Testing relationships: ethical arguments for screening with HbA1C

Since the 1990s, glycated haemoglobin (HbA1C) has been the gold standard for monitoring glycaemic control in people diagnosed as having either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Discussions are underway about diagnosing diabetes mellitus on the basis of HbA1C titres and using HbA1C tests to screen for T2DM. These discussions have focused on the relative benefits for individual patients, with some attention directed towards reduced costs to healthcare systems and benefits to society. We argue that there are strong ethical reasons for adopting HbA1C-based diagnosis and T2DM screening that have not yet been articulated. The rationale includes the differential impact of HbA1C-based diabetic testing on disadvantaged groups, and what we are beginning to learn about HbA1C vis-à-vis population health. Although it is arguable that screening must primarily benefit the individual, using HbA1C to diagnose and screen for T2DM may promote a more just distribution of health resources and lead to advances in investigating, monitoring and tackling the social determinants of health

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans

Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells

Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcγ receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-γ in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcγ receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45862/1/262_2005_Article_104.pd

Vesicular stomatitis virus and pseudorabies virus induce a vig 1/cig5 homologue in mouse dendritic cells via different pathways

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Influence of flanking sequences on the processing and presentation of a CD8+ cytotoxic T-cell epitope delivered by parvovirus-like particles

10 páginas, 5 figuras, 2 tablas -- PAGS nros. 563-572We have previously developed an antigen-delivery system based on hybrid recombinant porcine parvovirus-like particles (PPV-VLPs) formed by the self-assembly of the VP2 protein of PPV carrying a foreign epitope at its N terminus. In this study, different constructs were made containing a CD8+ T-cell epitope of chicken ovalbumin (OVA) to analyse the influence of the sequence inserted into VP2 on the correct processing of VLPs by antigen-presenting cells. We analysed the presentation of the OVA epitope inserted without flanking sequences or with either different natural flanking sequences or with the natural flanking sequences of a CD8+ T-cell epitope from the lymphocytic choriomeningitis virus nucleoprotein, and as a dimer with or without linker sequences. All constructs were studied in terms of level of expression, assembly of VLPs and ability to deliver the inserted epitope into the MHC I pathway. The presentation of the OVA epitope was considerably improved by insertion of short natural flanking sequences, which indicated the relevance of the flanking sequences on the processing of PPV-VLPs. Only PPV-VLPs carrying two copies of the OVA epitope linked by two glycines were able to be properly processed, suggesting that the introduction of flexible residues between the two consecutive OVA epitopes may be necessary for the correct presentation of these dimers by PPV-VLPs. These results provide information to improve the insertion of epitopes into PPV-VLPs to facilitate their processing and presentation by MHC class I moleculesG. Morón was supported by a post-doctoral fellowship of the Consejo Nacional de Inestigaciones Científicas y Tecnológicas (CONICET, Argentina) and by EEC grant QLK2-CT-1999-00429. This work was carried out as a collaborative project between INGENASA and the Institute Pasteur in an EU-supported project (EEC grant # QLK2-CT1999-0318)Peer reviewe