| 1. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Adjuvant properties of a biocompatible thermo-responsive polymer of N-isopropylacrylamide in autoimmunity and arthritis
- 2011
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Ingår i: Journal of the Royal Society Interface. - London : The Royal Society Publishing. - 1742-5689 .- 1742-5662. ; 8:65, s. 1748-1759
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the thermo-responsive poly(N-isopropylacrylamide) (PNiPAAm) polymer as an adjuvant, we synthesized PNiPAAm through free radical polymerization and characterized it both in vitro and in vivo. The polymer when mixed with collagen type II (CII) induced antigen-specific autoimmunity and arthritis. Mice immunized with PNiPAAm-CII developed significant levels of CII-specific IgG response comprising major IgG subclasses. Antigen-specific cellular recall response was also enhanced in these mice, while negligible level of IFN-gamma was detected in splenocyte cultures, in vitro. PNiPAAm-CII-immunized arthritic mouse paws showed massive infiltration of immune cells and extensive damage to cartilage and bone. As determined by immunostaining, most of the CII protein retained its native configuration after injecting it with PNiPAAm in naive mice. Physical adsorption of CII and the high-molecular-weight form of moderately hydrophobic PNiPAAm induced a significant anti-CII antibody response. Similar to CII, mice immunized with PNiPAAm and ovalbumin (PNiPAAm-Ova) induced significant anti-ovalbumin antibody response. Comparable levels of serum IFN-gamma, IL-1beta and IL-17 were observed in ovalbumin-immunized mice with complete Freund, incomplete Freund (CFA and IFA) or PNiPAAm adjuvants. However, serum IL-4 levels were significantly higher in PNiPAAm-Ova and CFA-Ova groups compared with the IFA-Ova group. Thus, we show for the first time, biocompatible and biodegradable thermo-responsive PNiPAAm can be used as an adjuvant in several immunological applications as well as in better understanding of the autoimmune responses against self-proteins. © 2011 The Royal Society
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| 2. |
- Shakya, Akhilesh Kumar, et al.
(författare)
-
Collagen type II and a thermo-responsive polymer of N-isopropylacrylamide induce arthritis independent of Toll-like receptors : a strong influence by major histocompatibility complex class II and Ncf1 genes
- 2011
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Ingår i: American Journal of Pathology. - New York : Elsevier. - 0002-9440 .- 1525-2191. ; 179:5, s. 2490-2500
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Tidskriftsartikel (refereegranskat)abstract
- We established and characterized an arthritis mouse model using collagen type II (CII) and a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm). The new PNiPAAm adjuvant is TLR-independent, as all immunized TLR including MyD88-deficient mice developed an anti-CII response. Unlike other adjuvants, PNiPPAm did not skew the cytokine response (IL-1beta, IFN-gamma, IL-4, and IL-17), as there was no immune deviation towards any one type of immune spectrum after immunization with CII/PNiPPAm. Hence, using PNiPAAm, we studied the actual immune response to the self-protein, CII. We observed arthritis and autoimmunity development in several murine strains having different major histocompatibility complex (MHC) haplotypes after CII/PNiPAAm immunization but with a clear MHC association pattern. Interestingly, C57Bl/6 mice did not develop CII-induced arthritis, with PNiPAAm demonstrating absolute requirement for a classical adjuvant. Presence of a gene (Ncf1) mutation in the NADPH oxidation complex has a profound influence in arthritis and using PNiPAAm we could show that the high CIA severity in Ncf1 mutated mice is independent of any classical adjuvant. Macrophages, neutrophils, eosinophils, and osteoclasts but not mast cells dominated the inflamed joints. Furthermore, arthritis induction in the adjuvant-free, eosinophil-dependent Vbeta12 DBA/1 mice could be shown to develop arthritis independent of eosinophils using CII/PNiPAAm. Thus, biocompatible and biodegradable PNiPAAm offers unique opportunities to study actual autoimmunity independent of TLR and a particular cytokine phenotype profile.
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| 3. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Macrophage-derived reactive oxygen species protects against autoimmune priming with a defined polymeric adjuvant
- 2016
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Ingår i: Immunology. - Chichester : Wiley-Blackwell. - 0019-2805 .- 1365-2567. ; 147:1, s. 125-132
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the nature of adjuvants and the immune priming events in autoimmune diseases, such as rheumatoid arthritis, is a key challenge to identify their aetiology. Adjuvants are, however, complex structures with inflammatory and immune priming properties. Synthetic polymers provide a possibility to separate these functions and allow studies of the priming mechanisms in vivo. A well-balanced polymer, poly-N-isopropyl acrylamide (PNiPAAm) mixed with collagen type II (CII) induced relatively stronger autoimmunity and arthritis compared with more hydrophilic (polyacrylamide) or hydrophobic (poly-N-isopropylacrylamide-co-poly-N-tertbutylacrylamide and poly-N-tertbutylacrylamide) polymers. Clearly, all the synthesized polymers except the more hydrophobic poly-N-tertbutylacrylamide induced arthritis, especially in Ncf1-deficient mice, which are deficient in reactive oxygen species (ROS) production. We identified macrophages as the major infiltrating cells present at PNiPAAm-CII injection sites and demonstrate that ROS produced by the macrophages attenuated the immune response and the development of arthritis. Our results reveal that thermo-responsive polymers with high immune priming capacity could trigger an autoimmune response to CII and the subsequent arthritis development, in particular in the absence of NOX2 derived ROS. Importantly, ROS from macrophages protected against the autoimmune priming, demonstrating a critical regulatory role of macrophages in immune priming events. © 2016 John Wiley & Sons Ltd.
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| 4. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Polymeric cryogels are biocompatible, and their biodegradation is independent of oxidative radicals
- 2014
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Ingår i: Journal of Biomedical Materials Research. Part A. - Hoboken, NJ : John Wiley & Sons. - 1549-3296 .- 1552-4965. ; 102:10, s. 3409-3418
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Tidskriftsartikel (refereegranskat)abstract
- Biocompatibility and in vivo degradation are two important characteristics of cell scaffolds. We evaluated these properties for four different polymeric macroporous cryogels, polyvinylcaprolactam, polyvinyl alcohol-alginate-bioactive glass composite, polyhydroxyethylmethacrylate-gelatin (pHEMA-gelatin), and chitosan-agarose-gelatin in mice. All the cryogels were synthesized at subzero temperature and were implanted subcutaneously in C57Bl/10.Q inbred mice. Both local and systemic toxicities were negligible as determined by serum tumor necrosis factor α analysis and histology of surrounding tissues nearby the implants. Complete integration of cryogels into the surrounding tissues with neovascular formation was evident in all the mice. At the implantation site, massive infiltration of macrophages and few dendritic cells were observed but neutrophils and mast cells were clearly absent. Macrophage infiltrations were observed even inside the pores of cryogel implants. To ascertain whether oxidative radicals are involved in the cryogel degradation, we implanted these gels in mice deficient for reactive oxygen species (ROS) production. Rapid gel degradation was observed in the absence of ROS, and there was no significant difference in the biodegradation of these cryogels between ROS sufficient and deficient mice thereby excluding any major role for ROS in this process. Thus, we demonstrate the biocompatibility and ROS-independent biodegradable properties of cryogels that could be useful for tissue-specific tissue engineering applications. © 2013 Wiley Periodicals, Inc.
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| 5. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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A Perspective on Oral Immunotherapeutic Tools and Strategies for Autoimmune Disorders
- 2023
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Ingår i: Vaccines. - Basel : MDPI. - 2076-393X. ; 11:6
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Forskningsöversikt (refereegranskat)abstract
- Oral immune tolerance is a physiological process to achieve tolerance against autoimmunity by oral ingestion of self-antigen(s) or other therapeutics. At the cellular level, oral tolerance suppresses autoimmune diseases by activating FoxP-positive and -negative regulatory T cells (Tregs) and/or causing clonal anergy or deletion of autoreactive T cells, affecting B cell tolerance. However, oral delivery of antigens/biologics is challenging due to their instability in the harsh environment of the gastrointestinal (GI) tract. Several antigen/drug delivery tools and approaches, including micro/nanoparticles and transgenic plant-based delivery systems, have been explored to demonstrate oral immune tolerance for different autoimmune diseases successfully. However, despite the effectiveness, variation in results, dose optimization, and undesirable immune system activation are the limitations of the oral approach to further advancement. From this perspective, the current review discusses the oral tolerance phenomenon, cellular mechanisms, antigen delivery tools and strategies, and its challenges. © 2023 by the authors.
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| 6. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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An update on smart biocatalysts for industrial and biomedical applications
- 2018
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 15:139
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Tidskriftsartikel (refereegranskat)abstract
- Recently, smart biocatalysts, where enzymes are conjugated to stimuli-responsive (smart) polymers, have gained significant attention. Based on the presence or absence of external stimuli, the polymer attached to the enzyme changes its conformation to protect the enzyme from the external environment and regulate the enzyme activity, thus acting as a molecular switch. Owing to this behaviour, smart biocatalysts can be separated easily from a reaction mixture and re-used several times. Several such smart polymer-based biocatalysts have been developed for industrial and biomedical applications. In addition, they have been used in biosensors, biometrics and nano-electronic devices. This review article covers recent advances in developing different kinds of stimuli-responsive enzyme bioconjugates, including conjugation strategies, and their applications.
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| 7. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Antigen-Specific Tolerization and Targeted Delivery as Therapeutic Strategies for Autoimmune Diseases
- 2018
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Ingår i: Trends in Biotechnology. - Cambridge, MA : Elsevier. - 0167-7799 .- 1879-3096. ; 36:7, s. 686-699
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Forskningsöversikt (refereegranskat)abstract
- The prevalence of autoimmune disorders is increasing steadily and there is no permanent cure available. Immunomodulation through repeated exposure of antigens, known as antigen-specific immune tolerance or antigen-specific immunotherapy (ASI), is a promising approach to treat or prevent autoimmune disorders. Different optimization protocols (immunization routes, delivery systems, and approaches) are being developed to implement ASI against self-proteins. Including appropriate adjuvants, altered peptide ligand, and using multipeptides are approaches that can be used to specifically target autoimmunity. This review explores various ASI application methods, including different routes of antigen-specific sensitization, delivery systems, immunomodulators containing specific antigens, and other targeted approaches that have been successfully demonstrated to have therapeutic effects on autoimmune diseases. © 2018 Elsevier Ltd.
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| 8. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Applications of nanomaterials for activation and suppression of immune responses
- 2014
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Ingår i: Handbook of Research on Diverse Applications of Nanotechnology in Biomedicine, Chemistry, and Engineering. - Pennsylvania, USA : IGI Global. - 9781466663633 - 1466663634 ; , s. 205-220
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Bokkapitel (refereegranskat)abstract
- Evaluation of immuno-modulating properties of nanomaterials is important to develop new potential therapeutics for inflammatory diseases and cancer. Activation and suppressive effects of nanomaterials on immune responses occur through various interactions with different host proteins. They can also be engineered as carriers and/or adjuvants for different proteins or antigens. Particles, emulsions, and tubes/rods are the major formats of nanomaterials currently used in biomedical applications. Sometimes, nanomaterials induce side effects like undesired immunosuppression and toxicities, which are major concerns at present in designing optimal nanotherapeutics. This chapter summarizes different types of nanomaterials and their effect on immune responses. © 2015 by IGI Global. All rights reserved.
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| 9. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Applications of polymeric adjuvants in studying autoimmune responses and vaccination against infectious diseases
- 2013
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Ingår i: Journal of the Royal Society Interface. - London : Royal Society Publishing. - 1742-5689 .- 1742-5662. ; 10:79
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Tidskriftsartikel (refereegranskat)abstract
- Polymers as an adjuvant are capable of enhancing the vaccine potential against various infectious diseases and also are being used to study the actual autoimmune responses using self-antigen(s) without involving any major immune deviation. Several natural polysaccharides and their derivatives originating from microbes and plants have been tested for their adjuvant potential. Similarly, numerous synthetic polymers including polyelectrolytes, polyesters, polyanhydrides, non-ionic block copolymers and external stimuli responsive polymers have demonstrated adjuvant capacity using different antigens. Adjuvant potential of these polymers mainly depends on their solubility, molecular weight, degree of branching and the conformation of polymeric backbone. These polymers have the ability not only to activate humoral but also cellular immune responses in the host. The depot effect, which involves slow release of antigen over a long duration of time, using different forms (particulate, solution and gel) of polymers, and enhances the co-stimulatory signals for optimal immune activation, is the underlying principle of their adjuvant properties. Possibly, polymers may also interact and activate various toll-like receptors and inflammasomes, thus involving several innate immune system players in the ensuing immune response. Biocompatibility, biodegradability, easy production and purification, and non-toxic properties of most of the polymers make them attractive candidates for substituting conventional adjuvants that have undesirable effects in the host. © 2012 The Author(s) Published by the Royal Society. All rights reserved.
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| 10. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Biomaterials for induction and treatment of autoimmunity
- 2017
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Ingår i: Advances in Biomaterials for Biomedical Applications. - Singapore : Springer. - 9789811033278 - 9789811033285 ; , s. 167-184
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Bokkapitel (refereegranskat)abstract
- Use of biomaterials in autoimmunity research is widely explored, as an adjuvant to induce antigen specific immune responses, for facilitating induction of experimental models to study disease pathogenesis and for designing novel therapeutic targets. Similarly, polymeric biomaterials are explored as a delivery vehicle for sustained and specific release of auto-antigens/drugs to treat autoimmune disorders. Although considered as biocompatible, implantation/injection of polymers like silica and metallic implants are associated with development of chronic inflammation and autoimmunity. Despite these compatibility concerns, biomaterials are still considered as favorable materials for several applications in the autoimmunity field.
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