The parasitic worm product ES-62 up-regulates IL-22 production by γδ T cells in the murine model of Collagen-Induced Arthritis

S-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that acts to modulate the host immune response to promote the establishment of chronic helminth infection. Reflecting its anti-inflammatory actions, we have previously reported that ES-62 protects mice from developing Collagen-Induced Arthritis (CIA): thus, as this helminth-derived product may exhibit therapeutic potential in Rheumatoid Arthritis (RA), it is important to understand the protective immunoregulatory mechanisms triggered by ES-62 in this model in vivo. We have established to date that ES-62 acts by downregulating pathogenic Th17/IL-17-mediated responses and upregulating the regulatory cytokine IL-10. In addition, our studies have identified that IL-22, another member of the IL-10 family of cytokines, exerts dual pathogenic and protective roles in this model of RA with ES-62 harnessing the cytokine’s inflammation-resolving and tissue repair properties in the joint during the established phase of disease. Here, we discuss the counter-regulatory roles of IL-22 in the murine model of CIA and present additional novel data showing that ES-62 selectively induces γδ T cells with the capacity to induce IL-22 production and that gd T cells with the capacity to produce IL-22, but not IL-17, induced during CIA can be identified by their expression of TLR4. Moreover, we also show that treatment of mice undergoing CIA with the active PC moiety of ES-62, in the form of PC conjugated to BSA, is not only sufficient to mimic the ES-62-dependent suppression of pathogenic IL-17 responses shown previously but also that of the IL-22 and IL-10 up-regulation observed with the parasitic worm product during CIA. These findings not only reinforce the potential of IL-22, firstly described as a Th17-related pro-inflammatory cytokine, as a protective factor in arthritis but also suggest that drugs based on the PC moiety found in ES-62 may be able to harness the joint-protecting activities of IL-22 therapeutically

Parasite excretory-secretory products and their effects on metabolic syndrome

Obesity, one of the main causes of metabolic syndrome (MetS), is an increasingly common health and economic problem worldwide, and one of the major risk factors for developing type 2 diabetes and cardiovascular disease. Chronic, low-grade inflammation is associated with MetS and obesity. A dominant type 2/anti-inflammatory response is required for metabolic homeostasis within adipose tissue: during obesity, this response is replaced by infiltrating, inflammatory macrophages and T cells. Helminths and certain protozoan parasites are able to manipulate the host immune response towards a TH2 immune phenotype that is beneficial for their survival and there is emerging data that there is an inverse correlation between the incidence of MetS and helminth infections, suggesting that, as with autoimmune and allergic diseases, helminths may play a protective role against MetS disease. Within this review, we will focus primarily on the excretory-secretory products that the parasites produce to modulate the immune system and discuss their potential use as therapeutics against MetS and its associated pathologies

Receptor usage by the Acanthocheilonema viteae-derived immunomodulator, ES-62

ES-62 is an immunomodulatory phosphorylcholine (PC)-containing glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae. Previously, the use of knockout mice has revealed the effects of ES-62 on macrophages and dendritic cells to be dependent on TLR4. However, it is possible that ES-62 may interact with additional proteins on the surfaces of target cells and hence that cells may vary with respect to receptor usage. In this study, we identified by molecular weight, proteins that interact with ES-62 and found differences amongst the immune system cells studied. Thus, whereas lymphocytes appear to have two major interacting proteins of 135 and 82 kDa, U937 monocytes only contain an ES-62-binding protein of the latter molecular weight. Binding to the proteins on B cells and U937 cells wasblocked by PC, suggesting a critical role for this ES-62 moiety in facilitating interaction. Finally, ES-62 binding is followed by internalization in both macrophages and B cells but only in the former was absence of TLR4 found to block internalization. These findings are consistent with differences in receptor usage by ES-62 amongst different cell-types

Small business sport sponsorship: A case study

Within a reasonably short timeframe sponsorship has morphed from a passive form of marketing that was often philanthropic in nature (Morgan et al., 2014), to a legitimate element of the promotional mix (Segium & O’Reilly, 2007), and a key strategic business partnership initiative (O’Reilly & Horning, 2013). Sport sponsorship has been defined as the provision of assistance by commercial organisations (sponsors), in cash or kind, to a sports property (sponsee), in exchange for the rights to be associated with the sports property for the purpose of gaining a commercial and economic advantage (Triodi, 2001). While substantial research has been directed towards large organisations and corporate sponsorship, little interest has been focussed on the relationship between small businesses and sport sponsorship (Mack, 1999, Jing 2010). Small businesses are extensively involved in the sponsorship of sports organisations, teams, individuals and events (Slack & Bentz, 2010). As more and more local and regional sport organisations look towards sponsorship as a means to financially support their organisations this relationship will continue to grow. Given that 97% of all enterprises in New Zealand are defined as “small” this research aims to address the gap in the literature and to contribute to the advancement of the ‘philanthropic-sponsorship’ continuum. The Waikato Rugby Union (WRU) was selected as the case study due to the nature of the sporting code, its established history, and its strong brand. The research applied a qualitative, exploratory approach in order to explore small business perceptions and experiences with sport sponsorship. A series of in-depth semi-structured interviews were conducted with relevant personnel from selected WRU small business sponsors. Interviews were recorded, transcribed and then analysed using grounded theory coding techniques, allowing for key themes to emerge. The study examined the objectives, practices and perceptions of small businesses related to sponsorship decision making. For the purpose of this study, a small business was defined as any enterprise with less than 20 employees. The research findings contradicted previous small business – sport sponsorship literature. The findings highlighted that there was long-term strategic planning, with 75% of the businesses initiated the first contact with the WRU. While decisions were still predominantly made by one individual, they were clearly based on ‘corporate’ objectives rather than personal preferences and/or a sense of “giving back” to the community. The three top objectives were hospitality, brand awareness and networking. The strength of the WRU brand was also a factor in the decision-making. However, there were little or no formalised internal policies to guide the small business sport sponsorship screening and selection processes in terms of sponsorship opportunities, and limited sponsorship evaluation. As sponsors become more and more a part of the social context that shapes and sustains local and regional sport it is important that both sport organisations and small businesses understand better what motivates, attracts and sustains small business sponsorship. It is unclear is this stage if the findings are a result of the status that Rugby holds in the New Zealand psyche and the professionalisation of the sport, or if this is an evolving trend. Further research into other sporting codes would contribute to the understanding of the small business – sport sponsorship dynamics

Federal Technology Transfer: Should We Build Subarus in Bethesda

A critical examination of a policy designed to encourage commercial exploitation of federally funded biomedical research. The author argues that the implementation of this policy threatens the integrity of basic science in America

The Human Genome Project and the Downside of Federal Technology Transfer

Mr. Harnett argues that emphasizing technology transfer at institutions such as the National Institutes of Health will interfere with what should be regarded as their primary mission, basic research

Lessons from helminth infections: ES-62 highlights new interventional approaches in rheumatoid arthritis

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialised countries, this "Hygiene Hypothesis" has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. Here we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine Collagen Induced Arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of IL-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by Th17 and γδ T cells, whilst leaving that of CD49b+ Natural Killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologics, such as "IL-17 blockers", that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential

Weak convergence of the Stratonovich integral with respect to a class of Gaussian processes

For a Gaussian process $X$ and smooth function $f$, we consider a Stratonovich integral of $f(X)$, defined as the weak limit, if it exists, of a sequence of Riemann sums. We give covariance conditions on $X$ such that the sequence converges in law. This gives a change-of-variable formula in law with a correction term which is an It\^o integral of $f"'$ with respect to a Gaussian martingale independent of $X$. The proof uses Malliavin calculus and a central limit theorem from [10]. This formula was known for fBm with $H=1/6$ [9]. We extend this to a larger class of Gaussian processes.Comment: 39 pages. arXiv admin note: text overlap with arXiv:1105.484