Active suppression is mediated by a subpopulation of CD4(+) T cells that prevents autoimmunity. However, the mechanisms involved in their differentiation in vivo are currently under intensive research. Here we show that in vitro culture of bone marrow cells in the presence of IL-10 induces the differentiation of a distinct subset of dendritic cells with a specific expression of CD45RB. These CD11c(low)CD45RB(high) DCs are present in the spleen and lymph nodes of normal mice and are significantly enriched in the spleen of IL-10 Tg mice. These natural or in vitro-derived DCs display plasmacytoid morphology and an immature-like phenotype, and secrete high levels of IL-10 after activation. OVA peptide-pulsed CD11c(low)CD45RB(high) DCs specifically induce tolerance through the differentiation of Tr1 cells in vitro and in vivo. Our findings identify a natural DC subset that induces the differentiation of Tr1 cells and suggest their therapeutic use.

Background— T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis. Methods and Results— Clones of ovalbumin (OVA)–specific Tr1 cells expanded in vitro were administered intraperitoneally (10 6 cells per mouse) with their cognate antigen (50 μg of OVA subcutaneously in complete Freund’s adjuvant [CFA]) to female apolipoprotein E–knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels ( P <0.0001), a decrease in the production of interferon-γ ( P <0.001), and an increase in interleukin-10 production ( P <0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A–stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls ( P =0.002 to P <0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice. Conclusions— Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.

This study has clearly demonstrated that irradiation with 1540 nm Er:glass laser can lead to new collagen formation, dermis thickening, reduction of anisotropy of the skin, and clinical improvements. The lack of adverse effects confirmed that this 1540 nm laser emitting in a pulsed mode coupled with an efficient cooling system is safe.

Introduction: Ensuring access to timely and appropriate primary healthcare for deprived patients is an issue facing all countries, even those with universal healthcare systems. There is a paucity of information on how patients living in a context of material and social deprivation perceive barriers in the healthcare system. This study combines the perspectives of persons living in poverty and of healthcare providers to explore barriers to responsive care for underserved persons with a view to developing equity-focused primary care. Methods: In this participatory action research we used photovoice, together with a method known as 'merging of knowledge and practice' developed by ATD Fourth World, an international community organization working to eradicate poverty. The study was conducted in two teaching primary care practices in the Canadian province of Quebec. Participants consisted of 15 health professionals and six members of ATD Fourth World; approximately 60 group meetings were held. Data were analyzed through thematic analysis, in part with the involvement of persons living in poverty. Results: Three main barriers to responsive care in a context of poverty were highlighted by all participants: the difficult living conditions of people living in poverty, the poor quality of interactions between providers and underserved patients, and the complexity of healthcare system organization and functioning. Conclusion: Our research revealed that unhealthy living conditions prevent persons living in poverty from accessing quality healthcare and maintaining good health. Also, the complexity of the healthcare system's organization and functioning has a negative impact on the interactions with healthcare providers. Changes in policy and practice are needed to address those barriers and to achieve greater equity and provide more responsive care for persons living in poverty.

In this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic cells (DC) and preferentially by CD14+/CD1a− DC derived from CD34+ progenitors. Moreover, flow cytometric analysis showed FDF03 expression by CD11c+ blood and tonsil DC, but not by CD11c− DC precursors. The FDF03 cytoplasmic tail contained two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited Src homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP)-2 and to a lesser extent SHP-1. Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, thus demonstrating that FDF03 can function as an inhibitory receptor. However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CSF-induced monocyte differentiation into DC. Thus, FDF03 is a novel ITIM-bearing receptor selectively expressed by cells of myeloid origin, including DC, that may regulate functions other than that of the broadly distributed LAIR-1/p40 molecule.

There is now compelling evidence that CD4+CD25+ T cells play a major role in the maintenance of tolerance. Besides CD4+CD25+ T cells, different populations of regulatory CD4+ T cells secreting high amounts of IL-10 (T regulatory type 1 (Tr1)) or TGF-β (Th3) have also been described in in vivo models. In the lymphocyte transfer model of inflammatory bowel disease, we show here that the control of inflammation during the first weeks is not due to a complete inhibition of differentiation of aggressive proinflammatory T cells, but is the result of a balance between proinflammatory and Tr cells. We also show that in the first weeks continuous IL-10 secretion was required to actively control inflammation. Indeed, treatment with anti-IL-10R Abs 3 wk after the start of the experiment completely reversed the protective effect of Tr cells. IL-10 secretion and control of inflammation could be provided by late injection of Tr1 cells that efficiently cure ongoing inflammatory responses in two different models of inflammation. In contrast, inflammation was not controlled when high numbers of CD4+CD45RBlow or CD4+CD25+ T cells were injected as early as 1 wk after the start of the experiment. These results confirm in vitro studies showing that CD4+CD45RBlow do not contain high IL-10-producing cells and suggest that CD4+CD45RBlow Tr cells maintain tolerance in vivo, in part indirectly, through the differentiation of IL-10-secreting Tr1 cells.

Summary Patients with chronic lymphocytic leukaemia (CLL) treated with a combination of fludarabine, cyclophosphamide and rituximab show a high response rate. However, only a poor response is observed following rituximab monotherapy. The use of chemo‐immunotherapy is often associated with haematological and infectious complications. Thus, an antibody with an enhanced ability to kill CLL cells could lead to better clinical responses to antibody monotherapy and the possibility of lowering drug doses during chemo‐immunotherapy. We generated a chimeric anti‐CD20 monoclonal antibody (mAb), EMAB‐6, which has a low fucose content. Apoptosis and complement activities for EMAB‐6 were similar to those seen for rituximab. By contrast, EMAB‐6 mAb showed improved Fcγ receptor IIIA (FcγRIIIA)/CD16 binding and FcγRIIIA‐dependent effector functions. It induced a higher in vitro antibody‐dependent cellular cytotoxicity against CLL cells and a higher FcγRIIIA‐mediated interleukin‐2 production by FcγRIIIA+ Jurkat cells in the presence of CLL cells at both low and maximally saturating concentrations. Comparative studies between CLL and lymphoma cells coated with EMAB‐6 or rituximab indicated that the difference of efficacy was more pronounced at low doses and when target cells expressed fewer CD20 molecules. Thus, EMAB‐6 mAb represents a promising drug candidate for the treatment of CLL by inducing a strong cytotoxicity against tumour cells that express low CD20 levels.

A range of product- and patient-specific factors influence the treatment plan. Truly optimized outcomes are possible only when the treating physician has the requisite knowledge, experience, and vision to use BoNTA as part of a unique solution for each patient's specific needs.