The human minor histocompatibility antigen HA-1 : its processing, presentation and recognition

The minor histocompatibility (mH) antigen HA-1 is expressed by cells of hematopoietic origin only. The sequences of the immunogenic CTL epitope VLHDDLLEA (HA-1H) and the VLRDDLLEA (HA-1R) counterpart differ by one aminoacid. Selectively infusing HA-1H specific donor cytotoxic T cells may mediate a strong GvL effect with a low risk for GvHD. However, this HA-1H specific immunotherapy is currently feasible only for HLA-A2 HA-1HH or HA-1HR patients who relapsed following an SCT from an HLA-A2 HA-1RR donor. In addition, the therapy is not guaranteed for all of these patients. For instance, the anonymous umbilical cord blood (UCB) donors cannot be traced again for use of DLI or adoptive immunotherapy following transplantation. Moreover, the success rate of HA-1H specific HLA2 restricted CTL induction is donor dependent. This thesis describes the following important features, which may lead to extension of the patient population that may benefit from HA-1 specific immunotherapy: - The instable natural presentation of HA-1R in HLA-A2. - A novel HLA-B60 restricted HA-1H epitope. - Hematopoietic-specific CTLs from UCB directed against HA-1H in the context of HLA-A2. - HA-1 specific TCR transfer directing non- HA-1 TCR expressing adult and UCB CD8+ T cells to hematopoietic-specific cytolytic activity.LEI Universiteit LeidenImmunogenetica en immunologie van bloedcomponenten en beenmer

Grassroots Creative Hubs: Urban Regeneration, Recovered Industrial Factories and Cultural Production in Buenos Aires and Rio de Janeiro

This chapter examines the nature, functioning and politics of grassroots creative hubs as contained in refurbished industrial factories. The renewal and transformation of factories into arts and cultural venues has been a key feature of post-industrial urbanism in the last three decades. Examples abound across the world, from railway and power stations to post office buildings and chocolate factories, these recovered infrastructures have been re-signified as cultural facilities – performing or multi-arts centres, galleries, cultural centres, creative economy laboratories, incubators and museums. These initiatives, be that they are led by local governments or community groups, are part of broader urban strategies for revitalising historical centres, revalorising cultural heritage and creating work opportunities as well as resources for tourism and business investment. But can a factory building be considered a creative hub? Does the materiality of these urban artefacts provide a solution to the oftentransient nature of ephemeral cultural urbanism? Refurbishing old industrial factories and warehouses for cultural use and creative production has been the subject of much investigation since the 1980s-1990s, mainly through the study of culture-led urban regeneration and gentrification (Zukin, 1989; Montgomery, 1995; Evans and Shaw, 2004; Mommaas, 2004; Pratt, 2009), and more recently, creative industry clusters and districts (Evans, 2009; Zukin and Braslow, 2011; O’Connor and Gu, 2012). These studies have pointed out the problems that arise from the organisation, management and long-term sustainability of converted industrial sites, as well as from the policy uses and abuses that often pave the way to real-estate development and social displacement. Drawing on insights from urban sociology and critical geography, the chapter conducts a case-study analysis of two cultural and creative economy factories in Latin America: Fábrica Bhering in Rio de Janeiro, Brazil, and IMPA, la Fábrica Cultural in Buenos Aires, Argentina. The chapter is comprised of three sections: the first discusses whether recovered industrial factories can be thought of as creative hubs in relation to ephemeral cultural urbanism; the second examines the two case-studies in the context of Brazil and Argentina; and the third offers concluding remarks. Overall the chapter contributes a Latin American perspective on culture-led urban regeneration to the study of creative hubs. Particularly, grassroots creative initiatives of urban renewal are presented as an alternative to the exclusionary gentrification processes to which creative hubs and other territorial forms of creativity are often related to, in times largely shaped by neoliberal operations driven by real-estate interests and alliances between political and economic urban elites

Despite the presence of UVB-induced DNA damage, HLA-DR+ cells from ex vivo UVB-exposed human skin are able to migrate and show no impaired allostimulatory capacity

In this study, we investigated the effect of ultraviolet B radiation on human Langerhans cell function. Normal human skin was irradiated ex vivo with single doses of ultraviolet B. For assessment of T-cell stimulatory function, cells that spontaneously migrated from epidermal sheets were used, whereas full-thickness skin biopsies were used to investigate alterations in migratory properties. The cells migrating from ultraviolet B-exposed epidermal sheets demonstrated a decrease in the percentage of HLA-DR positive Langerhans cells, as well as a reduced capacity to induce proliferation of allogeneic T cells, when compared with cells migrating from nonexposed sheets. When a correction was made for the decreased number of HLA-DR positive Langerhans cells migrating from ultraviolet B-exposed epidermis, however, it appeared that the capacity to induce T-cell proliferation was identical for Langerhans cells migrating from ultraviolet B-exposed and nonexposed epidermis. The presence of ultraviolet B-induced DNA damage could be demonstrated in the Langerhans cells from ultraviolet B-treated skin, indicating that the cells had received significant doses of ultraviolet B. As regards the effect of ultraviolet B on migratory properties of Langerhans cells, we found not only that reduced numbers of CD1a-positive Langerhans cells migrated from the ultraviolet B-exposed full-thickness skin, but also that there was a reduction in CD1a-positive Langerhans cells in the epidermis. This implies that ultraviolet B induces death of Langerhans cells as well as loss of cell surface molecules rather than altering Langerhans cells migration, whereas the Langerhans cells that were still able to migrate fully retained the capacity to activate allogeneic T cells

A Uniform Genomic Minor Histocompatibility Antigen Typing Methodology and Database Designed to Facilitate Clinical Applications

BACKGROUND: Minor Histocompatibility (H) antigen mismatches significantly influence the outcome of HLA-matched allogeneic stem cell transplantation. The molecular identification of human H antigens is increasing rapidly. In parallel, clinical application of minor H antigen typing has gained interest. So far, relevant and simple tools to analyze the minor H antigens in a quick and reliable way are lacking. METHODOLOGY AND FINDINGS: We developed a uniform PCR with sequence-specific primers (PCR-SSP) for 10 different autosomal minor H antigens and H-Y. This genomic minor H antigen typing methodology allows easy incorporation in the routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate the methodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (http://www.lumc.nl/dbminor) was developed. Input of the minor H antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on the putative graft-versus-host, graft-versus-tumor and host-versus-graft reactivities. SIGNIFICANCE: A simple, uniform and rapid methodology was developed enabling determination of minor H antigen genotypes of all currently identified minor H antigens. A dbMinor database was developed to interpret the genomic typing for its potential clinical relevance. The combination of the minor H antigen genomic typing methodology with the online dbMinor database and applications facilitates the clinical application of minor H antigens anti-tumor targets after stem cell transplantation

Transduction of Human T Cells with a Novel T-Cell Receptor Confers Anti-HCV Reactivity

Hepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B- and T-cell immunity in HCV-infected patients, chronic viral infection and HCV-related malignancies progress. Here we report the identification of a novel HCV TCR from an HLA-A2-restricted, HCV NS3:1073–1081-reactive CTL clone isolated from a patient with chronic HCV infection. We characterized this HCV TCR by expressing it in human T cells and analyzed the function of the resulting HCV TCR-transduced cells. Our results indicate that both the HCV TCR-transduced CD4+ and CD8+ T cells recognized the HCV NS3:1073–1081 peptide-loaded targets and HCV+ hepatocellular carcinoma cells (HCC) in a polyfunctional manner with cytokine (IFN-γ, IL-2, and TNF-α) production as well as cytotoxicity. Tumor cell recognition by HCV TCR transduced CD8− Jurkat cells and CD4+ PBL-derived T cells indicated this TCR was CD8-independent, a property consistent with other high affinity TCRs. HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections

Effects of Deletion of Macrophage ABCA7 on Lipid Metabolism and the Development of Atherosclerosis in the Presence and Absence of ABCA1

ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen