Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8+ T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8+ T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8+ T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.
The mechanisms by which CD8 effector populations interact with epithelial layers is a poorly defined aspect of adaptive immunity. Recognition that CD8 effectors have the capacity to express CD103, an integrin directed to the epithelial cell-specific ligand E-cadherin, potentially provides insight into such interactions. To assess the role of CD103 in promoting CD8-mediated destruction of epithelial layers, we herein examined the capacity of mice with targeted disruption of CD103 to reject pancreatic islet allografts. Wild-type hosts uniformly rejected islet allografts, concomitant with the appearance of CD8+CD103+ effectors at the graft site. In contrast, the majority of islet allografts transplanted into CD103−/− hosts survived indefinitely. Transfer of wild-type CD8 cells into CD103−/− hosts elicited prompt rejection of long-surviving islet allografts, whereas CD103−/− CD8 cells were completely ineffectual, demonstrating that the defect resides at the level of the CD8 cell. CD8 cells in CD103−/− hosts exhibited normal effector responses to donor alloantigens in vitro and trafficked normally to the graft site, but strikingly failed to infiltrate the islet allograft itself. These data establish a causal relationship between CD8+CD103+ effectors and destruction of graft epithelial elements and suggest that CD103 critically functions to promote intragraft migration of CD8 effectors into epithelial compartments.
Twinning has been recognized to be an important microstructural defect in nanoscale materials. Periodically twinned SiC nanowires were largely synthesized by the carbothermal reduction of a carbonaceous silica xerogel prepared from tetraethoxysilane and biphenyl with iron nitrate as an additive. The twinned β-SiC nanowires, with a hexagonal cross section, a diameter of 50-300 nm and a length of tens to hundreds of micrometers, feature a zigzag arrangement of periodically twinned segments with a rather uniform thickness along the entire growth length. Computer simulation has been used to generate three-dimensional atomic structures of the zigzag columnar twin structure by the stacking of hexagonal discs of {111} planes of SiC. A minimum surface energy and strain energy argument is proposed to explain the formation of periodic twins in the SiC nanowires. The thickness of the periodic twinned segments is found to be linearly proportional to the nanowire diameter, and a constant volume model is proposed to explain the relation.
CD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-β receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-β activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-β activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.
This paper proposes a new distributed Kalman filtering fusion with random state transition and measurement matrices, i.e., random parameter matrices Kalman filtering. It is proved that under a mild condition the fused state estimate is equivalent to the centralized Kalman filtering using all sensor measurements; therefore, it achieves the best performance. More importantly, this result can be applied to Kalman filtering with uncertain observations including the measurement with a false alarm probability as a special case, as well as, randomly variant dynamic systems with multiple models. Numerical examples are given which support our analysis and show significant performance loss of ignoring the randomness of the parameter matrices.
Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.
Five fluorescent labels were synthesized and used in the preparation of polystyrene fluorescent microspheres by the dispersion copolymerization and absorption method. Spectral properties of copolymerization fluorescent microspheres in tetrahydrofuran indicated these individual characteristics of labels should be maintained in the fluorescent microspheres. The differences of the fluorescent spectra between five fluorescent microspheres and their corresponding parent labels in ethanol have been investigated. These fluorescent microspheres were characterized by environmental scanning electron microscopy, laser scanning confocal microscopy and fluorescence spectrophotometry. They exhibited good dispersion and stable and high fluorescence intensity. Furthermore, copolymerization fluorescent microspheres were functionalized with amino groups. This means that a method for the preparation of copolymerization fluorescent microspheres was developed as a platform for the generation of functional fluorescent microspheres for diverse applications.
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