Involvement of dendritic cells in allograft rejection new implications of dendritic cell-endothelial cell interactions.

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs), which activate naïve allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigen-specific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to naïve host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigen-specific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings of laboratory animal studies, strong promises are deriving from these studies for clinical kidney, heart, and liver transplantation.

Renal ischemia-reperfusion injury: new implications of dendritic cell-endothelial cell interactions.

In renal ischemia/reperfusion (I/R) injury endothelial cells are a main target. The disturbance of endothelial cell physiology leads to endothelial swelling and narrowing of the blood vessel lumen. We attribute this effect to impairment of endothelial cell nitric oxide synthase (NOS). NO is significantly reduced in the course of hypoxia causing dysfunction of the vascular smooth muscle tone. Subsequently to an I/R injury, the inflammatory response results in endothelial activation with enhanced dendritic cell (DC) adhesion and migration. Thus, alloreactive leukocytes are recruited to the inflammatory site. Finally, dendritic cell-endothelial cell interactions may play a crucial role in antigen-specific allograft rejection in I/R renal injury. DCs, which activate naïve alloreactive T cells, play a central role in the establishment of alloantigen-specific immunity. In the course of hypoxia rejection is initiated at the activated layer of foreign endothelial cells (EC), which forms an immunogenic barrier for migrating DCs and T cells. Host DCs that bind to postischemic activated ECs invade the allografted tissues, or remain stationary in the subendothelial layer, or transmigrate into lymphoid vessels and secondary lymphoid organs, where they present alloantigens to naïve host T cells. Organ rejection is mediated by host alloreactive T cells, which are activated by donor DCs (direct activation) or host DCs (indirect activation). We hypothesized that DC-EC binding and migration is the first step in the renal I/R injury that mediates allotransplant rejection. We sought to better understand the downstream events of a renal I/R injury by understanding DC binding and migration, thereby seeking new strategies for more specific immunomodulatory interventions. Herein we developed a new allotransplant-rejection model after renal I/R injury.

Rating the severity of the medical consequences of drug-induced liver injury.

Risk analysis in drug development aims to allow for clear decisions showing whether or not the benefit of an intervention outweighs the risk. One of the difficulties in doing this in a repeatable and clear way is the problem of comparing different adverse events, as seriousness is often subjective. Using drug-induced liver injury as our model, we show that clinical, laboratory, and histological manifestations of liver reactions can be ranked by experienced hepatologists and these rankings can be used to rank the consequences of drug-induced side effects as a continuum. This risk ranked information could be transformed to standardized scores (z score) and the risks displayed by standard techniques; adverse events can then be compared with effects from other drugs and possibly with the consequences due to untreated disease or natural occurrences. As a risk is a function of both the seriousness of the event and the probability of its occurrence, risk can therefore be displayed in terms of probability and hazard to further ease communication. We propose that risk management of drugs in development would be improved, especially in terms of risk communication, if the hazard were ranked by means of a common scale and displayed in graphic form against the likelihood of occurrence.

Dendritic cells as pharmacological targets for the generation of regulatory immunosuppressive effectors. New implications for allo-transplantation.

Dendritic cells (DCs) play a central role in the establishment of tolerance/immunity, because they activate naïve T cells (TCs). Therefore, the pharmacological modulation of DCs has become a major field of interest in immunology. A large body of literature has arisen from the studies of DC biology during immunosuppressive drug treatment. Immunosuppressive drugs have improved the therapeutic management of allograft organ transplantation and autoimmune diseases, significantly. There is now strong evidence that, DCs might be the key for antigen specific tolerance induction. Recently, the existence of a population of DCs that migrate to the regional lymph node in the steady state has been identified. Such steady state immature migrating DCs are loaded with tissue antigens and deliver self-antigens towards secondary lymphatic organs and might educate TCs towards self-tolerance. Latest experimental data from rodent solid organ allo-transplantation supports the idea, that DCs might even become regulatory DCs towards foreign antigen specific tolerance induction. Apparently, regulatory donor DCs invade host secondary lymphatic organs where they might eventually educate host TCs towards foreign antigen specific tolerance. Seemingly, it depends on the DC maturation state whether pharmacologically modulated DCs induce antigen specific long-term tolerance in allo-transplantation solid organ transplantation. Several authors reported a positive self-limiting feedback loop between tolerogenic DCs and allo-specific regulatory TCs. Thus, the DC-TC network appears as an exceptionally good target for pharmacological manipulations. Here we review how immunosuppressive agents interfere with DC maturation, migration and homeostasis. We are developing a rational to select different drugs for the generation of regulatory DCs, for allo-transplantation clinical settings.

Dendritic cell endothelium interaction in autoimmunity.

Monocyte derived dendritic cells play a central role in controlling immunity by activating naïve T lymphocytes. Monocytes can leave the blood stream by endothelial cell transmigration and differentiation into dendritic cells. A fundamental aspect of dendritic cell biology is their capacity to engulf tissue antigens and revers-migrate into lymph nodes. In lymph nodes dendritic cells can traffic to T-cell areas where they activate naïve T-cells. Throughout this review we are developing a model of in vivo activation of auto-reactive T-cells by activated dendritic cells.

Mental performance during submaximal exercise in 13 and 17% oxygen.

Submarine crews live in atmospheres containing variable levels of O2 and CO2. Under these conditions, significant reduction of the O2 may impair mental function during physical exertion. Therefore, psychomotor performance was measured in exercising men during Hours 26 and 57 of exposure to 21, 17, and 13% O2 in a hypobaric chamber (each gas contained 0.9% CO2, balance N1). Sea-level pressure was used except when reduced to 576 Torr at Hour 57 in 17% O2 (hypobaric-17% O2). At Hour 26 the subjects exercised at 35 and 65% of predicted VO2max They were hypoxic during exercise in 17 and 13% O2, as indicated by reduced SaO2 values (P less than 0.05). The psychomotor test (timed arithmetic) was affected by the exposure condition (P less than 0.05) but not by the work rate. At Hour 57, subjects repeated the arithmetic task at rest and at 65% of predicted VO2max. SaO2 was reduced in hypobaric-17 and 13% O2 (P less than 0.05). The math scores were affected by the work rate (P less than 0.05) but not by the exposure condition. From post-hoc analyses we conclude that 17% O2 does not impair the timed arithmetic task during submaximal exercise at normobaric pressures.

Decreased vitamin B-6 status of submariners during prolonged patrol.

We investigated the effects of a 3-mo submarine patrol upon several vitamin B-6 indices in 23 male submariners. While on patrol, 12 subjects received a multivitamin-mineral supplement that provided 0.5 mg/d vitamin B-6 and 11 subjects received a placebo. The concentrations of plasma pyridoxal 5'-phosphate, total vitamin B-6, and urine 4-pyridoxic acid were significantly reduced during the patrol in both the placebo and the supplemented groups. The hematocrit of both groups also decreased by approximately 10% during the patrol and was not restored to prepatrol concentrations until several weeks postpatrol. Mood depressions, as measured by the Beck inventory and the depression adjective check list, were most pronounced during the 30 d before and at the beginning of the patrol. These depression measures did not correlate with the vitamin B-6 status indices, indicating that the mood depressions during a patrol do not appear to be related to the vitamin B-6 status of the submariners.

Cardiorespiratory fitness and cognitive performance before and after confinement in a nuclear submarine.

The aim of this study was to further document physiological deconditioning from occupational exposure to submarines as described in a small number of reports and determine whether cognitive performance parallels the physiological changes associated with physical training and deconditioning. We examined cardiorespiratory fitness and cognitive performance in 14 male subjects during 70 d of confinement in a nuclear submarine. Maximal oxygen consumption (VO2max) and anaerobic threshold (AT) were assessed before and after confinement. Six exercising subjects (ES) cycled 4-7 times per week for 20 min at 75% max heart rate for 8 weeks. Eight control subjects (CS) did no exercise. Every 14 d of the patrol, cognitive performance was evaluated in both groups by administering a mental arithmetic and choice reaction time tests before cycling, during cycling, and post cycling. The cycle bout consisted of exercising at 75% VO2max for 15 min. After confinement, VO2max remained constant for ES but declined 7% statistically nonsignificant for the CS. AT expressed as a percentage of VO2max increased 15% (p less than 0.05) in the ES and decreased 20% (p less than 0.05) in the CS. The only significant effect in the cognitive tests was that both groups responded faster in the choice reaction time test during the exercise session. In conclusion, these data demonstrate a training effect for AT in the ES and a deconditioning response for AT and a statistically nonsignificant reduction in VO2max in the CS. Under the conditions of this experiment we could find no effects of physical training and deconditioning on the cognitive performance test employed here, although some trends suggest that exercisers out-performed the control group.

Reaction time to spatial frequencies using yellow and luminance-matched neutral goggles.

The popularity of yellow goggles for outdoor activities has long been a paradox to visual scientists as previous tests of their effectiveness have failed to show any visual advantage. The achromatic/chromatic theory of color vision suggests a possible solution to the paradox which was tested by measuring reaction times to spatial frequencies of varying contrast. Reaction times were faster with yellow goggles than with luminance-matched neutrals under certain conditions. These conditions included frequencies in the middle of the range of human sensitivity and, specifically, the lower contrasts of these frequencies. The theoretical and practical applications of the results are discussed.

The perception of depth contours with yellow goggles.

The ability of subjects to discriminate the depth of depressions in the snow was conducted at a cross-country ski area. The percentage of correct judgments on an overcast day was significantly greater with yellow goggles than with luminance-matched neutral goggles. This experiment, suggested by the chromatic-achromatic theory of color vision, indicates why yellow goggles are popular despite many previous unsuccessful attempts to prove their effectiveness.

The vision of submariners and National Guardsmen: A longitudinal study.

This study was designed to differentiate among possible causes of an increased incidence of myopia and related symptoms among submariners by making a longitudinal comparison of the visual functions of two groups of subjects, submariners and National Guardsmen. Refractive error, visual acuity, phorias, accommodation, and depth perception were measured. Submariners showed statistically significantly greater losses in visual acuity, accommodation, and depth perception over a 3.5-year period than did the guardsmen, but the differences were very small. Comparison with data in the literature gives evidence of large shifts in refractive error for young men, both submariners and guardsmen, born in recent years. it is suggested that whatever factors are responsible for the increase in myopia in the general population are operating even more effectively among submariners.

Effects of pseudoephedrine and triprolidine on visual performance.

The effects of q.i.d. administration of 60 mg pseudoephedrine (Sudafed) tablets or pseudoephedrine-triprolidine (Actifed) tablets after 5 d of medication were measured on tests of night vision, color perception, stereopsis, and reaction time. Neither drug appeared to impair performance.