Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance

Despite significant medical advances since the advent of lung transplantation, improvements in long-term survival have been largely unrealized. Chronic lung allograft dysfunction, in particular obliterative bronchiolitis, is the primary limiting factor. The predominant etiology of obliterative bronchiolitis involves the recipient’s innate and adaptive immune response to the transplanted allograft. Current therapeutic strategies have failed to provide a definitive treatment paradigm to improve long-term outcomes. Inducing immune tolerance is an emerging therapeutic strategy that abrogates allograft rejection, avoids immunosuppression, and improves long-term graft function. The aim of this review is to discuss the key immunologic components of obliterative bronchiolitis, describe the state of establishing immune tolerance in transplantation, and highlight those strategies being evaluated in lung transplantation

Infrared Properties of High Redshift and X-ray Selected AGN Samples

The NASA/ISO Key Project on active galactic nuclei (AGN) seeks to better understand the broad-band spectral energy distributions (SEDs) of these sources from radio to X-rays, with particular emphasis on infrared properties. The ISO sample includes a wide variety of AGN types and spans a large redshift range. Two subsamples are considered herein: 8 high-redshift (1 < z < 4.7) quasars; and 22 hard X-ray selected sources. The X-ray selected AGN show a wide range of IR continuum shapes, extending to cooler colors than the optical/radio sample of Elvis et al. (1994). Where a far-IR turnover is clearly observed, the slopes are < 2.5 in all but one case so that non-thermal emission remains a possibility. The highest redshift quasars show extremely strong, hot IR continua requiring ~ 100 solar masses of 500 - 1000 Kelvin dust with ~ 100 times weaker optical emission. Possible explanations for these unusual properties include: reflection of the optical light from material above/below a torus; strong obscuration of the optical continuum; or an intrinsic deficit of optical emission.Comment: 8 pages, 3 figures (2 color), to be published in the Springer Lecture Notes of Physics Series as part of the proceedings for "ISO Surveys of a Dusty Universe," a workshop held at Ringberg Castle, Germany, November 8 - 12, 1999. Requires latex style files for this series: cl2emult.cls, cropmark.sty, lnp.sty, sprmindx.sty, subeqnar.sty (included with submission

Comparative genomics of the pathogenic ciliate Ichthyophthirius multifiliis, its free-living relatives and a host species provide insights into adoption of a parasitic lifestyle and prospects for disease control

Background: Ichthyophthirius multifiliis, commonly known as Ich, is a highly pathogenic ciliate responsible for ‘white spot’, a disease causing significant economic losses to the global aquaculture industry. Options for disease control are extremely limited, and Ich’s obligate parasitic lifestyle makes experimental studies challenging. Unlike most well-studied protozoan parasites, Ich belongs to a phylum composed primarily of free-living members. Indeed, it is closely related to the model organism Tetrahymena thermophila. Genomic studies represent a promising strategy to reduce the impact of this disease and to understand the evolutionary transition to parasitism. Results: We report the sequencing, assembly and annotation of the Ich macronuclear genome. Compared with its free-living relative T. thermophila, the Ich genome is reduced approximately two-fold in length and gene density and three-fold in gene content. We analyzed in detail several gene classes with diverse functions in behavior, cellular function and host immunogenicity, including protein kinases, membrane transporters, proteases, surface antigens and cytoskeletal components and regulators. We also mapped by orthology Ich’s metabolic pathways in comparison with other ciliates and a potential host organism, the zebrafish Danio rerio. Conclusions: Knowledge of the complete protein-coding and metabolic potential of Ich opens avenues for rational testing of therapeutic drugs that target functions essential to this parasite but not to its fish hosts. Also, a catalog of surface protein-encoding genes will facilitate development of more effective vaccines. The potential to use T. thermophila as a surrogate model offers promise toward controlling ‘white spot’ disease and understanding the adaptation to a parasitic lifestyle

Discovery of a z=4.93, X-ray selected quasar by the Chandra Multiwavelength Project (ChamP)

We present X-ray and optical observations of CXOMP J213945.0-234655, a high redshift (z=4.93) quasar discovered through the Chandra Multiwavelength Project (ChaMP). This object is the most distant X-ray selected quasar published, with an X-ray luminosity of L(X)=5.9x10^44 erg/s (measured in the 0.3-2.5 keV band and corrected for Galactic absorption). CXOMP J213945.0-234655 is a g' dropout object (>26.2), with r'=22.87 and i'=21.36. The rest-frame X-ray to optical flux ratio is similar to quasars at lower redshifts and slightly X-ray bright relative to z>4 optically-selected quasars observed with Chandra. The ChaMP is beginning to acquire significant numbers of high redshift quasars to investigate the unobscured X-ray luminosity function out to z~5.Comment: Published in ApJ Letters; 4 pages; 3 figures; http://hea-www.harvard.edu/CHAMP

3C 220.3: a radio galaxy lensing a submillimeter galaxy

Herschel Space Observatory photometry and extensive multiwavelength followup have revealed that the powerful radio galaxy 3C 220.3 at z=0.685 acts as a gravitational lens for a background submillimeter galaxy (SMG) at z=2.221. At an observed wavelength of 1mm, the SMG is lensed into three distinct images. In the observed near infrared, these images are connected by an arc of 1.8" radius forming an Einstein half-ring centered near the radio galaxy. In visible light, only the arc is apparent. 3C 220.3 is the only known instance of strong galaxy-scale lensing by a powerful radio galaxy not located in a galaxy cluster and therefore it offers the potential to probe the dark matter content of the radio galaxy host. Lens modeling rejects a single lens, but two lenses centered on the radio galaxy host A and a companion B, separated by 1.5", provide a fit consistent with all data and reveal faint candidates for the predicted fourth and fifth images. The model does not require an extended common dark matter halo, consistent with the absence of extended bright X-ray emission on our Chandra image. The projected dark matter fractions within the Einstein radii of A (1.02") and B (0.61") are about 0.4 +/- 0.3 and 0.55 +/- 0.3. The mass to i-band light ratios of A and B, M/L ~ 8 +/- 4 Msun/Lsun, appear comparable to those of radio-quiet lensing galaxies at the same redshift in the CASTLES, LSD, and SL2S samples. The lensed SMG is extremely bright with observed f(250um) = 440mJy owing to a magnification factor mu~10. The SMG spectrum shows luminous, narrow CIV 154.9nm emission, revealing that the SMG houses a hidden quasar in addition to a violent starburst. Multicolor image reconstruction of the SMG indicates a bipolar morphology of the emitted ultraviolet (UV) light suggestive of cones through which UV light escapes a dust-enshrouded nucleus.Comment: 17 pages, 14 Figures, accepted for publication in Ap

Prevalence of cutaneous neoplasms in dogs from the metropolitan area of Porto Alegre, RS, Brazil : 1,017 cases (2002-2007)

O objetivo deste trabalho foi realizar um estudo retrospectivo sobre neoplasias cutâneas diagnosticadas em cães. A avaliação foi realizada pela análise dos arquivos diagnósticos do Setor de Patologia Veterinária (SPV) da Universidade Federal do Rio Grande do Sul (UFRGS), Brasil, considerando-se um intervalo de seis anos (2002 a 2007). Neste intervalo, um total de 1.869 (37,3%) amostras de pele canina foram obtidas de 5.016 amostras variadas de tecidos de cães encaminhadas ao SPV. Dentre as amostras cutâneas, 1.002 pertenciam a cães diagnosticados com um tipo de neoplasia cutânea e 15 animais apresentaram mais de uma neoplasia de pele, totalizando 1.017 (20,3%) amostras. Os resultados revelaram que 50,5% (514/1017) das neoplasias cutâneas apresentaram origem mesenquimal, 45,1% (459/1017) para epitelial e 3,9% (40/1017) para melanocítica. Mastocitoma foi o tipo neoplásico cutâneo mais frequente, diagnosticado em 228 casos (22,4%), seguido por carcinoma de células escamosas (7,5%), lipoma (7,3%), adenoma de glândula perianal (7,1%) e tricoblastoma (5,8%). Cocker Spaniel, Boxer, Poodle e Pastor Alemão foram as raças mais representadas em diversos neoplasmas. Os dados obtidos, comparados aos estudos prévios, ressaltam as variáveis raças, idade e sexo, relacionadas a alguns tumores cutâneos e salientam a importância e prevalência dos diferentes tipos de neoplasia cutânea em cães. __________________________________________________________________________________________ ABSTRACTThe aim of this study was to perform a retrospective study of cutaneous neoplasms diagnosed in dogs. The evaluation was established by analyzing the diagnostic files at the Veterinary Pathology Sector, UFRGS, Brazil, over a 6-year period (2002 to 2007). During this period a total of 1869 (37.3%) skin samples were obtained from 5016 different tissue samples of dogs submitted for examination. Among the referred skin samples, 1002 were from dogs with the diagnosis of cutaneous neoplasia and 15 dogs exhibited more than one type of skin tumor, what amounted to a total of 1017 (20.3%) cutaneous tumor samples. Results confirmed 50.5% (514/1017), 45.1% (459/1017), and 3.9% (40/1017) of respectively mesenquimal, epithelial, and melanocytic origin. Mast cell tumor was the most frequent neoplasia, diagnosed in 228 cases (22.4%), and was followed by squamous cell carcinoma (7.5%), lipoma (7.3%), perianal gland adenoma (7.1%), and trichoblastoma (5.8%). Purebred dogs such as Cocker Spaniel, Boxer, Poodle and German Sheepdog were the most representative breeds affected by various neoplasms. The data obtained, compared to data from previous studies, emphasize the variables breed, age and sex related to some skin tumors, and reinforce the importance and prevalence of different types of skin tumors in dogs

Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor β1 (TGF-β1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-β1 in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-β1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-β1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-β), and whereas TGF-β1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-β1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-β1 expressio

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes

CD4 T cells but not Th17 cells are Required for Mouse Lung Transplant Obliterative Bronchiolitis

Lung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL-17. We have used this orthotopic mouse model to investigate the source of IL-17A and the requirement for T cells producing IL-17A. The major sources of IL-17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL-17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3-deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL-17A+ cells was not decreased in mice with STAT3-deficient T cells due mainly to the presence of IL-17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL-17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other

Hypoxia-Inducible Factor-1α Regulates CD55 in Airway Epithelium

Airway epithelial CD55 down-regulation occurs in several hypoxia-associated pulmonary diseases, but the mechanism is unknown. Using in vivo and in vitro assays of pharmacologic inhibition and gene silencing, the current study investigated the role of hypoxia-inducible factor (HIF)-1α in regulating airway epithelial CD55 expression. Hypoxia down-regulated CD55 expression on small-airway epithelial cells in vitro, and in murine lungs in vivo; the latter was associated with local complement activation. Treatment with pharmacologic inhibition or silencing of HIF-1α during hypoxia-recovered CD55 expression in small-airway epithelial cells. HIF-1α overexpression or blockade, in vitro or in vivo, down-regulated CD55 expression. Collectively, these data show a key role for HIF-1α in regulating the expression of CD55 on airway epithelium