29,710 research outputs found
Microchimerism, dendritic cell progenitors and transplantation tolerance
The recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrowâderived dendritic cell (DC). These cells have been classically perceived as the most potent antigenâpresenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GMâCSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to Tâdependent areas of host lymphoid tissue, where some at least upregulate cell surface MHC class II. These donorâderived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver. A key finding is that in mice, progeny of these donorâderived DC progenitors can be propagated ex vivo from the bone marrow and other lymphoid tissues of nonimmunosuppressed spontaneously tolerant liver allograft recipients. In humans, donor DC can also be grown from the blood of organ allograft recipients whose organâsource chimerism is augmented with donor bone marrow infusion. DC progenitors cannot, however, be propagated from the lymphoid tissue of nonimmunosuppressed cardiacâallografted mice that reject their grafts. These findings are congruent with the possibility that bidirectional leukocyte migration and donor cell chimerism play key roles in acquired transplantation tolerance. Although the cell interactions are undoubtedly complex, a discrete role can be identified for DC under wellâdefined experimental conditions. Bone marrowâderived DC progenitors (MHC class II+, B7â1dim, B7â2â) induce alloantigenâspecific hyporesponsiveness (anergy) in naive T cells in vitro. Moreover, costimulatory moleculeâdeficient DC progenitors administered systemically prolong the survival of mouse heart or pancreatic islet allografts. How the regulation of donor DC phenotype and function relates to the balance between the immunogenicity and tolerogenicity of organ allografts remains to be determined. Copyright © 1995 AlphaMed Pres
Chimerism after whole organ transplantation: an explanation of renal and other organ acceptance
Lymphoid/nonlymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct bone marrow
Background. The role of leukocyte migration and chimerism in organ allograft acceptance has been obscured by the lack of information about the late localization of the donor cells. Methods. Male Lewis ratâfemale Brown Norway abdominal heart transplantation was performed under tacrolimus immunosuppression (days 0-13, 20, and 27) with or without donor bone marrow and (in bone marrow subgroups) a 1-week postoperative course of a possibly chimerism-enhancing drug. Using rat sex-determining region-Y-specific oligonucleotide primers, we determined the donor DNA concentration by polymerase chain reaction in serial venous blood sampies for 100 days and in tissue specimens when animals were killed. Results. Chimerism was detected out to 56 days in 89% of the blood samples but in none of the samples at 100 days. However, donor DNA was detected when animals were killed in 95% of the native hearts, 80% of the skin biopsy specimens, and 23% of the spleens. The presence and quantity of early and late chimerism were strongly correlated the administration of adjunct bone marrow and with a reduction in the vasculopathy and inflammation index in the cardiac allografts. Marginally significant further increases in chimerism and/or reductions in chronic heart rejection beyond those achieved with adjunct bone marrow alone were associated with additional treatment with the growth factors Flt-3 ligand, granulocyte colonystimulating factor, and a recombinant molecular variant of interleukin-6 (interleukin-6 mutein) but not with hepatocyte growth factor or lisofylline. Conclusions. The previously suspected shift of early chimerism in the blood and lymphoid organs to dominance in host nonlymphoid tissues is consistent with the dual mechanisms of clonal exhaustion and immune indifference, governed by antigen migration and localization, that have been postulated elsewhere to account for organ allograft acceptance
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On the transport of heavy particles through an upward displacement-ventilated space
We explore the transport of heavy particles through an upward displacement-ventilated space. The space incorporates a localised source of buoyancy which generates a turbulent buoyant plume. The plume fluid is contaminated with a small concentration of particles, which are subject to gravitational settling. A constant flow of uncontaminated fluid is supplied at a low level into the space, while an equal amount of fluid is vented from the space at a high level. At steady state, a two-layer density stratification develops associated with the source of buoyancy. New laboratory experiments are conducted to explore how particles are transported by this flow. The experiments identify that the upper layer may either become well-mixed in particles or it may develop a vertical stratification in particle concentration, with the particle concentration decreasing with height. We develop a quantitative model which identifies that such stratification develops for larger particle setting speeds, or smaller ventilation rates. In accord with our experiments, the model predicts that the number of particles extracted from the space through the high-level vent is controlled by the magnitude of the particle stratification in the upper layer, and this in turn depends on the particle settling speed relative to the ventilation speed and also the cross-sectional area and height of the space. We compare the predictions of the model with measurements of the flux of particles vented from the space for a range of operating conditions. We explore the relevance of the model for the removal of airborne contaminants by displacement ventilation in hospital rooms, and we discuss how contamination is propagated in the room as a result of lateral mixing of pathogens in the upper layer.This work has been funded through the BP Institute, EPSRC and Hughes Hall, Cambridge. We gratefully acknowledge the technical assistance of A. Pluck, and the constructive comments of Professor C. Noakes, Dr. C. P. Caulfield and of two anonymous
referees.This is the author accepted manuscript. The final version is available via CUP at http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=9694505&fileId=S0022112015002049
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On turbulent particle fountains
We describe new experiments in which particle-laden turbulent fountains with source Froude numbers 20>Fr_{0}>6 are produced when particle-laden fresh water is injected upwards into a reservoir filled with fresh water. We find that the ratio of the particle fall speed to the characteristic speed of the fountain determines whether the flow is analogous to a single-phase fountain () or becomes a fully separated flow (). In the single-phase limit, a fountain with momentum flux and buoyancy flux oscillates about the mean height, , as fluid periodically cascades from the maximum height, , to the base of the tank. Experimental measurements of the speed and radius of the fountain at the mean height , combined with the conservation of buoyancy, suggest that . Using these values, we find that the classical scaling for the frequency of the oscillations, , is equivalent to the scaling for a fountain supplied at with (Burridge & Hunt, J. Fluid Mech., vol. 728, 2013, pp. 91â119). This suggests that the oscillations are controlled in the upper part of the fountain where , and that they may be understood in terms of a balance between the upward supply of a growing dense particle cloud, at the height where , and the downward flow of this cloud. In contrast, in the separated flow regime, we find that particles do not reach the height at which : instead, they are transported to the level at which the upward speed of the fountain fluid equals their fall speed. The particles then continuously sediment while the particle-free fountain fluid continues to rise slowly above the height of particle fallout, carried by its momentum.This work has been funded through the BP Institute, EPSRC and Hughes Hall, Cambridge. We gratefully acknowledge the technical assistance of A. Pluck, and the constructive comments of three anonymous referees.This is the author accepted manuscript. The final version is available from Cambridge University Press via http://dx.doi.org/10.1017/jfm.2016.16
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On the transport of heavy particles through a downward displacement-ventilated space
We investigate the transport of relatively heavy, small particles through a downward displacement-ventilated space. A flux of particles is supplied to the space from a localised source at a high level and forms a turbulent particle-laden plume which descends through the space. A constant flow of ambient fluid which does not contain particles is supplied to the space at a high level, while an equal amount of fluid is vented from the space at a low level. As a result of the entrainment of ambient fluid into the particle plume, a return flow is produced in the ambient fluid surrounding the plume in the lower part of the space. At steady state, particles are suspended by this return flow. An interface is formed which separates the ambient fluid in the lower part of the space, which contains particles, from the particle-free ambient fluid in the upper part of the space. New laboratory experiments show that the concentration of particles in the ambient fluid below the interface is larger than the average concentration of particles in the plume fluid at the level of the interface. Hence, as the plume fluid crosses the interface and descends through the particle-laden fluid underneath, it becomes relatively buoyant and forms a momentum-driven fountain. If the fountain fluid impinges on the floor, it then spreads radially over the surface until lifting off. We develop a quantitative model which can predict the height of the interface, the concentration of particles in the lower layer, and the partitioning of the particle flux between the fraction which sediments over the floor and that which is ventilated out of the space. We generalise the model to show that when particles and negatively buoyant fluid are supplied at the top of the space, a three-layer stratification develops in the space at steady state: the upper layer contains relatively low-density ambient fluid in which no particles are suspended; the central layer contains a mixture of ambient and plume fluid in which no particles are suspended; and the lower layer contains a suspension of particles in the same mixture of ambient and plume fluid. We quantify the heights of the two interfaces which separate the three layers in the space and the concentration of particles in suspension in the ambient fluid in the lower layer. We then discuss the relevance of the results for the control of airborne infections in buildings. Our experiments show that the three-layer stratification is subject to intermittent large-scale instabilities when the concentration of particles in the plume at the source is sufficiently small, or the rate of ventilation of the space is sufficiently large: we describe the transient concentration of particles in the space during one of these instabilities.This work has been funded through the BP Institute, EPSRC and Hughes Hall, Cambridge. We gratefully acknowledge the technical assistance of A. Pluck, and the constructive comments of Professor C. Noakes, Dr. C. P. Caulfield and of three anonymous referees.This is the author accepted manuscript. The final version is available from Cambridge University Press via http://dx.doi.org/10.1017/jfm.2015.24
Multilineage hematopoietic reconstitution of supralethally irradiated rats by syngeneic whole organ transplantation: with particular reference to the liver
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