The new formulation shows an attractive stability profile both, as an aq. In vitro studies showed that protamine nanocapsules were efficiently internalized by macrophages without eliciting significant toxicity.
In vivo studies indicate that antigen-loaded nanocapsules trigger immune responses comparable to those achieved with alum, even when using significantly lower antigen doses, thus indicating their adjuvant properties. These promising in vivo data, alongside with their versatility for the loading of different antigens and oily immunomodulators and their excellent stability profile, make these nanocapsules a promising platform for the delivery of antigens.
Wilson, John T. Protein subunit vaccines offer important potential advantages over live vaccine vectors but generally elicit weaker and shorter-lived cellular immune responses. Here we investigate the use of pH-responsive, endosomolytic polymer nanoparticles that were originally developed for RNA delivery as vaccine delivery vehicles for enhancing cellular and humoral immune responses. Micellar nanoparticles were assembled from amphiphilic diblock copolymers composed of an ampholytic core-forming block and a redesigned polycationic corona block doped with thiol-reactive pyridyl disulfide groups to enable dual-delivery of antigens and immunostimulatory CpG oligodeoxynucleotide CpG ODN adjuvants.
Polymers assembled into 23 nm particles with simultaneous packaging of CpG ODN and a thiolated protein antigen, ovalbumin ova. Conjugation of ova to nanoparticles significantly enhanced antigen cross-presentation in vitro relative to free ova or an unconjugated, phys.
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This work demonstrates the ability of pH-responsive, endosomolytic nanoparticles to actively promote antigen cross-presentation and augment cellular and humoral immune responses via dual-delivery of protein antigens and CpG ODN. Hence, pH-responsive polymeric nanoparticles offer promise as a delivery platform for protein subunit vaccines.
Controlled Release , , 93 — , DOI: Sloat, Brian R. An accumulation of research over the years has demonstrated the utility of nanoparticles as antigen carriers with adjuvant activity. Herein we defined the adjuvanticity of a novel lecithin-based nanoparticle engineered from emulsions.
The nanoparticles were spheres of around nm. Model protein antigens, bovine serum albumin BSA or Bacillus anthracis protective antigen PA protein, were covalently conjugated onto the nanoparticles. Immunization of mice with the PA-conjugated nanoparticles elicited a quick, strong, and durable anti-PA antibody response that afforded protection of the mice against a LD of anthrax lethal toxin challenge. The potent adjuvanticity of the nanoparticles was likely due to their ability to move the antigens into local draining lymph nodes, to enhance the uptake of the antigens by antigen-presenting cells APCs , and to activate APCs.
This novel nanoparticle system has the potential to serve as a universal protein-based vaccine carrier capable of inducing strong immune responses. The present studies were aimed at investigating the engineering of NPs with protein-conjugated-surfactant at their surface.
In order to increase the immunogenicity of a protein antigen, Brij 78 was functionalized by tresyl chloride and then further reacted with the primary amine of the model proteins ovalbumin OVA or horseradish peroxide HRP. The utility of these NPs for enhancing the immune responses to protein-based vaccines was evaluated in vivo using ovalbumin OVA as model protein and p24 as a relevant HIV antigen. In sep. These results suggested that with multiple antigens, covalent attachment of the antigen to the NP significantly enhanced antigen-specific immune responses.
This facile covalent conjugation and incorporation method may be utilized to further incorporate other protein antigens, even multiple antigens, into an enhanced vaccine delivery system. Virology , , — , DOI: The authors have constructed stable virus-like particles displaying the HIV-1 Gag p17 protein as an N-terminal fusion with an engineered protein domain from the Geobacillus stearothermophilus pyruvate dehydrogenase subunit E2.
Mice immunized with the Gag p17 -E2 mer scaffold particles mounted a strong and sustained antibody response. Antibodies directed to Gag p17 were boosted significantly with addnl. These results show that the E2 scaffold represents a powerful vaccine delivery system for whole antigenic proteins or polyepitope engineered proteins, evoking antibody prodn. Vaccine Immunol. Watson, Douglas S. American Society for Microbiology. Particulate delivery systems enhance antibody responses to subunit antigens.
However, covalent attachment of protein antigens can disrupt protein structure and mask crit. In this report, we evaluate noncovalent metal chelation via nitrilotriacetic acid NTA as a nondestructive method to attach peptide and protein antigens to liposomes. For both antigens, covalently attaching them to a lipid elicited significantly stronger antibody responses than NTA-anchored antigens OVA titer, 3. Moreover, enhancements in antigen-liposome affinity do not result in increased antibody titers. Thus, addnl. Moon, James J. National Academy of Sciences. For subunit vaccines, adjuvants play a key role in shaping immunol.
Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP, both entrapped in the aq. Immunization with these particles and monophosphoryl lipid A MPLA , a US Food and Drug Administration-approved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high-avidity antibody responses against VMP, lasting more than 1 y in mice at fold lower doses than conventional adjuvants.
Compared to sol. To begin to understand the underlying mechanisms, we examd. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells Tfh , compared to vaccinations with sol. VMP or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response.
Molino, Nicholas M. Many current cancer vaccine strategies suffer from the inability to mount a CD8 T cell response that is strong enough to overcome the low immunogenicity of tumors. Viruses naturally possess the sizes, geometries, and phys. Using the nonviral E2 core of pyruvate dehydrogenase, we have engineered a viral-mimicking vaccine platform capable of encapsulating dendritic cell DC -activating CpG mols. Encapsulated CpG activated bone marrow-derived DCs at a fold lower concn.
By codelivering peptide epitopes and CpG activator in a particle of optimal DC-uptake size, we demonstrate the ability of a noninfectious protein nanoparticle to mimic viral properties and facilitate enhanced DC activation and cross-presentation. Biomaterials , 35 , — , DOI: Temchura, Vladimir V. Crosslinking of the B-cell receptors of an antigen-specific B-cell is the initial signal for B-cell activation, proliferation, and differentiation into antibody secreting plasma cells.
Since multivalent particulate structures are efficient activators of antigen-specific B-cells, we developed biodegradable calcium phosphate nanoparticles displaying protein antigens on their surface and explored the efficacy of the B-cell activation after exposure to these nanoparticles.
The nanoparticles were characterized by SEM and dynamic light scattering. The functionalized calcium phosphate nanoparticles were preferentially bound and internalized by HEL-specific B-cells. Co-cultivation of HEL-specific B-cells with the functionalized nanoparticles also increased surface expression of B-cell activation markers. Functionalized nanoparticles were able to effectively cross-link B-cell receptors at the surface of antigen-matched B-cells and were fold more efficient in the activation of B-cells than sol.
Thus, calcium phosphate nanoparticles coated with protein antigens are promising vaccine candidates for induction humoral immunity. Vaccine , 32 , — , DOI: The frequent outbreak of respiratory infectious diseases such as influenza and pulmonary tuberculosis calls for new immunization strategies with high effectiveness. Nasal immunization is one of the most potential methods to prevent the diseases infected through the respiratory tract. In this study, the authors designed a water-sol. N-trimethylaminoethylmethacrylate chitosan TMC was synthesized by free radical polymn.
OVA group were not increased. After immunofluorescence staining of nasal cavity, IgA antibody secreting cells were mainly obsd. OVA-TMC showed little toxicity to the nasal epithelia or cilia of rats after nasal administration for 3 consecutive days. These results demonstrated that antigen conjugated TMC can induce both systemic and mucosal immune responses after nasal administration and may serve as a convenient, safe and effective vaccine for preventing respiratory infectious diseases. As one of the most serious infectious respiratory diseases, influenza A H1N1 is a great threat to human health, and it has created an urgent demand for effective vaccines.
Nasal immunization can induce both systemic and mucosal immune responses against viruses, and it can serve as an ideal route for vaccination. However, the low immunogenicity of antigens on nasal mucosa is a high barrier for the development of nasal vaccines. We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies.
Previously, we coupled well-ordered cleavage-independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remained over the potentially longer-term in vivo instability of noncovalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the polyhistidine tail to include a free cysteine on each protomer of model BG NFL trimers to allow covalent linkage. Both cobalt and cysteine coupling resulted in a high-d.
Binding anal. Following immunization of mice, serol. Importantly, the covalent coupling not only enhanced gpdirected responses compared to sol. In contrast, sol. These data indicate that covalent linkage of well-ordered trimers to liposomes in high-d. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus SIV. Rhesus macaques RMs were immunized with NPs contg. SIVmac Env and Gag. NP-adjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines.
NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells LLPCs , which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were assocd. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a mol.
This systems approach identified early blood transcriptional signatures that correlate with Env-specific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus HIV.
Cancer Nanomedicine: Progress, Challenges and Opportunities. Cancer , 17 , 20 — 37 , DOI: Nature Publishing Group. The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine.
Considerable technol. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumor biol. Controlled Release , , 88 — 97 , DOI: Induction of mucosal immunity with vaccines is attractive for the immunol. An example is infection with Chlamydia trachomatis Ct , which is the most common sexually transmitted infection in the world, and there is an unmet medical need for an effective vaccine.
A vaccine against Ct should elicit protective humoral and cell-mediated immune CMI responses in the genital tract mucosa. We previously designed an antibody- and CMI-inducing adjuvant based on poly DL-lactic-co-glycolic acid PLGA nanoparticles modified with the cationic surfactant dimethyldioctadecylammonium bromide and the immunopotentiator trehalose-6,6'-dibehenate. Here we show that immunization with these lipid-polymer hybrid nanoparticles LPNs coated with the mucoadhesive polymer chitosan enhances mucosal immune responses. Glycol chitosan GC -modified LPNs were engineered using an oil-in-water single emulsion solvent evapn.
The nanoparticle design was optimized in a highly systematic way by using a quality-by-design approach to define the optimal operating space and to gain maximal mechanistic information about the GC coating of the LPNs. Cryo-transmission electron microscopy revealed a PLGA core coated with one or several concentric lipid bilayers. The GC coating of the surface was identified as a saturable, GC concn. Increased antigen-specific mucosal immune responses were induced in the lungs and the genital tract with the optimized GC-coated LPN adjuvant upon nasal immunization of mice with the recombinant Ct fusion antigen CTH This study demonstrates that mucosal administration of CTH adjuvanted with chitosan-coated LPNs represents a promising strategy to modulate the magnitude of mucosal vaccine responses.
Design of Biodegradable Particles for Protein Delivery. Controlled Release , 78 , 15 — 24 , DOI: Elsevier Science Ireland Ltd. Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate protein carriers in order to overcome mucosal barriers. We have attempted to combine both issues through the conception of new biodegradable polymer nanoparticles: i poly ethylene glycol PEG -coated poly lactic acid PLA nanoparticles, chitosan CS -coated poly lactic acid-glycolic acid PLGA nanoparticles and chitosan CS nanoparticles.
These nanoparticles have been tested for their ability to load proteins, to deliver them in an active form, and to transport them across the nasal and intestinal mucosae. Results showed that the PEG coating improves the stability of PLA nanoparticles in the gastrointestinal fluids and helps the transport of the encapsulated protein, tetanus toxoid, across the intestinal and nasal mucosae. Furthermore, intranasal administration of these nanoparticles provided high and long-lasting immune responses.
On the other hand, the coating of PLGA nanoparticles with the mucoadhesive polymer CS improved the stability of the particles in the presence of lysozyme and enhanced the nasal transport of the encapsulated tetanus toxoid. Finally, nanoparticles made solely of CS were also stable upon incubation with lysozyme.
Moreover, these particles were very efficient in improving the nasal absorption of insulin as well as the local and systemic immune responses to tetanus toxoid, following intranasal administration. In summary, these results show that a rational modification in the compn. Vaccines , 3 , — , DOI: The safety and precision of peptide antigens has prompted the search for adjuvants capable of increasing the immune response against these intrinsically poorly immunogenic antigens. The integration of both immunostimulants and peptide antigens within nanometric delivery systems for their co-delivery to immune cells is a promising vaccination strategy.
The value of this nanostructured combination of materials was assessed for a peptide antigen aa derived from the HPV L2 protein. They also showed capacity for the assocn. The influence of the presence of pIC and PADRE in the nanocomposition, as well as that of the peptide presentation form encapsulated vs. The data obtained highlights the possibility to engineer nanoparticles through the rational combination of a no. Bioconjugate Chem. Cui, Lina; Cohen, Joel A. Biotherapeutic delivery is a rapidly growing field in need of new materials that are easy to modify, are biocompatible, and provide for triggered release of their encapsulated cargo.
Herein, we report on a particulate system made of a polysaccharide-based pH-sensitive material that can be efficiently modified to display mannose-based ligands of cell-surface receptors. These ligands are beneficial for antigen delivery, as they enhance internalization and activation of APCs, and are thus capable of modulating immune responses.
When compared to unmodified particles or particles modified with a nonspecific sugar residue used in the delivery of antigens to dendritic cells DCs , the mannosylated particles exhibited enhanced antigen presentation in the context of major histocompatibility complex MHC class I mols. This represents the first demonstration of a mannosylated particulate system that enables enhanced MHC I antigen presentation by DCs in vitro.
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Our readily functionalized pH-sensitive material may also open new avenues in the development of optimally modulated vaccine delivery systems. Wiley-Liss, Inc. The objective of the present study was to evaluate immunol. CS-DS nanoparticles were prepd.
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The immunol. This study indicated the potential of CS-DS nanoparticles to be a simple and effective particulate delivery system with in-built immunol. J Pharm Sci. Iron-dextran nanoparticles functionalized with T cell activating proteins have been used to study T cell receptor TCR signaling. However, nanoparticle triggering of membrane receptors is poorly understood and may be sensitive to physiol. To enhance T cell activation, a magnetic field was used to drive aggregation of paramagnetic nano-aAPC, resulting in a doubling of TCR cluster size and increased T cell expansion in vitro and after adoptive transfer in vivo.
T cells activated by nano-aAPC in a magnetic field inhibited growth of B16 melanoma, showing that this novel approach, using magnetic field-enhanced nano-aAPC stimulation, can generate large nos. Weiss, J. Termeer, Christian C. American Association of Immunologists.
The extracellular matrix component hyaluronan HA exists physiol. To det. Only small HA fragments of tetra- and hexasaccharide size sHA , but not of intermediate size m. Likewise, only sHA increased DC prodn. These effects were highly specific for sHA, because they were not induced by other glycosaminoglycans such as chondroitin sulfate or heparan sulfate or their fragmentation products. Interestingly, sHA-induced DC maturation does not involve the HA receptors CD44 or the receptor for hyaluronan-mediated motility, because DC from CDdeficient mice and wild-type mice both responded similarly to sHA stimulation, whereas the receptor for hyaluronan-mediated motility is not detectable in DC.
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Food Chem. The immunostimulatory activities of two low mol. The results demonstrated that LMWHA-1, LMWHA-2 and HA could promote the splenocyte proliferation, increase the activity of acid phosphatase in peritoneal macrophages and strengthen peritoneal macrophages to devour neutral red in vitro in a dose-dependent manner.
For assay in vivo, LMWHA-1 and LMWHA-2 significantly increased the indexes of spleen and thymus, the activity of lysozyme in serum and the swelling rate of earlap in delayed-type hypersensitivity in a dose-dependent manner. All these results suggested that LMWHA might be a potential natural immunomodulator and a potential candidate compd. Akerberg, Jonathan; Moon, James J. Here we report the development of a new cationic liposome-hyaluronic acid HA hybrid nanoparticle NP system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague.
Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. F1-V vaccine failed to achieve sero-conversion. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y. ACS Appl. Interfaces , 8 , — , DOI: In vivo expts.
The use of biodegradable nanoparticles as antigen delivery vehicles is an attractive approach to overcome the problems assocd. Herein we report, the design and development of protamine-based nanoparticles as novel antigen delivery systems, using recombinant hepatitis B surface antigen as a model viral antigen. The nanoparticles, composed of protamine and a polysaccharide hyaluronic acid or alginate , were obtained using a mild ionic crosslinking technique.
The size and surface charge of the nanoparticles could be modulated by adjusting the ratio of the components. Prototypes with optimal physicochem. In vitro studies showed that antigen-loaded nanoparticles induced the secretion of cytokines by macrophages more efficiently than the antigen in soln. Finally, in vivo studies showed the capacity of these systems to trigger efficient immune responses against the hepatitis B antigen following i. Correia-Pinto, J.
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The main objective of this work is to study the possibility of enveloping particulated antigens using biomaterials and polynucleotides with immunostimulant properties, and to assess the value of this potential adjuvant strategy. The nanoparticulate structure 22 nm of the recombinant Hepatitis B surface antigen rHBsAg has inspired us to use it as a substrate in the design of multi-enveloped nanoparticles. Our approach relies on the adsorption of polymers and immunostimulants by electrostatic interactions.
Considering the neg. With regard to the capacity of these new nanocompositions to elicit immune responses, the results obsd. Overall, this work highlights the possibility to protect antigens and modify their presentation using a simple layer-by-layer approach. Current research and development of antigens for vaccination often center on purified recombinant proteins, viral subunits, synthetic oligopeptides or oligosaccharides, most of them suffering from being poorly immunogenic and subject to degrdn. Hence, they call for efficient delivery systems and potent immunostimulants, jointly denoted as adjuvants.
Particulate delivery systems like emulsions, liposomes, nanoparticles and microspheres may provide protection from degrdn. Synthetic double-stranded ds RNA, such as polyriboinosinic acid-polyribocytidylic acid, poly I:C , is a mimic of viral dsRNA and, as such, a promising immunostimulant candidate for vaccines directed against intracellular pathogens. However, stability and toxicity issues so far prevented the clin. This review addresses these concerns and suggests strategies to improve the safety and efficacy of immunostimulatory dsRNA formulations. The focus is on technol. Prime-boost immunization with heterologous vaccines elicits potent cellular immunity.
Here, the authors show that the resulting succinimide thioether formed by the Michael-type addn. After ring-opening, the resultant succinimide thioether did not show retro and exchange reactions. The kinetics of the retro reactions and extent of exchange can be modulated by the Michael donor's reactivity; therefore, the degrdn. Such approaches may find a new niche for controlled release in reducing environments relevant in chemotherapy and subcellular trafficking. A general approach for forming peptide dendrimers with oxime, hydrazone, and thiazolidine linkages was developed using unprotected peptides as building blocks and selective ligation between an aldehyde and a weak base.
To illustrate the generality of this approach, a branched lysine core matrix with an aldehyde was used to ligate four copies of unprotected peptides contg. Various parameters affecting the ligations were studied, and optimal conditions gave fold rate increases and shortened the reaction time from to h.
Among the three reactions studied, ligation by thiazolidine appeared to be superior to ligation by oxime or hydrazone in reaction rate and product stability. Their macromol. CD spectra of the dendrimers showed that they have an increased ordered helical structure. Ligation reactions using a mutually reactive weak base and aldehyde pair should provide a useful approach for the synthesis of peptide dendrimers and artificial proteins. The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacol.
We report here the first clin. Incorporation of p-acetylphenylalanine pAcF at distinct locations in human growth hormone hGH allowed site-specific conjugation with polyethylene glycol PEG to produce homogeneous hGH variants. This example illustrates the utility of nonnative amino acids to optimize protein therapeutics in an analogous fashion to the use of medicinal chem.
Royal Society of Chemistry. Cyclopeptides have been recently used successfully as carriers for the multivalent presentation of carbohydrate and peptide antigens in immunotherapy. Beside their synthetic versatility, these scaffolds are indeed interesting due to their stability against enzyme degrdn. This mini-review highlights the recent advances in the utilization of cyclopeptides to prep. Nanoencapsulation of individual mammalian cells has great potential in biomedical, biotechnol.
However, existing techniques for cell nanoencapsulation generally yield short sustaining period and loose structure of encapsulation shell, which fails to meet the long-term cytoprotection and immunosuppression requirements. Here, we report a mild method to realize the nanoencapsulation of individual mammalian cells by layer-by-layer LbL assembly of gelatin inner layer and crosslinking of poly ethylene glycol PEG outer layer through thiol-click chem.
With the present method, the encapsulated individual HeLa cells showed a high viability, long persistence period and effective resistance against macro external entities and high phys. Moreover, on-demand cell release could also be achieved by selective cleavage of succinimide thioether linkage in the outer PEG layer. In vitro studies show that isoflurane and sevoflurane suppress NK cell cytotoxicity and cytokine-associated NK cell activation. Resident cells in tissues, such as alveolar macrophages, platelets, and glial cells, can also be affected by volatile anesthetics, thereby affecting the immune response.
Alveolar cells are in direct contact with volatile anesthetics. In rat alveolar type II cells in primary culture, isoflurane reduced cell secretions of interleukin-6, MIP-2, and monocyte chemoattractant protein-1, but did not change total protein secretion. Platelets also play a significant role in the immune response, as they are critical for cellular adhesion. After blood was incubated with 1 or 2 MAC sevoflurane for more than an hour, the binding of platelets to lymphocytes, neutrophils, and monocytes was enhanced, and the expression of P-selectin on platelets increased.
Microglia, which are resident neural immune cells, were recognized recently to contribute to neuroinflammation and postoperative delirium and cognitive decline. In cultured H4 human neuroglioma cells, isoflurane was found to induce caspase-3 activation, cause mitochondrial dysfunction, promote ROS accumulation, induce apoptosis, and reduce cell viability. In other studies, beneficial effects to reduce neuroinflammation are noted from preconditioning with volatile anesthetics.
Overall, because of the complexity of various tissue responses to volatile anesthetics, the anesthetic effects on innate immunity remain an active area of investigation. Adaptive immune responses are distinct from innate immunity because they are generated by clonal selection of lymphocytes. Given the variety of lymphocytes and the multiple mechanisms involved in their recognition and response to antigens, investigations into the impact of volatile anesthetics on the adaptive immune system have been challenging.
In general, volatile anesthetics induced a decrease in proliferation of lymphocytes or an increase in lymphocyte apoptosis. Cell-mediated immunity within the adaptive response includes T lymphocytes T cells , distinguished from other lymphocytes by the T-cell receptor, which can be modified and tailored for specific antigens. From that point, they circulate in the blood and throughout the secondary lymphoid tissues, such as lymph nodes, in search of antigens sequestered there by antigen-presenting cells that have traveled from infected sites.
Upon activation, T cells proliferate and differentiate. T helper T h cells remain in the lymph nodes. There are three subsets of T h cells: T h 1 cells that magnify inflammation via soluble protein secretion and macrophage stimulation; T h 2 cells that stimulate B lymphocytes to mature and produce antibodies; and the more recently discovered T h 17 cells that produce interleukin, interleukinF, and interleukin and secrete interleukin to communicate with the cells in the immune system.
Patients exposed to isoflurane or propofol had drastically different T-cell responses. Similar to T cells, B lymphocytes B cells can modify their cell surface receptors or immunoglobulins to recognize specific pathogens. A previous study implied that surgical trauma or associated perioperative conditions, not the specific anesthetic agent employed, was the dominant factor responsible for most postoperative specific humoral immunity impairment.
Complement-mediated immunity plays a role in both innate and adaptive immunity. It can act as an extension of the immunity provided by the B cells and the antibodies that they produce. To date, there are few reports concerning the effects of volatile anesthetics on the complement system. The combination of anesthesia and surgery was recognized as being associated with a decrease in complement levels, which may represent complement pathway activation. Volatile anesthetics can indirectly affect immunity through their impact on stress hormone levels as well as other effectors of immunity.
Stress is inherent in the perioperative setting and a known modulator of the immune system. The major stress hormones include endogenous glucocorticoid e. Surgery-induced inflammatory response and alteration in cell-mediated immunity were found to be more pronounced after a balanced volatile anesthesia when compared to total intravenous anesthesia.
These can, in turn, depress the T h 1 phenotype or promote cell-mediated immunity. Blood glucose levels were found to be higher in patients anesthetized with a combination of sevoflurane and fentanyl versus those anesthetized with propofol and fentanyl. Potential Mechanisms of Immunomodulation by Volatile Anesthetics. Although specific targets of volatile anesthetics in the immune system have not been well defined, molecular and cellular events involved in immune modulation by volatile anesthetics have been identified, including a reduction in the number of immune cells due to cell death and the suppression of immune activities fig.
In reality, with the heterogeneity in immune responses, immunomodulation is likely more complicated than what is shown in figure 2. For instance, cross talks may occur among different pathways, such as interactions between ROS and inducible nitric oxide synthase iNOS. Understanding individual pathways and their relationships will facilitate mechanistic understanding of immune modulation by volatile anesthetics. Potential mechanisms involved in the immunomodulation by volatile anesthetics VAs. Depicted here are schematic representations of major immunomodulation pathways affected by VAs.
The thick solid line shows the cytoplasmic membrane and the dashed line marks the nuclear membrane. The pink shaded areas are cytoplasmic and extracellular space, and the light purple shaded area is the cell nucleus. Lymphocytes are more prone to apoptosis than other immune cells. ROS is another major signaling molecule in the mitochondrial pathway for apoptosis. In addition to apoptosis, cell necrosis could also contribute to the isoflurane-induced decrease in immune cell count.
Adhesion molecules are important for immune cell recruitment and accumulation at inflammatory sites. The human leukocyte antigen heterodimers are cell surface antigen for the T-cell receptor. Volatile anesthetics may interact directly with these molecules to modify their functions or reduce their expression. Immune cell trafficking and penetration depend predominantly on integrin lymphocyte function—associated antigen-1 LFA As a result, immune cell adhesion is inhibited.
Structural biology approaches, combined with computational docking and mutations of key residues at the anesthetic binding site in LFA-1 and MAC-1, have shed new lights on how volatile anesthetic binding to a functionally important protein domain the so-called I domain in LFA-1 and the homologous MAC-1 can allosterically change the binding pocket at a remote location on these immune signaling proteins to change their interaction with intercellular adhesion molecule-1, thereby inhibiting the downstream events of leukocyte recruitment and migration.
Isoflurane and sevoflurane at clinical concentrations abolished the upward regulation of CD11b on neutrophils and resulted in reduced neutrophil adhesion. Volatile anesthetics mostly suppress, but in some cases up-regulate, iNOS expression and nitric oxide production. Isoflurane and desflurane at clinically relevant concentrations mediated the inhibitory effect on iNOS expression by inhibiting mobilization of cytosolic-free calcium, which occurred upon macrophage activation. Isoflurane, but not halothane, can activate p38 MAPK in a concentration-dependent manner.
Similarly, phosphorylation of ERK can activate the transcription factor cyclic adenosine monophosphate response element—binding protein, which in turn modulates many cyclic adenosine monophosphate response element—binding protein—targeted genes. Surgical intervention remains a primary treatment for cancer. Anesthetics used during the perioperative period may influence the immune system, directly affect cancer cells, and ultimately modify oncologic outcomes. Several retrospective studies suggested that, in comparison to general anesthesia, regional anesthesia was associated with better outcomes.
The beneficial effect of regional anesthesia on cancer recurrence was not observed in all types of cancer. In addition, in order to optimize anesthesia management strategies for oncologic surgical patients, more mechanistic studies at the cellular level are also needed. Positive Immune Modulation by Volatile Anesthetics.
The majority of studies reported thus far show that volatile anesthetics have immunosuppressive effects. Whether a short period of immunosuppression has a prolonged effect on patient outcomes merits further investigation. Well-controlled randomized clinical trials are highly desirable, although isolating effects of volatile anesthetics from other factors in a perioperative setting remains challenging.
Future studies should take into consideration the surgical procedures involved, the anesthetics and other medications used, and the time dependence in immune modulation and resolution. Because immunosuppression is in general detrimental for cancer patients, but potentially beneficial for septic patients, the choice of anesthesia regimens should be carefully evaluated in the overall planning for the perioperative care.
In vitro — and in vivo —level mechanistic studies focusing on how volatile anesthetics modulate various immune responses should continue. These studies not only can provide valuable clues to initiate more complex clinical trials, but also can identify useful biomarkers to detect the detrimental effects of volatile anesthetics.
Desirable off-label effects of volatile anesthetics have been demonstrated in a few areas, but on a large scale, they are underexplored. Tang and R01GM to Drs. Dou and Xu. The authors declare no competing interests. Nat Immunol. Iwasaki, A, Medzhitov, R Control of adaptive immunity by the innate immune system.. Can J Anaesth. Franks, NP General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal.. Nat Rev Neurosci. Trends Pharmacol Sci. Tang, P, Xu, Y Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: The implication of molecular mechanisms of general anesthesia..
Eur J Anaesthesiol. Curr Opin Anaesthesiol. Kurosawa, S, Kato, M Anesthetics, immune cells, and immune responses.. J Anesth. Curr Ther Res Clin Exp. Int J Clin Exp Pathol. Curr Pharm Des. Sci Total Environ. A nesthesiology. Br J Anaesth. Skickas inom vardagar. Laddas ned direkt. The articles represent papers by invited speakers as well as papers selected by the Scientific Council, from among those submitted by the participants, on the basis of quality and timeliness.
This symposium series was established in for the purpose of bringing together, once every two or three years, active investigators in the forefront of contemporary immunology, to present their findings, discuss their significance in the light of current concepts and identify important new directions of investigation.
The founding of the symposium was stimulated by the achievement of major breakthroughs in the understanding of the immune recognition of proteins and peptides. We believed that these breakthroughs would lead to the creation of a new generation of peptide reagents, which could have enormous potential in biological, therapeutic, and basic applications.
This anticipated explosion has since occurred and many applications ofthese peptides are now being realized. The eighth symposium focused on the manipulation or modulation of the immune response. This volume broadly covers the areas of adjuvants, cytokines, vaccines, and the use of intravenous immunoglobulins for disease management.