Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection.

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.

Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 microM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.

Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection.

The p40 subunit of interleukin 12 (IL-12p40) has been known to act as an IL-12 antagonist in vitro. We here describe the immunosuppressive effect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was transduced with retro-virus vectors carrying the lacZ gene as a marker and the IL-12p40 gene. IL-12p40 secreted from the transfectant inhibited the IL-12-induced interferon gamma (IFN-gamma) production by splenocytes in vitro. Survival of C2C12 transplanted into allogeneic recipients was substantially prolonged when transduced with IL-12p40. Cytokine (IL-2 and IFN-gamma) production and cytotoxic T lymphocyte induction against allogeneic C2C12 were impaired in the recipients transplanted with the IL-12p40 transfectant. Delayed-type hypersensitivity response against C2C12 was also diminished in the IL-12p40 recipients. Furthermore, serum antibodies against beta-galactosidase of the T-helper 1-dependent isotypes (IgG2 and IgG3) were decreased in the IL-12p40 recipients. These results indicate that locally produced IL-12p40 exerts a potent immunosuppressive effect on T-helper 1-mediated immune responses that lead to allograft rejection. Therefore, IL-12p40 gene transduction would be useful for preventing the rejection of allografts and genetically modified own cells that are transduced with potentially antigenic molecules in gene therapy.

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection.

During tumor progression, variants may arise that grow more vigorously. The fate of such variants depends upon the balance between aggressiveness of the variant and the strength of the host immunity. Although enhancing host immunity to cancer is a logical objective, eliminating host factors necessary for aggressive growth of the variant should also be considered. The present study illustrates this concept in the model of a spontaneously occurring, progressively growing variant of an ultraviolet light-induced tumor. The variant produces chemotactic factors that attract host leukocytes and is stimulated in vitro by defined growth factors that can be produced or induced by leukocytes. This study also shows that CD8+ T-cell immunity reduces the rate of tumor growth; however, the variant continues to grow and kills the host. Treatment with a monoclonal anti-granulocyte antibody that counteracts the infiltration of the tumor cell inoculum by non-T-cell leukocytes did not interfere with the CD8+ T-cell-mediated immune response but resulted in rejection of the tumor challenge, indicating a synergy between CD8+ T-cell-mediated immunity and the inhibition of paracrine stimulation.

Lightweight peer-to-peer secure multi-party VoIP protocol

Multi-party voice-over-IP (MVoIP) services provide economical and convenient group communication mechanisms for many emerging applications such as distance collaboration systems, on-line meetings and Internet gaming. In this paper, we present a light peer-to-peer (P2P) protocol to provide MVoIP services on small platforms like mobile phones and PDAs. Unlike other proposals, our solution is fully distributed and self-organizing without requiring specialized servers or IP multicast support.

Evaluación de las comunicaciones de un congreso de marketing y su posterior publicación

Tradicionalmente, la literatura ha evidenciado debilidades en el sistema de revisión por pares en el ámbito de los artículos publicados en revistas. Hasta la fecha apenas se ha dedicado atención a estas debilidades en el campo de los congresos. Este trabajo examina los factores determinantes de las evaluaciones por pares que reciben las comunicaciones de los congresos a partir de las características de sus autores y del propio manuscrito. Asimismo, analiza la relación existente entre el grado de aceptación/rechazo de las comunicaciones y la calidad de las publicaciones posteriores que se derivan de las mismas. Los resultados obtenidos en un congreso de marketing evidencian que la orientación cuantitativa, las referencias bibliográficas y las notas a pie de página influyen en la evaluación por pares de las comunicaciones. Además, se detecta que aquellas comunicaciones que son aceptadas para su presentación en el congreso, posteriormente resultan publicadas en revistas de mayor calidad.

An Exploration of Sociometric Status and Peer Relations in Youth Sport

More than 10 years ago, it was suggested that sociometry and systematic observation were two potentially useful but under-utilized methods for the study of peers in youth sport (Smith, 2003). Despite this call, the methods used to study peers in sport remain largely focused on athletes' perceptions through questionnaires and interviews. Thus, the purpose of this descriptive study was to investigate the utility of sociometry in relation to sport competence and observed athlete behavior in youth sport. Three adolescent female volleyball teams were videotaped during three practice sessions, and sport competence and sociometric status were assessed using questionnaires. An observational coding system was developed and used to code athlete behaviors and data were compared across sociometric status groups. Results revealed significant differences between sociometric status groups on peer ratings of sport competence, but not on athlete behavior. However, interesting findings emerged with respect to how status groups interacted with teammates and coaches. Thus, sport competence seems to be an important factor in gaining acceptance among youth peer groups. Further, sociometry and behavioral observation appear to be useful techniques that should continue to be employed in the study of peer relations in youth sport.

Postcolonial Language: Rejection and Subversion

A literatura pós-colonial é muitas vezes pensada como uma forma de tradução cultural, como um lugar privilegiado a partir do qual se pode reescrever a história e retroactivamente reflectir sobre a experiência colonial. Tomando como ponto de partida esta noção de tradução cultural, o presente ensaio procura analisar as obras Une Tempête (1969), de Aimé Césaire, e Foe (1986), de J. M. Coetzee, no que diz respeito à re-escrita das personagens Caliban e Friday, respectivamente. Ambas as figuras serão comparadas e contrastadas relativamente ao uso particular que fazem da língua enquanto instrumento de poder, subversão e rejeição do domínio europeu. Palavras-chave: Literatura Pós-colonial, Mecanismo de “Writing Back”, Tradução Cultural, Língua, Alteridade Postcolonial literature is often depicted as a form of cultural translation, a privileged space from which to rewrite history and retroactively reflect upon the colonial experience. Based on this notion of cultural translation, the article seeks to examine, respectively, Aimé Césaire’s Une Tempête (1969) and J. M. Coetzee’s Foe (1986) as regards the “written-back” characters Caliban and Friday. Both characters will be compared and contrasted concerning their peculiar use of language as an instrument of power, subversion, and rejection of the European ruling. Keywords: Postcolonial Literature, Writing Back, Cultural Translation, Language, Other(ness)

Euro-enthusiasm, Euro-rejection, and various shades of grey: The 2014 European Parliament election campaign in the Netherlands. EPIN Commentary No. 18/29 April 2014

With less than a month to go to the European Parliament (EP) elections, campaigning has barely begun in the Netherlands. Whether the campaign will address concrete EU policies or the future of the European Union remains to be seen, but this author argues that the outcomes will probably have less to with the parties’ stance on Europe than with the unpopularity of the incumbent parties and the ‘second order’ character of EP elections.

Ireland's Rejection of the Lisbon Treaty and the EU's Impasse.

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