Introduction Recent malicious use of chemical warfare agents (CWAs) is a reminder of their severity and ongoing threat. One of the main categories of CWAs is the organophosphate (OP) nerve agents. Presently, there is an urgent need to identify and evaluate OP nerve agent biomarkers that can facilitate identification of exposed individuals post-CWA incident. While exposures to OP nerve agents may be scenario-specific, the public is commonly exposed to OP compounds through the ubiquitous use of OP pesticides, which are chemically related to nerve agents. Therefore, a systematic literature review and methodological quality assessment were conducted for OP pesticide biomarker studies to serve as a baseline to assess if these approaches may be adapted to OP nerve agent exposures. Materials and Methods We conducted a systematic literature review to identify biomarkers of OP pesticide exposures. English language studies of any design that reported primary data on biomarkers for exposures in nonhuman primates or adult human study participants were eligible for inclusion. Using standard criteria for assessing the completeness of reported analytical methods, the quality of study methods was critically evaluated. Results A total of 1,044 studies of biomarkers of OP pesticide exposure were identified, of which 75 articles satisfied the inclusion and exclusion criteria. These studies described 143 different analyte/sample matrix combinations: 99 host-based biomarkers, 28 metabolites, 12 pesticides, and 4 adducts. The most commonly reported biomarkers were dialkyl phosphate urinary metabolites (22 studies), blood acetylcholinesterase, and plasma butyrylcholinesterase (26 studies each). None of the assessed quality review criteria were fully addressed by all identified studies, with almost all criteria scoring less than 50%. Conclusion Cholinesterase activity may have utility for identifying individuals with exposures surpassing a given threshold of OP nerve agent, but further investigation of how acetylcholinesterase and butyrylcholinesterase levels correlate with observed patient symptoms may be required to ensure accuracy of results. As CWAs and nerve agents are more readily used, more standardized reporting of biomarker measurements are needed to develop new approaches for OP nerve agent biomarkers.
The use of therapeutic proteins and peptides is of great interest for the treatment of many diseases, and advances in nanotechnology offer a path toward their stable delivery via preferred routes of administration. In this study, we sought to design and formulate a nanostructured lipid carrier (NLC) containing a nominal antigen (insulin peptide) for oral delivery. We utilized the design of experiments (DOE) statistical method to determine the dependencies of formulation variables on physicochemical particle characteristics including particle size, polydispersity (PDI), melting point, and latent heat of melting. The particles were determined to be non‐toxic in vitro, readily taken up by primary immune cells, and found to accumulate in regional lymph nodes following oral administration. We believe that this platform technology could be broadly useful for the treatment of autoimmune diseases by supporting the development of oral delivery‐based antigen specific immunotherapies.
Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via lipid nanoparticles (LNp) and assess the impact of an oral short-term administration strategy on T1D development. We identified a LNp formulation with negligible toxicity, readily taken up by multiple immune cells, and with favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Importantly, short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and, surprisingly, promotion of anergy in diabetogenic T cells. Ex-vivo stimulation confirmed the hyporeactivity of these cells and adoptive transfer experiments confirmed their ability to act as reservoir of induced regulatory T cells. These results highlight the versatility of this novel LNp-based drug delivery strategy. This work was supported by grant 2-SRA-2016-310-S-B from the Juvenile Diabetes Research Foundation.
Type 1 diabetes (T1D) remains an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Because of its complex etiology, many immunotherapy strategies have been investigated, but with disappointing results. Costimulation blockade, blocking the CD28 pathway via administration of CTLA4-Ig, is a promising approach, but recent observations suggest its efficacy is antagonized by inflammatory factors. As antigen presenting cells malfunctions and aberrant accumulation of type 1 interferons are associated with T1D, we pose that inhibiting the signaling of inflammatory cytokines via Tofacitinib (Tofa), a JAK inhibitor, would enhance the efficacy of CTLA4-Ig to prevent T1D development. The objective of this study was to design the controlled and localized delivery of Tofa via implementation of biocompatible lipid nanoparticles, Nanostructured Lipid Carrier (NLC), and assess the immunomodulatory impact of this strategy. We identified a specific composition of NLC that had negligible toxicity, could be readily taken up by multiple immune cells, and had a favorable Tofa encapsulation efficiency. Live animal imaging using fluorescently-labeled NLC confirmed that these particles have the unique property of accumulating in lymphoid tissues. Moreover, when administrated via oral gavage, they bypassed first-pass metabolism and accumulated in spleen, pancreatic and mesenteric lymph nodes. Ex-vivo, Tofa- NLC rapidly delivered Tofa to mouse antigen presenting cells preventing their maturation and the release of inflammatory cytokines. Ongoing experiments show that short-term administration of Tofa-NLC via oral gavage at early (3-week-old) or late (10-week-old) stage in NOD promotes a significant reduction of T1D onset. Overall, Tofa-NLC represent a promising strategy to complement CTLA4-Ig (currently investigated) and we envision this combination strategy could enhance the efficacy of antigen specific immunotherapy. Disclosure Y. Zhang: None. J. Wang: None. X. Calderon-Colon: None. O. Tiburzi: None. M. Iglesias Lozano: None. J. Patrone: None. G. Raimondi: None.
The use of therapeutic proteins and peptides is of great interest for the treatment of many diseases, and advances in nanotechnology offer a path toward their stable delivery via preferred routes of administration. In this study, we sought to design and formulate a nanostructured lipid carrier (NLC) containing a nominal antigen (insulin peptide) for oral delivery. We utilized the design of experiments (DOE) statistical method to determine the dependencies of formulation variables on physicochemical particle characteristics including particle size, polydispersity (PDI), melting point, and latent heat of melting. The particles were determined to be non-toxic in vitro, readily taken up by primary immune cells, and found to accumulate in regional lymph nodes following oral administration. We believe that this platform technology could be broadly useful for the treatment of autoimmune diseases by supporting the development of oral delivery-based antigen specific immunotherapies.
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