The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
Background and aims:Crohn’s disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based ...on data from adults with chronic Crohn’s disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn’s disease.Methods:Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn’s disease, children with long-standing Crohn’s disease, infectious colitis, and children without gut inflammation.Results:As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn’s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn’s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn’s disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn’s disease.Conclusions:At the onset of Crohn’s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn’s disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.
AbstractBackgroundRabies is a neglected zoonotic disease with a global burden of approximately 59,000 human deaths a year. Once clinical symptoms appear, rabies is almost invariably fatal; however, ...with timely and appropriate post-exposure prophylaxis (PEP) consisting of wound washing, vaccine, and in some cases rabies immunoglobulin (RIG), the disease is almost entirely preventable. Access to PEP is limited in many countries, and when available, is often very expensive. MethodsWe distributed a standardized assessment tool electronically to a convenience sample of 25 low- and middle-income countries in Asia and Africa to collect information on rabies PEP procurement, forecasting, distribution, monitoring and reporting. Information was collected from national rabies focal points, focal points at the World Health Organization (WHO) country offices, and others involved in procurement, logistics and distribution of PEP. Because RIG was limited in availability or unavailable in many countries, the assessment focused on vaccine. Data were collected between January 2017 and May 2018. ResultsWe received responses from key informants in 23 countries: 11 countries in Asia and 12 countries in Africa. In 9 of 23 (39%) countries, rabies vaccine was provided for free in the public sector and was consistently available. In 10 (43%) countries, all or some patients were required to pay for the vaccine in the public sector, with the cost of a single dose ranging from US$ 6.60 to US$ 20/dose. The primary reason for the high cost of the vaccine for patients was a lack of funding at the central level to subsidize vaccine costs. In the remaining 4 (17%) countries, vaccine was provided for free but was often unavailable so patients were required to purchase it instead. The majority of countries used the intramuscular route for vaccine administration and only 5 countries exclusively used the dose-sparing intradermal (ID) route. Half (11/22; 50%) of all countries assessed had a standardized distribution system for PEP, separate from the systems used for routine childhood vaccines, and almost half used separate storage facilities at both central and health facility levels. Approximately half (9/22; 41%) of all countries assessed reported having regular weekly, monthly or quarterly reporting on rabies vaccination. ConclusionsWhile all countries in our assessment had rabies vaccines available in the public sector to some extent, barriers to access include the high cost of the vaccine to the government as well as to patients. Countries should be encouraged to use ID administration as this would provide access to rabies vaccine for many more people with the same number of vaccine vials. In addition, standardized monitoring and reporting of vaccine utilization should be encouraged, in order to improve data on PEP needs.
On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in ...Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three “classical” transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small‐group breakout sessions, and large‐group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross‐cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.
Animal models of inflammatory bowel disease (IBD) have been useful in the identification of those immune responses uniquely involved in IBD pathogenesis and in defining the important roles of ...environmental influences, such as normal luminal bacterial flora and the genetic composition of the host, in modifying IBD-associated inflammation. Recent studies have focused particular attention on CD4
+ T cells which produce excessive quantities either of Th1 cytokines (IFN-γ and TNF) directed by IL-12 or of aTh2 cytokine (IL-4), relative to the production of suppressive cytokines such as IL-10 and transforming growth factor β. Such insights will be extremely beneficial in the development of novel approaches to the control of IBD-type inflammation, such as the use of anticytokine therapies and gene therapy, and, finally, in the identification of the genetic abnormalities and the antigens driving the inflammation that underlies the human disease.
The cytochrome CYP3A gene products, expressed in mammalian liver, are essential
for the metabolism of lipophilic substrates, including endogenous steroid
hormones and prescription drugs. CYP3A ...enzymes are extremely
versatile and are inducible by many of their natural and xenobiotic substrates.
Consequently, they form the molecular basis for many clinical drug-drug
interactions. The induction of CYP3A enzymes is species-specific, and we have postulated that it involves one or more cellular
factors, or receptor-like xeno-sensors. Here we identify one
such factor unequivocally as the nuclear receptor pregnenolone X receptor
(PXR) and its human homologue, steroid and xenobiotic receptor
(SXR). We show that targeted disruption of the mouse
PXR gene abolishes induction of CYP3A by prototypic inducers such as dexamethasone
or pregnenolone-16α-carbonitrile. In transgenic mice, an activated form
of SXR causes constitutive upregulation of CYP3A gene expression and
enhanced protection against toxic xenobiotic compounds. Furthermore, we show
that the species origin of the receptor, rather than the promoter structure
of CYP3A genes, dictates the species-specific pattern of CYP3A inducibility.
Thus, we can generate 'humanized' transgenic mice that are responsive
to human-specific inducers such as the antibiotic rifampicin. We conclude
that SXR/PXR genes encode the primary species-specific xeno-sensors that mediate
the adaptive hepatic response, and may represent the critical biochemical
mechanism of human xenoprotection.
The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid ...and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements in these genes are also distinct, furthering the concept of independent regulation. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cells and in transgenic mice via adaptive recognition of the phenobarbital response element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but also reveal the existence of a metabolic safety net that confers a second layer of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug-drug interactions.
The purpose of this project report is to introduce the European "GOLIATH" project, a new research project which addresses one of the most urgent regulatory needs in the testing of ...endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as "metabolism disrupting compounds" (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world's first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption-hepatocytes, pancreatic endocrine cells, myocytes and adipocytes-and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.
Background & Aims: Peroxisome proliferator–activated receptor γ (PPARγ) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the ...regulation of intestinal inflammation. We sought to determine whether PPARγ could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. Methods: PPARγ-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPARγ-specific ligand was also performed. Results: In a murine model of intestinal I/R injury, we observed more severe injury in PPARγ-deficient mice and protection against local and remote tissue injury in mice treated with a PPARγ-activating ligand, BRL-49653. Activation of PPARγ resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor α messenger RNA levels most likely by inhibition of the NF-κB pathway. Conclusions: These data strongly suggest that an endogenous PPARγ pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
GASTROENTEROLOGY 2001;120:460-469
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