Alum/Toll-Like Receptor 7 Adjuvant Enhances the Expansion of Memory B Cell Compartment Within the Draining Lymph Node.

Vaccination is one of the most cost-effective health interventions and, with the exception of water sanitization, no other action has had such a major effect in mortality reduction. Combined with other approaches, such as clean water, better hygiene, and health education, vaccination contributed to prevent millions of cases of deaths among children under 5 years of age. New or improved vaccines are needed to fight some vaccine-preventable diseases that are still a threat for the public health globally, as reported also in the Global Vaccine Action Plan (GVAP) endorsed by the World Health Assembly in 2012. Adjuvants are substances that enhance the effectiveness of vaccination, but despite their critical role for the development of novel vaccines, very few of them are approved for use in humans. Aluminum hydroxide (Alum) is the most common adjuvant used in vaccines administered in millions of doses around the world to prevent several dangerous diseases. The development of an improved version of Alum can help to design and produce new or better vaccines. Alum/toll-like receptor (TLR)7 is a novel Alum-based adjuvant, currently in phase I clinical development, formed by the attachment of a benzonaphthyridine compound, TLR7 agonist, to Alum. In preclinical studies, Alum/TLR7 showed a superior adjuvant capacity, compared to Alum, in several disease models, such as meningococcal meningitis, anthrax, staphylococcus infections. None of these studies reported the effect of Alum/TLR7 on the generation of the B cell memory compartment, despite this is a critical aspect to achieve a better immunization. In this study, we show, for the first time, that, compared to Alum, Alum/TLR7 enhances the expansion of the memory B cell compartment within the draining lymph node (LN) as result of intranodal sustained proliferation of antigen-engaged B cells and/or accumulation of memory B cells. In addition, we observed that Alum/TLR7 induces a recruitment of naïve antigen-specific B cells within the draining LN that may help to sustain the germinal center reaction. Our data further support Alum/TLR7 as a new promising adjuvant, which might contribute to meet the expectations of the GVAP for 2020 and beyond.

Immune-modulation and properties of absorption and blood brain barrier permeability of 1,8-naphthyridine derivatives.

Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosis.