 0.75 ± 0.064 (mean ± SD, n = 3) at 60 min for MFX-M, MFX-E and MFX-S, respectively, indicating that the difference in filter performance was able to classify in the sieving coefficient of β-LG.
CONCLUSION
β-lactoglobulin existed stably as a dimer and was able to classify the performance of filters used for hemodiafiltration as a marker solute in the 30.000 molecular weight region.
Abstract
BACKGROUND AND AIMS
The conventional perfusion model of the isolated rat kidney circulates perfusate to the isolated kidney removed from the body. On the other hand, an in situ perfusion ...model, within the body, of an isolated kidney is expected to allow research on drug metabolism and physiological functioning of the kidney under physiological conditions and also allow local organ therapy, such as selective perfusion of the organ with therapeutic agents such as anticancer agents. The aims of the present study were to establish an in situ perfusion model of an isolated rat kidney and to clarify the composition of the perfusate necessary to obtain physiological perfusion of the isolated kidney model.
METHOD
Male Sprague Dawley rats (300–350 g) were used for the experiments. Cannulations of the renal vein, renal artery and ureter were performed, in that order, for the left kidney, and the perfusion experiment was performed for 2 h. The flow rate of the perfusate during the organ perfusion was adjusted (0.3–2.0 mL/min) to maintain the renal artery pressure at 100–120 mm Hg. The circulation conditions were adjusted to maintain the renal artery pressure in the aforementioned range and urine production until the end of the perfusion experiment. The perfusate was oxidized with a 95% oxygen and 5% carbon dioxide gas mixture during the experiment and had the following composition: Na+, 140 mEq/L; K+, 5 mEq/L; Ca2+, 1.9 mEq/L; Mg2+, 2.5 mEq/L; Cl−, 126 Eq/L; and HCO3−, 25 mEq/L. The effects of erythrocytes (Ht: 25%) in the perfusate on the renal arterial pressure, urine production rate and oxygen-carrying capacity were examined, as also those of albumin (4 g/dL) in the erythrocyte-containing perfusate on the blood flow resistance of the kidney and urine production rate during the circulation experiment.
RESULTS
When a perfusate not containing erythrocytes was used, urine production from the isolated kidney decreased with time, and the renal artery pressure failed to be maintained within the target range. In contrast, when a perfusate containing erythrocytes was used, urine was constantly produced, and the renal artery pressure was maintained within the target range throughout the 2-hour experimental period. When a perfusate containing erythrocytes and albumin was used, the urine production rate of the kidney was close to the physiological urine production rate in rats and significantly lower than that observed when the perfusate did not contain albumin.
Urine production was maintained from the isolated rat kidney until the end of the perfusion experiment when the perfusate contained erythrocytes, suggesting that a perfusate with adequate viscosity and sufficient oxygen-carrying capacity is important to maintain the renal artery pressure and renal functions. The addition of albumin to the perfusate containing erythrocytes resulted in appropriate physiological urine production, probably due to the higher colloid osmotic pressure of the perfusate.
CONCLUSION
We established an in situ perfusion model of an isolated rat kidney that exhibited almost physiological functioning when the perfusate used contained erythrocytes to supply sufficient oxygen and albumin to maintain the colloid osmotic pressure.
The performance of nickel-based anode materials for solid oxide fuel cells (SOFCs) could be deteriorated by redox treatments accompanied with the microstructural change. In this study, ...Ni-yttria-stabilized zirconia (Ni-YSZ) anode was subjected to thermal cycles with redox treatments (thermal-redox cycles: repetition of oxidation in cooling and reduction in heating processes). The microstructural change of anodes was quantified by focused ion beam-scanning electron microscopy. The decrement in the active triple phase boundary (TPB) length caused by sintering and agglomeration of Ni particles was correlated with the performance deterioration. Furthermore, it was found that the onset temperature of reduction treatment in the heating process was one of the critical factors for the microstructural evolution of anode; the agglomeration of Ni particles was promoted significantly under the reduction started from 500°C, while no notable change was confirmed for the case of 900°C.
Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue ...homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.
Abstract
BACKGROUND AND AIMS
When polymethyl methacrylate (PMMA) membranes are used in renal replacement therapy, inflammatory cytokines and other substances are removed by adsorption. However, these ...filters are also prone to clogging and the filter lifetimes are likely to be short. In the present study, we investigated the effects of the hollow fiber inner diameter and membrane area of PMMA membranes on the filter lifetime and protein removal performance using an in vitro continuous hemofiltration (CHF) experimental model with porcine blood.
METHOD
Three filters with different hollow fiber inner diameters and membrane areas were used: CH-1.0N (membrane area, 1.0 m2; hollow fiber inner diameter, 200 µm), CH-1.0W (prototype: 1.0 m2; 240 µm), and CH-1.8W (1.8 m2; 240 µm). Blood samples from one pig were divided into three portions, and in vitro CHF experiments for each filter were performed at QB = 100 mL/min and QS = QF = 10 mL/min. The pressure changes, total protein concentration in the blood, and total protein amount in the filtrate were measured during the experiments. From the results of the pressure changes, the time for the TMP to reach 200 mmHg (corresponding to the time when the membrane pores were clogged) and the time for the pressure drop through the filter to reach 200 mmHg (corresponding to the time when the hollow fibers were clogged) were calculated as the filter lifetime for comparative evaluation.
RESULTS
The time for the TMP to reach 200 mmHg was significantly longer with CH-1.8W than that with CH-1.0N or CH-1.0W (Friedman test, P < .05, n = 15). The time for the pressure drop through the filter to reach 200 mmHg was significantly longer with CH-1.8W than that with CH-1.0N or CH-1.0W (Friedman test, P < 0.05, n = 15). The results suggest that an increased membrane surface area is an essential factor for extending the filter lifetime. The total protein adsorption was significantly higher for the CH-1.0W and CH-1.8W filters than for the CH-1.0N filter (two-way ANOVA and post hoc Tukey test, P < 0.01, n = 15). Thus, the membranes with larger hollow fiber inner diameters (CH-1.8W and CH-1.0W) adsorbed more protein.
CONCLUSION
A larger membrane area contributes to a longer filter lifetime, whereas increase in the hollow fiber inner diameter does not. On the other hand, the protein removal performance, especially the adsorption performance, was higher for membranes with larger hollow fiber inner diameters.
T lymphocytes migrate to barrier sites after exposure to pathogens, providing localized immunity and long-term protection. Here, we obtained blood and tissues from human organ donors to examine T ...cells across major barrier sites (skin, lung, jejunum), associated lymph nodes, lymphoid organs (spleen, bone marrow), and in circulation. By integrating single-cell protein and transcriptome profiling, we demonstrate that human barrier sites contain tissue-resident memory T (T
) cells that exhibit site-adapted profiles for residency, homing and function distinct from circulating memory T cells. Incorporating T cell receptor and transcriptome analysis, we show that circulating memory T cells are highly expanded, display extensive overlap between sites and exhibit effector and cytolytic functional profiles, while T
clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while T
cells exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue targeting.
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