An Update on Human Papilloma Virus Vaccines: History, Types, Protection, and Efficacy.

Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide. Early prevention with HPV vaccination is a safe and effective method against this disease. HPV vaccines provided more protection against several oncogenic HPV strains. Three prophylactic HPV vaccines have been approved to target high-risk HPV types and protect against HPV-related disorders. These existing vaccines are based on the recombinant DNA technology and purified L1 protein that is assembled to form HPV empty shells. The prophylactic vaccines are highly immunogenic and can induce production of specific neutralizing antibodies. However, therapeutic vaccines are different from these prophylactic vaccines. They induced cell-mediated immunity against transformed cells, instead of neutralizing antibodies. The second generation of prophylactic HPV vaccines, made from alternative viral components using cost-effective production strategies, is undergoing clinical evaluation. The purpose of this review is to provide a complete and up-to-date review of the types of HPV vaccines and the efficiency of each of them for readers.

Effects of fostriecin on ß2-adrenoceptor-driven responses in human mast cells.

As part of the intracellular processes leading to mast cell and basophil activation, phosphorylation of key substrates is likely to be important. These processes, mediated by phosphatases, are responsible for regulating phosphorylation. The aim of the present study was to determine effects fostriecin - a selective inhibitor of PP2A (protein phosphatase-2) - on ß2-adrenoceptor-driven responses in human mast cells. Here, the effects of fostriecin (PP inhibitors) on the inhibition of histamine release from HLMC, on ß-adrenoceptor-driven responses in mast cells and on desensitization were investigated. Long-term incubation (24 h) of mast cells with fostriecin (10-6 M) resulted in a significant (p < 0.001) reduction in the maximal response (from 41.2 [± 3.0] to 29.9 [± 4.2] %) to salbutamol following fostriecin treatment. The results showed that fostriecin pretreatment significantly attenuated the inhibitory effects of salbutamol. Overall, the present study suggested that PP2A has an important role in regulating mast cell ß2-adrenoceptors.

Cyclic nucleotide phosphodiesterase isoforms in human basophils and mast cells.

Cyclic nucleotide phosphodiesterase (PDE) exists as multiple molecular forms. Of the 11 families of PDE identified so far, PDE4, a cAMP-specific PDE, has been identified as the major isoform regulating inflammatory activity. The principle aim of the present study was to determine whether human basophils and human lung mast cells express PDE4. Four sub-classes of PDE4 (A, B, C, and D) have been identified and expression of these was determined by RT-CPR and by western blotting. In basophils, prominent expression of mRNA for PDE4A and PDE4D was observed whereas little if any expression of PDE4B and PDE4C was detected. These findings were paralleled by immunoblotting experiments as human basophils were found to express PDE4A and PDE4D with little evidence for the presence of either PDE4B or PDE4C. By contrast, human lung mast cells expressed very little, if any, mRNA for PDE4 sub-classes although, in some preparations, some modest levels of mRNA for PDE4D were detected. However, there was no evidence, at the protein level, that mast cells express PE4. Overall, these data indicate that basophils express PDE4 (4A and 4D) whereas human lung mast cells do not.

A short review on structure and role of cyclic-3',5'-adenosine monophosphate-specific phosphodiesterase 4 as a treatment tool.

Cyclic nucleotide phosphodiesterases (PDEs) are known as a super-family of enzymes which catalyze the metabolism of the intracellular cyclic nucleotides, cyclic-3',5'-adenosine monophosphate (cAMP), and cyclic-3',5'-guanosine monophosphate that are expressed in a variety of cell types that can exert various functions based on their cells distribution. The PDE4 family has been the focus of vast research efforts over recent years because this family is considered as a prime target for therapeutic intervention in a number of inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis, and it should be used and researched by pharmacists. This is because the major isoform of PDE that regulates inflammatory cell activity is the cAMP-specific PDE, PDE4. This review discusses the relationship between PDE4 and its inhibitor drugs based on structures, cells distribution, and pharmacological properties of PDE4 which can be informative for all pharmacy specialists.

The effect of cyclic nucleotide analog drugs on the mediators release from basophils.

BACKGROUND: The cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are intracellular second messengers that play an important role in modulating inflammatory cells involved in allergic diseases. In general, cAMP suppresses the activity of immune and inflammatory cells. We aim to evaluate the roles of cAMP and cGMP in regulating basophil activity. MATERIALS AND METHODS: Basophil-enriched preparations were incubated with analogs and then challenged with anti-IgE or IL-3 (4 or 24 hours). Supernatants were assayed for histamine, IL-4, and IL-13 release. The effects of Sp-8-CPT-cAMPS and Sp-8-CPT-cGMPS on IL-3-dependent mediator release from basophils were determined. The cells were pre-incubated with an analog and then incubated with IL-3 for 24 hours. RESULTS: Sp-8-CPT-cAMPS was an effective (P < 0.05) inhibitor of IL-4, IL-13, and histamine release from basophils. However, paradoxically, Sp-8-CPT-cGMPS enhanced histamine release and IL-13 generation, but by contrast, had little effect on IL-4 generation. Sp-8-CPT-cGMPS inhibited cytokine generation, but enhanced the release of histamine release to a modest extent. CONCLUSION: This study shows that the cAMP/protein kinase A (PKA) pathway may be inhibitory to the IgE- and non-IgE-dependent release of mediators from basophils.

Role of protein phosphatases inhibitors on the histamine release and the functional desensitization in human lung mast cells.

BACKGROUND: The ß2-adrenoceptor agonist, isoprenaline, is an effective inhibitor of histamine release from human lung mast cells (HLMC). Since phosphorylations of the ß2-adrenoceptors are probably important in inducing desensitization, we sought to investigate the importance of phosphorylation events by targeting protein phosphatases (PPs) in mast cells. To this end, the effects of the inhibitor of on the functional desensitization of ß-adrenoceptor-mediated responses in mast cells were investigated. MATERIALS AND METHODS: In this study the effects of PP inhibitors on the inhibition of histamine release from HLMC, on ß-agonists in mast cells and on desensitization were investigated. RESULTS: Long-term exposure of mast cells to both isoprenaline and salbutamol substantially reduced the extent to which isoprenaline inhibited histamine release. Pretreatments of up to 24 h with inhibitors alone had no effect on immunoglobulin E-mediated histamine release. Shorter (≤4 h) pretreatments had little effect on the activity of isoprenaline and salbutamol to inhibit histamine release from mast cells. CONCLUSION: Collectively, these data suggest that PP has an important role in regulating mast cell ß2-adrenoceptors.

Evaluation of the correlation and reproducibility between histamine, IL-4, and IL-13 release from human basophils.

Human basophils play a key role in allergic diseases such as asthma and in a variety of immunological disorders. The generation of IL-4 and IL-13 can be induced from basophil by IgE-mediated and non-IgE-mediated mechanisms. Time and stimulus-dependent differences in the regulation of these cytokines could have relevance to their biological effects. The aim of the present study was activation of basophils in order to evaluate the extent of histamine, IL-4, and IL-13 generations. Basophil-enriched suspensions were prepared by Percoll gradients. The release of histamine and cytokines was assessed after activation with either anti-human IgE (1/1000 or 1/10000, 4 h or 24 h) or IL-3 (100 ng/ ml, 24 h). Results were analysed statistically, using ANOVA test. Using anti-IgE, there was no significant correlation between the extent of either IL-4 (r=0.24, p=0.35) or IL-13 (r=0.47, p=0.098) and histamine release. Using IL-3 as stimulator, results showed that the extent of IL-13 correlated with histamine release(r=0.44, p=0.036). There was no correlation between the extent of IL-4 and the degree of either histamine (r=0.077, p=0.72) or IL-13 (r=0.162, p=0.5). The reproducibility of cytokines isolated from the same donor (on different occasions) indicated that the ability of anti-IgE to induce cytokines was consistently similar for a given donor. Our data showed that the pathways leading to IL-3-triggering histamine release and IL-13 generation show similarity. Donor-dependent differences may be responsible for this wide range in the extent of releasibility. The ability of IL-3 to release cytokines from basophils showed a wider range.