Search Results (8)

Background: Chronic kidney disease (CKD) is an established global health problem, with the increased prevalence of vascular inflammation, accelerated atherogenesis, and thrombotic risk all contributing to overall cardiovascular risk. The major CKD-specific risk factor is presumed to be the accumulation of uremic toxins in circulation and tissues, further accelerating the progression of CKD and its co-morbidities, including those of bone mineral disorders and cardiovascular diseases. Materials and Methods: In our narrative review, we focused on non-traditional cardiovascular risk factors, as they evolve with declined kidney function and are potentially further modulated by the choice of kidney replacement therapy. Results: Based on the data from the literature to date, the pre-eminent role of non-traditional risk factors emerges to mediate inflammation and increased cardiovascular mortality. In particular, patients receiving hemodialysis (HD) display dramatically increased CVD-mediated mortality. This intensified state of inflammation may be linked to the direct exposure of the bloodstream to a bio-incompatible environment in HD; for both complement-mediated and non-complement-mediated reactions, the possible contribution of neutrophil extracellular traps and complement activation-related pseudoallergy are reviewed in detail. Conclusions: Our narrative review emphasizes key elements of a bio-incompatible HD environment that may contribute to increased cardiovascular mortality in patients receiving HD. Summarizing these results may provide conceptual opportunities to develop new therapeutic targets. Full article

Lipidic nanoparticles (LNP), particularly liposomes, have been proven to be a successful and versatile platform for intracellular drug delivery for decades. Whilst primarily developed for small molecule delivery, liposomes have recently undergone a renaissance due to their success in vaccination strategies, delivering nucleic acids, in the COVID-19 pandemic. As such, liposomes are increasingly being investigated for the delivery of nucleic acids, beyond mRNA, as non-viral gene delivery vectors. Although not generally considered toxic, liposomes are increasingly shown to not be immunologically inert, which may have advantages in vaccine applications but may limit their use in other conditions where immunological responses may lead to adverse events, particularly those associated with complement activation. We sought to assess a small panel of liposomes varying in a number of physico-chemical characteristics associated with complement activation and inflammatory responses, and examine how basophil-like cells may respond to them. Basophils, as well as other cell types, are involved in the anaphylactic responses to liposomes but are difficult to isolate in sufficient numbers to conduct large scale analysis. Here, we report the use of the human KU812 cell line as a surrogate for primary basophils. Multiple phenotypic markers of activation were assessed, as well as the release of histamine and inflammasome activity within the cells. We found that larger liposomes were more likely to result in KU812 activation, and that non-PEGylated liposomes were potent stimulators of inflammasome activity (four-fold greater IL-1β secretion than untreated controls), and a lower ratio of cholesterol to lipid was also associated with greater IL-1β secretion ([Cholesterol:DSPC ratio] 1:10; 0.35 pg/mL IL-1β vs. 5:10; 0.1 pg/mL). Additionally, PEGylation appeared to be associated with direct KU812 activation. These results suggest possible mechanisms related to the consequences of complement activation that may be underpinned by basophilic cells, in addition to other immune cell types. Investigation of the mechanisms behind these responses, and their impact on use in vivo, are now warranted. Full article

Anaphylactic reactions were observed after Singapore’s national coronavirus disease 2019 (COVID-19) vaccination programme started in December 2020. We report the clinical and laboratory features of three patients in our institution who developed anaphylactic reactions after receiving the Pifzer BNT162b2 vaccine. IgM and IgG antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine, were detected in all subjects. Similarly, mild to high elevated levels of anti-polyethylene glycol (PEG) IgG (1035–19709 U/mL, vs. vaccine-naive < 265 U/mL, vaccine-tolerant < 785 U/mL) and IgM (1682–5310 U/mL, vs. vaccine-naive < 1011 U/mL, vaccine-tolerant < 1007 U/mL) were detected in two out of three patients via commercial ELISA. High levels of serum anaphylatoxin C3a (79.0 ± 6.3 μg/mL, mean ± SD, vs. normal < 10 μg/mL) were observed in all three patients during the acute phase of the reaction, while tryptase levels, a marker of mast cell activation, were not elevated. Finally, one patient with the highest levels of anti-PEG IgG, IgM, and anti-Pfizer BNT162b2 IgG and IgM exhibited an enhanced Th2 cytokine serum profile during an acute reaction, with high levels of IL-4 (45.7 pg/mL, vs. vaccine-naive/tolerant < 2.30 pg/mL), IL-33 (86.4 pg/mL, vs. vaccine-naive/tolerant < 5.51 pg/mL) and IL-10 (22.9 pg/mL, vs. vaccine-naive/tolerant < 12.49 pg/mL) diminishing over time following corticosteroid treatment. Taken together, we propose these cases of anaphylaxis described are driven by a complement activation-related pseudoallergy (CAPRA), rather than classical IgE-mediated mechanisms. Full article

The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs’ interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs’ physicochemical properties—composition, shape, and size—determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs’ interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy. Full article

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs. Full article

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways. Full article

Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety. Full article

Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as “nanomedicines”, can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then focus on the reactions caused by mAb therapy. Because the alternative pathway of complement activation may amplify such adverse reactions, we highlight the potential use of complement factor H as an inhibitor of CARPA. Full article