scholarly journals Small Molecule Potentiator of Adjuvant Activity Enhancing Survival to Influenza Viral Challenge

2021 ◽  
Vol 12 ◽  
Author(s):  
Tetsuya Saito ◽  
Yukiya Sako ◽  
Fumi Sato-Kaneko ◽  
Tadashi Hosoya ◽  
Shiyin Yao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
High Titer ◽  
Adjuvant Activity ◽  
Murine Bone Marrow ◽  
Virus Challenge ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Ligand

As viruses continue to mutate the need for rapid high titer neutralizing antibody responses has been highlighted. To meet these emerging threats, agents that enhance vaccine adjuvant activity are needed that are safe with minimal local or systemic side effects. To respond to this demand, we sought small molecules that would sustain and improve the protective effect of a currently approved adjuvant, monophosphoryl lipid A (MPLA), a Toll-like receptor 4 (TLR4) agonist. A lead molecule from a high-throughput screen, (N-(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide, was identified as a hit compound that sustained NF-κB activation by a TLR4 ligand, lipopolysaccharide (LPS), after an extended incubation (16 h). In vitro, the resynthesized compound (2D216) enhanced TLR4 ligand-induced innate immune activation and antigen presenting function in primary murine bone marrow-derived dendritic cells without direct activation of T cells. In vivo murine vaccination studies demonstrated that compound 2D216 acted as a potent co-adjuvant when used in combination with MPLA that enhanced antigen-specific IgG equivalent to that of AS01B. The combination adjuvant MPLA/2D216 produced Th1 dominant immune responses and importantly protected mice from lethal influenza virus challenge. 2D216 alone or 2D216/MPLA demonstrated minimal local reactogenicity and no systemic inflammatory response. In summary, 2D216 augmented the beneficial protective immune responses of MPLA as a co-adjuvant and showed an excellent safety profile.

Expression of human adenosine deaminase in murine hematopoietic cells

1988 ◽  
Vol 8 (12) ◽  
pp. 5116-5125
Author(s):  
J W Belmont ◽  
G R MacGregor ◽  
K Wager-Smith ◽  
F A Fletcher ◽  
K A Moore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adenosine Deaminase ◽  
High Titer ◽  
Virus Production ◽  
Marrow Transplant ◽  
Mouse Bone Marrow ◽  
Regulation Of Expression ◽  
Murine Bone Marrow

Multiple replication-defective retrovirus vectors were tested for their ability to transfer and express human adenosine deaminase in vitro and in vivo in a mouse bone marrow transplantation model. High-titer virus production was obtained from vectors by using both a retrovirus long terminal repeat promoter and internal transcriptional units with human c-fos and herpes virus thymidine kinase promoters. After infection of primary murine bone marrow with one of these vectors, human adenosine deaminase was detected in 60 to 85% of spleen colony-forming units and in the blood of 14 of 14 syngeneic marrow transplant recipients. This system offers the opportunity to assess methods for increasing efficiency of gene transfer, for regulation of expression of foreign genes in hematopoietic progenitors, and for long-term measurement of the stability of expression in these cells.

scholarly journals The Combinations Chitosan-Pam3CSK4 and Chitosan-Monophosphoryl Lipid A: Promising Immune-Enhancing Adjuvants for Anticaries Vaccine PAc

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Yongli Bi ◽  
Qingan Xu ◽  
Lingkai Su ◽  
Jiantao Xu ◽  
Zhongfang Liu ◽  
...  
Keyword(s):  
Lipid A ◽  
Vaccine Development ◽  
Protection Effect ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Tooth Surfaces ◽  
Antibody Titers

ABSTRACT We previously demonstrated that recombinant protein PAc could be administered as an anticaries vaccine. However, the relatively weak immunogenicity of PAc limits its application. In the present study, we investigated the effect of two adjuvant combinations of chitosan plus Pam3CSK4 (chitosan-Pam3CSK4) and of chitosan plus monophosphoryl lipid A (chitosan-MPL) in the immune responses to the PAc protein in vivo and in vitro. PAc-chitosan-Pam3CSK4 or PAc-chitosan-MPL promoted significantly higher PAc-specific antibody titers in serum and saliva, inhibited Streptococcus mutans colonization onto the tooth surfaces, and endowed better protection effect with significantly less caries activities than PAc alone. Chitosan-Pam3CSK4 and chitosan-MPL showed no statistically significant differences. In conclusion, our study demonstrated that the chitosan-Pam3CSK4 and chitosan-MPL combinations are promising for anticaries vaccine development.

scholarly journals Influence of Epinastine Hydrochloride, an -Receptor Antagonist, on the Function of Mite Allergen-Pulsed Murine Bone Marrow-Derived Dendritic Cells In Vitro and In Vivo

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Ken-Zaburo Oshima ◽  
Kazuhito Asano ◽  
Ken-Ichi Kanai ◽  
Miyuki Suzuki ◽  
Harumi Suzaki
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Clinical Status ◽  
Mouse Bone Marrow ◽  
Dc Functions ◽  
Receptor Antagonists ◽  
Murine Bone Marrow

There is established concept that dendritic cells (DCs) play essential roles in the development of allergic immune responses. However, the influence of receptor antagonists on DC functions is not well defined. The aim of the present study was to examine the effect of epinastine hydrochloride (EP), the most notable histamine receptor antagonists in Japan, onDermatophagoides farinae (Der f)-pulsed mouse bone marrow-derived DCs in vitro and in vivo. EP at more than 25 ng/mL could significantly inhibit the production of IL-6, TNF- and IL-10 fromDer f-pulsed DCs, which was increased byDer fchallenge in vitro. On the other hand, EP increased the ability ofDer f-pulsed DCs to produce IL-12. Intranasal instillation ofDer f-pulsed DCs resulted in nasal eosinophilia associated with a significant increase in IL-5 levels in nasal lavage fluids.Der f-pulsed and EP-treated DCs significantly inhibited nasal eosinophila and reduced IL-5. These results indicate that EP inhibits the development of Th2 immune responses through the modulation of DC functions and results in favorable modification of clinical status of allergic diseases.

scholarly journals A Live Attenuated Equine Infectious Anemia Virus Proviral Vaccine with a Modified S2 Gene Provides Protection from Detectable Infection by Intravenous Virulent Virus Challenge of Experimentally Inoculated Horses

2003 ◽  
Vol 77 (13) ◽  
pp. 7244-7253 ◽  
Author(s):  
Feng Li ◽  
Jodi K. Craigo ◽  
Laryssa Howe ◽  
Jonathan D. Steckbeck ◽  
Sheila Cook ◽  
...  
Keyword(s):  
Immune Responses ◽  
Equine Infectious Anemia Virus ◽  
High Dose ◽  
Accessory Gene ◽  
Virus Challenge ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Vaccine Immunity

ABSTRACT Previous evaluations of inactivated whole-virus and envelope subunit vaccines to equine infectious anemia virus (EIAV) have revealed a broad spectrum of efficacy ranging from highly type-specific protection to severe enhancement of viral replication and disease in experimentally immunized equids. Among experimental animal lentivirus vaccines, immunizations with live attenuated viral strains have proven most effective, but the vaccine efficacy has been shown to be highly dependent on the nature and severity of the vaccine virus attenuation. We describe here for the first time the characterization of an experimental attenuated proviral vaccine, EIAVUKΔS2, based on inactivation of the S2 accessory gene to down regulate in vivo replication without affecting in vitro growth properties. The results of these studies demonstrated that immunization with EIAVUKΔS2 elicited mature virus-specific immune responses by 6 months and that this vaccine immunity provided protection from disease and detectable infection by intravenous challenge with a reference virulent biological clone, EIAVPV. This level of protection was observed in each of the six experimental horses challenged with the reference virulent EIAVPV by using a low-dose multiple-exposure protocol (three administrations of 10 median horse infectious doses [HID50], intravenous) designed to mimic field exposures and in all three experimentally immunized ponies challenged intravenously with a single inoculation of 3,000 HID50. In contrast, naïve equids subjected to the low- or high-dose challenge develop a detectable infection of challenge virus and acute disease within several weeks. Thus, these data demonstrate that the EIAV S2 gene provides an optimal site for modification to achieve the necessary balance between attenuation to suppress virulence and replication potential to sufficiently drive host immune responses to produce vaccine immunity to viral exposure.

scholarly journals STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

2018 ◽  
Vol 30 (8) ◽  
pp. 385-385
Author(s):  
Sanjay Varikuti ◽  
Steve Oghumu ◽  
Gayathri Natarajan ◽  
Jennifer Kimble ◽  
Rachel H Sperling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Th1 And Th2

scholarly journals Biological Activities of Anti-Merozoite Surface Protein-1 Antibodies Induced by Adjuvant-Assisted Immunizations in Mice with Different Immune Gene Knockouts

2008 ◽  
Vol 15 (8) ◽  
pp. 1145-1150 ◽  
Author(s):  
George Hui ◽  
Dan Choe ◽  
Caryn Hashimoto
Keyword(s):  
Lipid A ◽  
Biological Activities ◽  
Merozoite Surface Protein ◽  
Intercellular Adhesion Molecule ◽  
Immune Gene ◽  
Intercellular Adhesion Molecule 1 ◽  
Inhibitory Antibody ◽  
Monophosphoryl Lipid A

ABSTRACT Immunizations with Plasmodium falciparum MSP1-42 or MSP1-19 induce antibodies that inhibit parasites in vitro, which correlates with in vivo protective immunity by vaccination. We previously showed that several adjuvant formulations can induce anti-MSP1-19 antibodies in interleukin-6, intercellular adhesion molecule 1, CD80, and CD86 knockout (KO) mice and at levels similar to those obtained in the healthy uninfected hosts. Here, we determine whether these immune gene KOs or the immunopotentiating activities of the adjuvants have a more important influence on the induction of parasite-inhibitory anti-MSP1-19 antibodies. Results showed that the biological activities of the anti-MSP1-19 antibodies induced by these adjuvants were not affected by the immune gene KOs. All adjuvant formulations that induced significant inhibitory antibody responses (i.e., >50% inhibition of parasite growth) contained monophosphoryl lipid A (MPL) in emulsion carriers, whereas MPL or emulsion carriers alone were ineffective. The ability to retain vaccine efficacy by the MSP1-19 and adjuvant formulations in the altered immunological background is a valuable and significant attribute in light of many instances of skewed immune status in the targeted vaccine populations.

scholarly journals Expression of human adenosine deaminase in murine hematopoietic cells.

1988 ◽  
Vol 8 (12) ◽  
pp. 5116-5125 ◽  
Author(s):  
J W Belmont ◽  
G R MacGregor ◽  
K Wager-Smith ◽  
F A Fletcher ◽  
K A Moore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adenosine Deaminase ◽  
High Titer ◽  
Virus Production ◽  
Marrow Transplant ◽  
Mouse Bone Marrow ◽  
Regulation Of Expression ◽  
Murine Bone Marrow

Multiple replication-defective retrovirus vectors were tested for their ability to transfer and express human adenosine deaminase in vitro and in vivo in a mouse bone marrow transplantation model. High-titer virus production was obtained from vectors by using both a retrovirus long terminal repeat promoter and internal transcriptional units with human c-fos and herpes virus thymidine kinase promoters. After infection of primary murine bone marrow with one of these vectors, human adenosine deaminase was detected in 60 to 85% of spleen colony-forming units and in the blood of 14 of 14 syngeneic marrow transplant recipients. This system offers the opportunity to assess methods for increasing efficiency of gene transfer, for regulation of expression of foreign genes in hematopoietic progenitors, and for long-term measurement of the stability of expression in these cells.

scholarly journals Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2056-2065 ◽  
Author(s):  
Jennifer Carlring ◽  
Marika J. Szabo ◽  
Robert Dickinson ◽  
Evy De Leenheer ◽  
Andrew W. Heath
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lipid A ◽  
Keyhole Limpet Hemocyanin ◽  
Potential Candidate ◽  
Antitumor Effects ◽  
Gm Csf ◽  
Humoral Immune ◽  
Monophosphoryl Lipid A

AbstractPersonalized immunotherapy of lymphoma based on tumor idiotype (Id) has shown anti-idiotype humoral immune responses in 40%-50% and cellular immune responses in 50%-75% of follicular lymphoma patients, indicating that this therapy can be clinically successful. We have developed a novel vaccine against lymphoma consisting of an anti-CD40 Ab (ADX40) chemically conjugated to the tumor idiotype A20 and tested it in a murine lymphoma model. BALB/c mice were immunized with 2 doses of immunogen alone or in conjunction with additional adjuvants before tumor challenge. ADX40-Id vaccination resulted in significantly retarded tumor growth and reduced mouse morbidity. Moreover, similar mouse survival was obtained with 2 injections of ADX40-Id as with 8 injections using the standard therapy of keyhole limpet hemocyanin Id + GM-CSF. Co-administration of ADX40-Id with 3-O-deacyl-4′-monophosphoryl lipid A further significantly enhanced vaccine efficacy, resulting in an increased overall survival. Anti-Id–specific Abs were detected at elevated levels after ADX40-Id immunization; however, in vivo depletion of CD4 and/or CD8 T cells before challenge showed that CD8 effector T cells were the major mediators of tumor protection. The results of the present study show that the ADX40-Id conjugate vaccine is a potential candidate as a stand-alone vaccine or in combination with currently licensed adjuvants for lymphoma immunotherapy.

scholarly journals STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

2016 ◽  
Vol 28 (11) ◽  
pp. 565-570 ◽  
Author(s):  
Sanjay Varikuti ◽  
Steve Oghumu ◽  
Gayathri Natarajan ◽  
Jennifer Kimble ◽  
Rachel H. Sperling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Th1 And Th2

scholarly journals Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1118 ◽  
Author(s):  
Chen Chen ◽  
Chengguang Zhang ◽  
Ruiming Li ◽  
Zongmei Wang ◽  
Yueming Yuan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Lipid A ◽  
Survival Ratio ◽  
Effective Measure ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

Rabies, as one of the most threatening zoonoses in the world, causes a fatal central nervous system (CNS) disease. So far, vaccination with rabies vaccines has been the most effective measure to prevent and control this disease. At present, inactivated rabies vaccines are widely used in humans and domestic animals. However, humoral immune responses induced by inactivated rabies vaccines are relatively low and multiple shots are required to achieve protective immunity. Supplementation with an adjuvant is a practical way to improve the immunogenicity of inactivated rabies vaccines. In this study, we found that monophosphoryl-lipid A (MPLA), a well-known TLR4 agonist, could significantly promote the maturation of bone marrow-derived dendritic cells (BMDC) through a TLR4-dependent pathway in vitro and the maturation of conventional DCs (cDCs) in vivo. We also found that MPLA, serving as an adjuvant for inactivated rabies vaccines, could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs), consequently enhancing the production of RABV-specific total-IgG, IgG2a, IgG2b, and the virus-neutralizing antibodies (VNAs). Furthermore, MPLA could increase the survival ratio of mice challenged with virulent RABV. In conclusion, our results demonstrate that MPLA serving as an adjuvant enhances the intensity of humoral immune responses by activating the cDC–Tfh–GC B axis. Our findings will contribute to the improvement of the efficiency of traditional rabies vaccines.

Sign in / Sign up

Export Citation Format

Share Document