Modulation of Phenotype and Function of Human CD4CD25 T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents.

We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4 T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4CD25 T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4CD25 and further enhance its expression in CD4CD25 T cells.

Human monocytes respond to extracellular cAMP through A2A and A2B adenosine receptors.

In this study, we test the hypothesis that cAMP, acting as an extracellular mediator, affects the physiology and function of human myeloid cells. The cAMP is a second messenger recognized as a universal regulator of several cellular functions in different organisms. Many studies have shown that extracellular cAMP exerts regulatory functions, acting as first mediator in multiple tissues.

The Innovative Medicines Initiative moves translational immunology forward.

The Innovative Medicines Initiative (IMI) was established in 2008 as a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations with the mission to promote the development of novel therapies through collaborative efforts based on the concept of pre-competitive research. Several consortia supported by IMI are dedicated to immuno-inflammatory disorders, immune-based biopharmaceuticals and vaccines. Herein, we present the key principles underlying IMI, briefly review the status of projects related to translational immunology, and present future topics of interest to immunologists.

Cholera toxin impairs the differentiation of monocytes into dendritic cells, inducing professional antigen-presenting myeloid cells.

Cholera toxin (CT) is a potent adjuvant for mucosal vaccination; however, its mechanism of action has not been clarified completely. It is well established that peripheral monocytes differentiate into dendritic cells (DCs) both in vitro and in vivo and that monocytes are the in vivo precursors of mucosal CD103(-) proinflammatory DCs. In this study, we asked whether CT had any effects on the differentiation of monocytes into DCs.

Persistence of mucosal and systemic immune responses following sublingual immunization.

The development of mucosal vaccines for prevention of infectious diseases caused by pathogens entering through the mucosal surfaces is an important and challenging objective. To this purpose, we evaluated the efficacy and durability of immune response induced by sublingual immunization with tetanus toxoid (TT) as an antigen in the presence of mucosal adjuvants, such as E. coli Heat-Labile enterotoxin (LT) or the mutant of LT lacking ADP ribosyltransferase activity (LTK63).

Development of antigen-specific T cells in mediastinal lymph nodes after intranasal immunization.

The power of cholera toxin (CT) as an effective mucosal adjuvant is well established. Because of the high toxicity of CT, its clinical use is unlikely. Therefore, the need to identify effective and non toxic mucosal adjuvants for human use is important.

Cholera toxin and Escherichia coli heat-labile enterotoxin, but not their nontoxic counterparts, improve the antigen-presenting cell function of human B lymphocytes.

B lymphocytes play an important role in the immune response induced by mucosal adjuvants. In this study we investigated the in vitro antigen-presenting cell (APC) properties of human B cells upon treatment with cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) and nontoxic counterparts of these toxins, such as the B subunit of CT (CT-B) and the mutant of LT lacking ADP ribosyltransferase activity (LTK63). Furthermore, forskolin (FSK), a direct activator of adenylate cyclase, and cyclic AMP (cAMP) analogues were used to investigate the role of the increase in intracellular cAMP caused by the A subunit of CT and LT.

Inhibition of T cell proliferation by cholera toxin involves the modulation of costimulatory molecules CTLA-4 and CD28.

Cholera toxin (CT) is known to inhibit the proliferation of murine and human T lymphocytes. In this study we have analysed the mechanisms underlying the inhibitory effect of CT on subpopulations of human CD4+ and CD8+ T lymphocytes. We show that CT dramatically prevents the activation of resting T lymphocytes, whereas it has a minor effect on cells that have been previously activated.

Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP.

We have previously shown that cholera toxin (CT) and other cAMP-elevating agents induce up-regulation of the inhibitory molecule CTLA-4 on human resting T lymphocytes. In this study, we evaluated the function of these cells. We found that purified human CD4(+) T lymphocytes pretreated with CT were able to inhibit proliferation of autologous PBMC in a dose-dependent manner.

Zonula occludens toxin as a new promising adjuvant for mucosal vaccines.

Cholera toxin (CT) and CT-related molecules have been known since a long time to act as powerful mucosal adjuvants. We have studied the stimulatory effects of CT on human dendritic cells and its inhibitory activity on T lymphocytes. We have also identified a third bacterial enterotoxin, Zonula occludens toxin (Zot) that acts as an effective mucosal adjuvant.

Mucosal delivery of vaccine antigens and its advantages in pediatrics.

The delivery of vaccines through the mucosal route is very practical, non-invasive and efficacious for the induction of mucosal and systemic immune responses. Appropriately formulated mucosal vaccines can stimulate all arms of the immune system and could be exploited for protection against pathogens that infect the host through the mucosal surfaces as well as those acquired through other routes. There are few available mucosal vaccines so far and these are mainly based on whole microorganisms.

Mucosal delivery of the human immunodeficiency virus-1 Tat protein in mice elicits systemic neutralizing antibodies, cytotoxic T lymphocytes and mucosal IgA.

Human immunodeficiency virus (HIV)-1 Tat protein induces protection in non-human primates upon systemic vaccination. In view of the design of mucosal vaccines against HIV-1 we studied the immune response to native Tat (aa 1-86) in mice following intranasal delivery of the protein with two mucosal adjuvants, Escherichia coli heat-labile enterotoxin (LT) and LT-R72, a non-toxic mutant of LT. Immunization with Tat and the two adjuvants induced in BALB/c but not in C57BL/6 mice high and persistent levels of serum IgG and secretory IgA in vaginal and intestinal fluids.

Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses.

Zonula occludens toxin (Zot) is produced by Vibrio cholerae and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions. Because of this property, Zot is a promising tool for mucosal drug and antigen (Ag) delivery. Here we show that Zot acts as a mucosal adjuvant to induce long-lasting and protective immune responses upon mucosal immunization of mice.

Maturation of human dendritic cells induced by the adjuvant cholera toxin: role of cAMP on chemokine receptor expression.

Cholera toxin (CT) is a very effective adjuvant for mucosal vaccination. It binds to cells through its B subunit and induces intracellular increase of cAMP through the A subunit. We previously showed that CT induces maturation of human dendritic cells (DCs) and this may account for its adjuvant property.

Cyclic adenosine 5'-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4+ T lymphocytes.

The CTLA-4 (CD152) molecule is up-regulated upon T cell activation and proliferation, and plays a critical role in the inhibition of immune responses. We show in this study that cAMP induces up-regulation of CD152 in human CD4(+) T lymphocytes. This effect occurs in the absence of the up-regulation of CD69 and CD25 activation markers and T cell proliferation.