Intr oduction
Nanomaterials are characterized their sizes which are the range several nanometers several hundreds well below the micrometer range. Because their nanoscale dimensions and hence lar specific surface nanomaterials exhibit remarkable physicochemical such optical property ( 1 ) , catalytic property ( 2 ) , mechanical property ( 3 ) and drug delivery property ( 4 ) , which are usually not active for their bulk Due these specific properties, research and development new nanomaterials have steadily which can reflected the increasing number publications nanomaterials research, from about 1 publications 1990 4200 publications 2000 followed a burst more than 77900 publications 2013 (key word: ISI web / a result, nanomaterials, rapidly introduced into electronic devices, construction and composite are more and more present workplaces well consumer products since lar - scale producing, handling and processing facilities nanomaterials are easily
Although properties nanomaterials are impressive from physicochemical they also raise safety concerns One major concern that nanomaterials may lead potential toxic fect environment human because nanomaterials readily penetrate cell travel throughout the body , and deposit tar get gans. Therefore, may trigger injurious responses ( 5 , 6 ) . recent years, nanotoxicology has become one the major research focuses
While the number publications dealing with nanotoxicity study was about 1350 2000, this increased 5500 2010, then rapidly jumped more than 8200 2013 (key words: particle / toxicity , ISI web knowledge, / 2013). These clearly indicate that nano toxicology has been widely recognized and gained more and more These studies would help determine whether and what extent these properties may present a threat environment and human and guide applications nanomaterials daily life well ( 7 ) . Among several mechanisms proposed explain the adverse fect nanomaterials, generation reactive oxygen species and oxidative stress has received the most attention ( 8 ) . surface chemistry , surface char and aggregation nanomaterials are related their nanotoxicity ( 5 ) . dif ficult identify the health risk each new nanomaterials because all material properties need taken into account during the toxicity study . Despite safety concerns that nanomaterials could present adverse fect human beings, has been reported that nanomaterials serving fective vaccine / drug carriers could improve and / facilitate the extended release and hence enhance the immune response level and quality antigens ( 9 , ) . This has drawn more and more research focuses worldwide nanomedicine especially vaccine immunology , and nanomaterial has been referred nano adjuvant enhance the immunogenicity specific vaccine antigen. From ISI web knowledge (key words: particle / / there were only 380 publications nano - adjuvant research 2000 and increased more than 1350 and then rapidly jumped more than 1800 publications
adjuvant a substance which not immunogenic but increases prolongs immune response introduced combination with a vaccine antigen vitr o vivo ( 1 1 ) Ideally , adjuvants should biodegradable, stable with long shelf cheap produce ( ) . They are introduced enhance immunogenicity reducing the administration amount required vaccine antigen for protective immunity without inducing immune responses against themselves ( ) . Nano adjuvants take the advantages nanomaterials deliver peptides and nucleic acids ficiently tar control their release and induce immune response while protecting the integrity delivered vaccines from enzymatic degradation from degradation physiological conditions body ( 9 , , ) . However , due the concerns about safety and toxicity , there only limited vaccine adjuvant approved for human use the United States, such aluminum Despite the wide use alum, has comparatively weak immune response and works only with certain nanomaterial adjuvant vaccine immnunology one the major areas currently being studied widely because new , safe and ficient nano adjuvants are highly Apparently , further forts improvement optimization nanomaterial - based adjuvants immunology , such new particle surface properties and loading methods vaccine etc., are required help induce, strengthen and prolong the immune response before nano adjuvants are used with vaccine human
Due their positive adjuvant fect immunology and their adverse adjuvant fect human health, nanomaterials could viewed a double - edged the purpose this manuscript present overview the positive adjuvant fect nanomaterials immunology where more specifically , nanoparticles are developed vaccine antigen carriers / adjuvants. T categories nanoparticles from previous reports (polymeric and inor ganic nanoparticles) will W e also consider the fact that human exposure nanomaterials the environment more and more which brings potential adverse fect when aller gens / antigens are present the body . the adverse adjuvant fect - prepared nanomaterials and ambient particulate matter from air pollution will also discussed the end this
Adjuvant Polymeric Nanoparticles
Over the last several decades, many nanoparticles - based delivery systems have been developed and these systems have received extensive interests potential adjuvants for immunology . Based the polymer the nanoparticles can divided into biodegradable and non - biodegradable polymeric
Nanoparticle Adjuvant Biodegradable Polymers
Polymeric nanoparticles formulated from dif ferent biodegradable polymers and copolymers have been widely explored controlled delivery vehicles dif ferent agents, such peptides, proteins and nucleic acid vaccines ( , ) . They are well established delivery systems and the encapsulation biomolecules polymeric nanoparticles protects them from extreme conditions while maintaining their integrity and activity , and herein enhances the immune response the antigens ( ) .
Polyester a thermoplastic polymer with labile aliphatic ester bonds the backbones which can degrade hydrolytically under physiological conditions ( ) . one major nanoparticle materials used vaccine delivery determine the antigen immunogenicity . Poly(lactide) (PLA) and poly(lactide - - glycolic acids) (PLGA), the most popular materials for formulation polymeric nanoparticles, have been approved FDA for the applications human The application these PLGA nanoparticles antigen delivery enhanced cellular and humoral immune response compared the free antigen dose ( , ) , which confirms their adjuvant fect. Both nano - and micro - particles PLGA can used adjuvants and antigen carriers facilitate presenting antigens T cells and increase the immune response ( , ) . 2012, Bershteyn and coworkers synthesized PEGylated phospholipid - enveloped PLGA (50:50) microparticles (MP) conjugated with thiolated protein antigens (ovalbumin, and studied the adjuvant fect carriers mice ( ) . The CD8 + T - cells responses day 7 from dif ferent dose combinations , monophodphoryl lipid
A(MPLA, immunostimulatory molecule) showed very dif ferent levels. The CD8 + T - cells response mice from antigen - was significantly greater than soluble antigen immunization alone both doses (either detectable slightly higher responses compared control showed much higher response than alum - immunized (FDA approved) mice which was not detectable compared even very high alum dose ( Figure 1 A Thus these results clearly identify that lipid - enveloped PLGA one ficient adjuvant immune response More recently , Moon and coworkers synthesized similar lipid - enveloped PLGA nanoparticles and then conjugated vivax malaria protein (VMP001) the lipid membrane particles with MPLA ( ) . The mice were immunized twice days 0 and and the sera were collected and analyzed days and 120 compare the antibody responses promoted the immunization free VMP001 and VMP001 - shown
Figure 1 B - F , the nanoparticle vaccines generated a more balanced Th1 / Th2 antibody The level IgG 1 and IgG 2 c were persistent while IgG 2 b and IgG 3 responses were lost day 120. Compared free the immunization with nanoparticles showed much higher antibody responses ( Figure 1 B - F though cytokine production restimulated spenocytes vivo did not show greater dif ferences either nanoparticles loaded not loaded groups.
Particle size a critical factor that fects the immune Generally , small nanoparticles are known more fective tar geted - delivery system than lar particles because small nanoparticles can easily penetrate the biological barriers. one would expect stronger immune response from small
nanoparticle - antigen
However , several reports related degradable particles from PLA, PLGA sulfobutylated poly(vinyl alcohol) - graft - PLGA have shown that immune response from model antigens entrapped particles exhibits such trend ( – ) and the relation between immune response and particle size varies with dif ferent polymer materials and antigens. But there evidence that the size particle adjuvants may related dif ferent categories the immune responses with preferred humoral immune response for lar particles and preferred cellular immune response for small particles ( , ) Overall, polyester nanoparticle vaccines elicited enhanced immunogenicity and prolonged antibody response mice which proved the adjuvant fect nanoparticles ( ) .
Figur e 1 (A) equencies ova - specific CD8 + T - cells spleens wer e analyzed peptide - MHC tetramer staining and flow cytometry . (*, **, (Repr oduced with permission r efer ence (22) Copyright 2012 Elsevier - C57Bl / 6 mice wer e immunized s.c. days 0 and with MPLA and 1 VMP001 either soluble VMP001formulations, and anti - VMP001 IgG sera wer e characterized days and 120 for (B) (C) IgG 1 , (D) IgG 2 b , (E) IgG 2 c , and (F) IgG 3 titers. (Repr oduced with permission r efer ence (23) Copyright 2012 PLoS One)
Chitosan (poly(D - glu - the most investigated can prepared from natural polymer (chitin) via partial Ndeacetylation. soluble acidic solutions and prone chemical biological functionalization due the presence highly reactive amino groups its structure ( ) . widely studied nano vaccine carriers and adjuvants against a variety antigens, such H1N1 hemagglutinin antigen delivered chitosan - coated poly(ε - caprolactone) (PCL) nanoparticles ( ) , swine influenza DNA vaccine ( ) and hepatitis B surface antigen (rHBsAg) ( , ) And the results suggest enhanced immunological properties these chitosan - based nano adjuvants. Zhao and coworkers reported that spherical chitosan nanoparticles conjugated with swine influenza antigen (plasmid DNA) were prepared complex coacervation method with high encapsulation ficiency and high antigen stability ( ) , which indicates that the encapsulated DNA was protected from degradation after incorporated with nanoparticles. The presented much higher antibody serum IgG titers 3 times higher than naked using ELISA from BALB / c mice which were immunized with antigen - loaded chitosan nanoparticles, naked antigen and blank chitosan suggest significant adjuvant immune response from chitosan nanoparticles. Even more, the antibody presentation sustained almost same level prolonged time (up 8 weeks during the tested time interval) which indicates continuous release profile the incorporated DNA antigen from chitosan This may bring the potential increase DNA vaccination ficiency and worth further study for clinical use the future. A similar adjuvant fect was also reported Prego and coworkers ( , ) when ionic gelated chitosan nanoparticles loaded with hepatitis B antigen (HB) were prepared and intramuscularly administrated mice (two doses). Although the immune response (IgG level) from antigen - loaded nanoparticles existed a slight delay compared FDA approved alum, the adjuvant immunological fect nanoparticles was - fold higher than the alum vaccine with extended antigen release profile accounting for the prolonged immune response. The surface char and composition the antigen - loaded chitosan nanoparticles also play important roles modulating the immune response ( ) . When incorporating nanoparticles with less excess excess antigen, the resulted antigen - nanoparticle complexes could have positive ζ potential leaving chitosan predominant composition the particle surface when less excess antigen was used) negative ζ potential (CSNC leaving antigen predominant composition exposure towards the external medium when excess antigen was The immunological response CSNC - (two doses) was much lower than even lower than the control (alum - antigen) during the - week study , and was not able induce fective immunogenicity against antigen ( , ) . This consistent with previous reports that exposure repetitive antigens induced weak immune response ( ) , and cationic surface char nano adjuvant enhanced the immune response ( ) . This might explained the fact that CSNC+ could facilitate antigen internalization through strong association with outer membrane dendritic cells ( ) , and CSNC+ could induce adequate presentation the immune system and enhanced activation APCs with further development a strong adaptive immune Despite that immunization via multiple doses are widely applied immunology research,
single - dose approach antigen (HB) chitosan nanoparticles also show high specific and long - lasting IgG antibody levels against antigen ( ) , which suggest nano adjuvant could achieve the goal vaccination reducing the injection frequency while maintaining ficient immune
Other biodegradable polymers have also been studied adjuvants immunonology , such micro / nano - particles from poly(ε - caprolactone) (PCL) ( ) , nanoparticles from poly(anhydrides) ( ) and poly(γ - glutamic acid) ( ) etc. The results from those studies all suggest nanoparticles formulated from these polymer materials exhibit adjuvant immune response while - administrated with specific
Nanoparticle Adjuvant Non - Biodegradable Polymers
Unlike biodegradable polymers, non - biodegradable polymers cannot broken down degraded vivo hydrolysis and / bacteria Hence the study non - degradable nano adjuvants immunology attracted much less attention compared biodegradable polymer due slow clearance and the risk chronic toxicity after However , they are considered have extended immune response and thus improve the immunogenicity due the prolonged persistence nanoparticles tissues ( ) Especially , a great number non - biodegradable nanoparticles have been proved biocompatible, though not there are still considerable reports related their adjuvant studies immune response.
Polystyrene latex nanoparticles have been incorporated with A investigate their adjuvant immunogenicity ( – ) . When antigen A was covalently linked polystyrene nanoparticles ( ) , displayed much higher MHC class I - restricted T cell immune response and titers than those currently used adjuvants (Alum, s complete adjuvant (CF A), monophodphoryl lipid (MPL)) after one two And the conjugates antigen and nanoparticles via covalent linkage showed higher immune response than soluble antigen alone a simple mixture antigen and nanoparticles. Especially , the fect particle size was addressed the study and the result suggests that - sized particles exhibited superior antibody and cellular immune response which indicate they are ideal immune adjuvants the Moreover , tumor models EG7 - A (ovalbumin - expressing EG7 - HPV (HPV - expressing tumors) and their established tumor , mice immunized with nanoparticle - antigen conjugates cleared the tumor after certain time whereas mice treated with antigens only all showed grown tumors. Other literatures ( , ) using latex nanoparticles also demonstrated 1000 - 10000 fold more ficient immune response than soluble antigen alone via MHC - class I molecules presentation.
Another biocompatible but non - biodegradable polymer , poly( N - isopropylacrylamide) (PNiP AAm) with thermo - responsive property , has been studied nano adjuvant investigate antigen - specific immune responses ( , ) . Shakya al. synthesized well - controlled PNiP AAm with lower critical solution temperature (LCST) °C. PNiP AAm conjugated with collagen type and formed clear and visible white precipitate around the injection site
(>32 °C), which confirms the thermo - responsive property while And this adjuvant enhanced immunogenicity collagen type with induced collagen - related arthritis, and PNiP AAm covalently conjugated with antigen induced much weaker arthritis than that with physically adsorbed which suggests that one major mechanisms corresponding the adjuvant fect polymeric nanoparticles might depot fect (slow release the entrapped antigen). Moreover , this polymer adjuvant also showed enhanced immune response These results suggest PNiP AAm may used one general adjuvant immunology and vaccination.
However , several factors might need considered order use non - biodegradable polymer nanoparticles immunological adjuvants, such toxicity , particle aggregation and accumulation the tissue after which require further studies vivo clearance and safety
Although several factors the conjugates polymeric nanoparticle and antigen (from either biodegradable non - biodegradable polymer) can fect the adjuvant immunogenicity , such particle size and covalent linkage physical there are clear trends which can used predict whether nanoparticles would exhibit negative positive adjuvant fect. However , clear that positive surface char nanoparticle and antigen conjugates can form complex with DNA easily , facilitate higher transfection ficiency and herein enhance the adjuvant immune response ( , )
Adjuvant Inorganic Nanoparticles
The development functional, inor ganic nanoparticles has progressed exponentially over the past two decades. alternative polymeric nanoparticle adjuvant, inor ganic nano adjuvants have also been widely studied antigen carriers vaccine immunology due the fact that there are a variety inor ganic nanoparticles being prepared ( ) and utilized biomedical applications ( ) , such imaging ( ) , tumor detection ( ) , and drug delivery ( ) . These inor ganic particles may also have prolonged adjuvant fect due the slow clearance from Particle size and surface functionality char can easily tuned during particle preparation via simple surface chemical reactions ( ) This may extend the research varieties inor ganic nano Several inor ganic nanoparticles acting immune adjuvants will included here details for understanding their adjuvant activities.
Alum (Al(OH) 3 ) the first adjuvant and has been approved and used human beings for long time. Recently , aluminum oxide nanoparticles have been addressed more attention perhaps due the similar component alum. Antigen peptomers (head - - tail linked - mer synthetic peptides) were covalently conjugated surface - derivatized aluminum oxide nanoparticles (355 mean diameter) and their systemic immunization study was reported with the peptomer - particle conjugates without - administration hydrophilic adjuvant muramyl dipeptide (MDP) resulted the highest serum antibodies titers ( ) Both free C4 (the 4th conserved region HIV - 1 gp120) peptides and peptomers with and without MDP exist lower antibody This suggests the
formulation provided adjuvant activity when administered systemically . More recently , Maquieira and coworkers have first covalently coupled non - immunogenic hapten (one small molecular mass compound) aluminum oxide nanoparticles carrier and adjuvant for haptens immunization ( ) . Aluminum oxide particles (amorphous and 3000 nm, crystalline 300 nm) were prepared and coupled with hapten covalently . The immune response related particle size ( Figure 2 ) and crystallinity with the highest response from crystalline 300nm particles - hapten conjugates with without s consistent previous reports with higher response from crystalline materials ( ) , and particle size fect also consistent with previous results ( , ) The results also suggest the covalent linkage aluminum oxide nano adjuvant system essential induce the enhanced immune response compared with response from free hapten a simple mixture particles and
Figur e 2 . Effect the size aluminum oxide particles the conjugates mouse serum antibody expr essed absorbance Asterisk (*) denotes immunization using s adjuvant. (Repr oduced with permission r efer ence (55) Copyright 2012 American Chemical Society
Gold nanoparticles have also attracted much attention antigen carriers and adjuvants. Chen conjugated pFMDV (VP1 protein foot - and - mouth disease) with gold nanoparticle with dif ferent sizes - nm) form nanoparticle vaccines and immunized mice model study the size - dependent immunogenicity ( ) The results showed significant size - dependent immuno - genicity against pFMDV with the highest immune response from 8 and particle conjugates. And gold nanoparticle was demonstrated ideal candidate vaccine carrier due detectable antibody - binding activity . The fect size and shape gold nanoparticles immune response was studied Niikura and coworkers ( ) . Dif ferent sized and shaped gold nanoparticles were synthesized ( Figure 3 A - D ) via seeding growth method and coated with anionic polymer (PSS - MA) electrostatically attach W est Nile virus envelope (WNVE) protein produce
and spherical (Sphere40 - Sphere20 - rod (Rod - × and cubic (Cube - × × nm) particle - antigen conjugates (AuNP - Es) for vivo and vitr o immunization study Sphere40 - induced the highest level WNVE specific antibodies and Rod - induced only 50% that from Sphere40 - E ( Figure 3 E Results from cell uptake experiments nanoparticles showed the uptake Rod - more ficient than which suggest that antibody production was not dependent the uptake ficiency dif ferent AuNP - Although the mechanism shape - dependent WNVE antibody production needs further investigated, this report ( ) will pave the way for future development nano Other researchers also demonstrated gold nanoparticles along with alum ( ) with fragment from human IgG ( ) can improve the cell uptake antigen and enhance the immunogenicity against respective
Figur e 3 . TEM images - epar (A) Spher (B) Spher e40, (C) Cube, and (D) Rod gold nanoparticles befor e conjugated with antigen (Scale bar: nm). (E) WNVE - specific IgG ELISA end point titers mice immunized twice 3 - week intervals with 100 WNVE / animal / dose AuNP - Significant differ ences: < ***p < (mean ± n = (Repr oduced with permission r efer ence (59) . Copyright 2013 American Chemical Society
Mesoporous silica nanoparticle (MSN) one the most popular materials used antigen delivery systems due its high surface area and porous structure. W ang and coworkers ( ) prepared three dif ferent sized MSNs vaccine adjuvants and investigated the fect their pore structure immune After bovine serum albumin (BSA) was entrapped into oral
Interactions of Nanomaterials with Emerging Environmental Contaminants; Doong, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
immunization suggests MSN - BSA conjugates (430 nm) displayed the highest response compared those from 130 - and 1 - 2 - MSNs which might attributed the releasing rate (depot fect) and pore structure for dif ferent sized MSN - BSA conjugates (430 nm) also showed much higher immune response than free BSA BSA - A adjuvant, which suggests MSNs are acting fective - presentence Th1 and Th2 responses was proved the comparison IgG 1 and IgG 2 a titer ’ s change after 4 week vaccination. Most recently , A model antigen was ficiently conjugated amino - functionalized MSN (AMMSN, nm) A / g MSN compared only A / g non - aminated MSN ( ) due the stronger electrostatic interaction between A andMSN. Mice immunization using A - - MSNs high (10 μg) and low μg) loading A induced enhanced antibody immune but cell - mediated immunity was observed when mice were immunized with high loading AMSNs, not with low loading AMSNs. This indicates that there might a minimal threshold amount antigen loading - MSNs required induce both cellular and humoral adaptive immunity . discernible local systemic morphology change the injection site was observed after administration A -MSNs. These results indicate the adjuvant activity with A antigen and a new nano vaccine Non toxic mesoporous silica cylinders (SBA - 15) have also been used investigate the adjuvant immunogenicity against BSA ( ) and Micrurus snake toxins and Int1 β ( ) . The results clearly suggest that SBA - increased the immunogenicity compared respective antigens alone other common and positively modulated the immune response low responder individuals into high antibody producers. These cylindrical silica nanomaterials stimulated mutually TH1 and TH2 immune
Single - walled carbon nanotubes (SWNT) were covalently conjugated with W s tumor and were used immunize mice with without another immunological adjuvant, T iter max ( ) . The SWNT - WT1Pep427 conjugates with T iter max induced specific serum IgG response against antigen, whereas antigen alone, SWNT - antigen alone antigen - T iter max alone did not induce such This clearly suggests carbon nanotubes could serve antigen carriers and induce immune response against weak MHC class antigen. Quantom dots (QD, CdSe / ZnS) and Iron oxide nanoparticles (IO) conjugated with merozoite surface protein 1 a recombinant malaria vaccine antigen, were also used adjuvants immunize mice literatures ( – ) - rMSP1 induced significantly higher antibody response and parasite inhibitory antibodies against rMSP1 than those from rMSP1 with other conventional adjuvant together The enhanced immunogenicity might due the uptake QDs dendritic cells resulting the activation dendritic cells and secretion key cytokines ( )
Similar polymeric nano adjuvants, there are a variety inor ganic nano adjuvants due the extensive development synthesis inor ganic Their adjuvant fect immune response related their size, shape, linkage method between antigen and nanoparticles, their chemical composition and antigen loading amount These inor ganic nanoparticles are biocompatible due the low toxicity examined vitr o , which
suggests they are novel vaccine carriers and adjuvant candidates for the future clinical application.
Both polymeric and inor ganic nanoparticles can act adjuvants, combined with the usually through a depot fect via slow dissolution after administration. This overcomes the problem rapid loss free antigen and allows lower administration dose antigen while maintaining similar enhanced immune response benefit the vaccination development.
Allergic Adjuvant Effect
Particulate Matter
Nanomaterials and Ambient
W e have discussed a variety nanoparticles prepared from dif ferent materials adjuvants enhance immune responses against specific antigens and prevent human diseases. mentioned above, adjuvants are intended lower antigen dosage and improve ficiency the delivered vaccine ( ) ; hence they are beneficial vaccine immunology and could used future novel vaccine development. However , like a double - edged sword, nanoparticles have also been reported exhibit adverse aller gic fect raised from aller gen / nanoparticle complexes ( ) . Y ang and coworkers ( ) have reported that silica nanoparticles (nano - SiO 2 , - nm) showed adverse fect lung function rats with A immunization compared the saline - treated control rats. The A - sensitized and saline - sensitized control rats were treated daily with intratracheal instillation nano - SiO 2 solutions (0.1 and / mL) for days, rather than few immediately high dose exposure, which simulates the real environmental The results suggest that nano - SiO 2 has adverse fect lar airways the lung evidenced the increasing inspiratory and expiratory resistance while increasing the dose methacholine (MCH) challenge airway hyper - responsiveness assessment. The pulmonary histological assay lung indicates the obvious airway remodeling rats via exposure / nano - SiO 2 , and A - treated rats exhibit much more aggravated inflammation than that from the saline - treated control This may attribute the unbalance Th1 / Th2 cytokine accelerated nano - SiO 2 through the increasing - 4 production the W e have studied the enhanced aller gic fect engineered silica nanoparticles (SNP , polyethylene glycol coated particle hydrodynamic diameter) airway diseases assessing the magnitude A - induced histopathological and immunological responses the lung mice ( ) . Female BALB / c mice were intranasally sensitized with aller gen A along with - exposure SNP 100 and 400 μg) and secondary A challenge. The significantly greater level A - specific serum IgE and IgG1, airway eosinophil mucous cell and Th2 and Th17 cytokine gene and protein expression were observed from the SNP / A - mice compared those from A - mice SNP / saline - and these results indicate that airway exposure engineered SNP during the sensitization mice A enhances aller gic airway disease with a dose - dependent fashion upon secondary A Besides silica the adverse adjuvant fect other
such carbon black nanoparticles (CNP , ( ) single - walled carbon nanotubes (SWCNT , ( ) silver nanoparticles (AgNP , ( ) ) and latex nanoparticles (LNP , ( ) ) have also been studied CNP (14 and ( ) ) was used and intratracheally administrated with bacterial endotoxin (lipopolysaccharide, LPS) ICR male mice and the results indicate that CNP can aggravate the LPS - related lung inflammation with - CNP having more severe inflammation than - CNP . The enhancement mediated through the local expression - and Inoue and coworkers ( ) also studied the impact repeated pulmonary exposure SWCNT ICR male mice model immunized aller gen A aller gic The adjuvant activity SWCNT for the enhanced titers A - specific IgG1 / IgE was evidenced the increased lung levels proinflammatory cytokines and chemokines related aller compared with A The exacerbation lung inflammation possibly through the inappropriate activation antigen - presenting cells and associated with the greater oxidative stress the airway from SWCNT - A treatment. However , two kinds SWCNT with dif ferent dimensions (0.81.2 diameter and 100 - 1000 length - 2 diameter and 1μm) showed almost identical enhanced aller gic inflammation, which indicates the negligible size fect SWCNT More recently , the adverse asthmatic fect AgNP (33 nm) was reported Cheng and coworkers using proteomic approach aller gen A - AgNP sensitized female BALB / c mice model ( ) The protein profiles bronchoalveolar lavage fluid (BALF) and plasma suggested that metabolic, cellular , and immune system processes were associated with pulmonary exposure and significant aller responses were observed after AgNP exposure both control and aller gic mice determined greater level A - specific The size fect adjuvant activity spherical LNP (25, and 100 nm, carboxylated particle surface) lung inflammation mice induced LPS A aller gen was studied Inoue and coworkers ( ) . Surprisingly , LNP with all sizes mice model sensitized A - LNP did not enhance significant aller gic However , pulmonary exposure LNP showed enhanced lung inflammation induced LPS and the enhancement was mediated through the increased local expression proinflammatory cytokines and The enhancing fect lung inflammation from LPS combined with LNP smaller than diameter was more prominent than that with lar ger diameter (100 These results suggest that exposure LNP , particular smaller sized nanoparticle can directly / indirectly facilitate systemic inflammation accompanied lung discussed above, nanomaterials exhibit enhanced aller gic fect mice models under the sensitization aller especially asthma - like airway diseases. However , ambient particulate matter (PM, ranging from nanometers micrometers) one the major air pollutants from fossil vehicular traf fic, consumer products and bulk manufacture and handling nanomaterials ( 5 ) . Exposure and inhalation are more common for human the real world and are believed associated with the increasing aller gic disorders from cardiorespiratory diseases, such asthma and rhinitis ( 8 , ) . This also evidenced epidemiology studies showing a close relation between residential freeway proximity and aller gic disease incidence ( ) . the adverse adjuvant
aller gic fect airway diseases other diseases has drawn extensive interests and the recent advances will reviewed and discussed.
Lar numbers vitr o and vivo studies upon exposure showed enhanced adjuvant fect aller gic inflammation antigen / aller gen especially for asthma - like airway diseases ( – ) . This clearly indicates the adverse health fect airway diseases which could exacerbate further serious aller gic inflammation, especially already - sensitized subjects. and coworkers ( ) demonstrated that the collected ultrafine (<150 nm) could enhance significant aller gic inflammation mice model and act adjuvant promote T H 2 The results also showed bigger (<2500 nm) exhibits lower adjuvant fect aller gic inflammation compared ultrafine (UFP , < 150 The enhanced aller gic inflammation can suppressed partially adding thiol antioxidant ( N - acetyl which suggests the adjuvant fect UFP might through oxidative stress mechanism. They also designed one protocol which enable them elucidate the potential adjuvant fect UFP (<180 nm) the secondary immune response ( ) . This - exposure ambient could ficiently promote the secondary immune response and exacerbate the existing aller gic airway inflammation / disease already - sensitized Similar previous study , oxidative stress may still play a role the enhanced secondary immune response. This report suggests that exposure may more deleterious the already infected human Samuelsen al. ( ) compared the enhanced aller gic sensitization similar sized from wood smoke and road traf fic with reference diesel exhaust particles (DEP) against aller gen and concluded that from wood smoke showed comparable enhanced aller gic sensitization with road traf fic particles, but much less than DEP . Considering the exposure ambient childhood might increase s asthma risk, more recently , Herbert al. ( ) developed one procedure for the first time demonstrate that exposure the weanling BALB / c mice ambient particulates and A sensitization early life can induce the asthmatic inflammation development keeping repeatable low - level inhalational exposure aller gen. These findings are likely relevant the induction childhood asthma and help reduce the risk getting asthma T o test the hypothesis diabetes patients having high risk developing atherosclerosis upon chronic exposure ( ) , Jacobs and coworkers recently have showed the positive aller gic fect atherosclerosis non - smoking adult testing the concentration oxidized low - density lipoprotein (an atherosclerosis marker). The exposure has fect both oxidative modification lipoprotein process and the increased blood leukocytes and platelets process which contribute the initiation and progress the adverse health fects are likely depend several factors, including its size and the level and duration and age and sensitivity the exposed individuals, and on.
Although there are a great number reports related the adverse adjuvant fect ambient particulate matter , the immunological mechanism adjuvant fect still not understood completely ( 8 ) and there are still debates over dif ferent proposed elucidate the mechanisms adjuvant fect still remains one critical tasks for toxicological and immunological scientists
and more carefully designed studies are needed for a better understanding the mechanisms. One possible approaches might design and preparation engineered nanoparticles mimic dif ferent properties ambient And the adjuvant fect those engineered nanoparticles with well controlled properties might help understand their aller gic mechanism. These studies would serve and suggest how prevent the adverse adjuvant fect and thus reduce the health risk exposure for human beings.
Conclusion
Nanomaterials show significantly promising applications the development new vaccines. The adjuvants, nanoparticles can enhance the immune response greatly and reduce the vaccine / antigen dosage with great vaccine ficiency This review discussed the application nanoparticles nano adjuvants vaccination
development, including a broad range polymeric and inor ganic nanoparticles. Given the promising results nanoparticles can used discover and improve the safety and ficiency new vaccines.
Due safety concerns nanomaterials and ambient particulate matter , recent progresses - prepared nanomaterials and particulate matter from air pollution adjuvants promote the adverse aller gic sensitization human diseases have also been discussed. This would promote people take precautions about the ambient particulate matter air and thus improve the public
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