Peripheral-specific y2 receptor knockdown protects mice from high-fat diet-induced obesity.

Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone.

The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer.

The neuropeptide Y (NPY) system--comprising of neuropeptide Y, peptide YY, pancreatic polypeptide and the corresponding Y receptors through which they act (Y1, Y2, Y4, Y5 and y6)--is well known for its role in the regulation of energy homeostasis and associated processes. Dysfunctions of the system have been implicated in human diseases such as obesity and cancer, raising the possibility that correction of the system may provide therapeutic benefits for these diseases. In addition to the regulation of appetite and satiety that has attracted most attention during the past years, insight has also been gained into the critical role of NPY in the control of energy expenditure, oxidative fuel selection and bone metabolism.

Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation.

Anti-tumor vaccines consisting of extended CTL peptides in combination with CpG-ODN were shown to be superior to those comprising minimal CTL epitopes and CpG-ODN, in that they elicit stronger effector CTL responses with greater tumoricidal potential. We now demonstrate that this improved performance is primarily due to the focusing of CTL epitope presentation onto activated DC in the inflamed lymph nodes draining the vaccination site. In the case of vaccination with minimal peptides, additional APC including T and B cells are also loaded with CTL epitopes.

CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity.

Therapeutic vaccination trials, in which patients with cancer were vaccinated with minimal CTL peptide in oil-in-water formulations, have met with limited success. Many of these studies were based on the promising data of mice studies, showing that vaccination with a short synthetic peptide in IFA results in protective CD8(+) T cell immunity. By use of the highly immunogenic OVA CTL peptide in IFA as a model peptide-based vaccine, we investigated why minimal CTL peptide vaccines in IFA performed so inadequately to allow full optimization of peptide vaccination.

Design and development of synthetic peptide vaccines: past, present and future.

Synthetic peptide vaccines aiming at the induction of a protective CD8(+) T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal models, they do not yet live up to their promise in humans. This review assesses the development of synthetic peptide vaccines, weighs it against the immunological concepts that have emerged, and identifies the key issues that play a role in the failure or success of a synthetic peptide vaccine. The current state-of-the-art peptide vaccine is a complete synthetic inflammatory product that is ingested by professional antigen-presenting cells and stimulates both CD4(+) and CD8(+) T cells.

Distinct uptake mechanisms but similar intracellular processing of two different toll-like receptor ligand-peptide conjugates in dendritic cells.

Covalent conjugation of Toll-like receptor ligands (TLR-L) to synthetic antigenic peptides strongly improves antigen presentation in vitro and T lymphocyte priming in vivo. These molecularly well defined TLR-L-peptide conjugates, constitute an attractive vaccination modality, sharing the peptide antigen and a defined adjuvant in one single molecule. We have analyzed the intracellular trafficking and processing of two TLR-L conjugates in dendritic cells (DCs).

Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells.

The concept of tumor surveillance implies that specific and nonspecific components of the immune system eliminate tumors in the early phase of malignancy. Understanding the biochemical mechanisms of tumor immunosurveillance is of paramount significance because it might allow one to specifically modulate spontaneous antitumor activity. We report that inactivation of the E3 ligase Casitas B cell lymphoma-b (Cbl-b) confers spontaneous in vivo rejection of tumor cells that express human papilloma virus antigens.

Multiple CD4 and CD8 T-cell activation parameters predict vaccine efficacy in vivo mediated by individual DC-activating agonists.

A systematic comparison of the immunostimulatory capacity of TLR 2, 3, 4, 5, 7 and 9 agonists and an agonistic CD40-specific antibody was performed in a single long peptide vaccination model. All adjuvants activated DC in vitro but not all induced a strong functional T-cell response in vivo. Optimal clonal CD8(+) T-cell expansion depended on the capacity of agonists to mature pro-inflammatory DC and the duration of their in vivo stimulatory effect.

Improved peptide vaccine strategies, creating synthetic artificial infections to maximize immune efficacy.

Soon after it was realized that T-cells recognize their target antigens as small protein fragments or peptides presented by MHC molecules at the cell surface, these peptide epitopes have been tried as vaccines. Human testing of such vaccines, although protective in mouse models, has produced mixed results. Since these initial trials, there has been an tremendous increase in our understanding of how infectious organisms can induce potent immune responses.

Dynamic programming of CD8+ T lymphocyte responses.

The initial encounter with an antigen-presenting cell (APC) is the primary force behind the expansion, differentiation and survival of naive T cells. Using an APC that permits temporal control of priming, we examined whether the duration of antigenic stimulation can influence the functional development of CD8+ cytotoxic T lymphocytes (CTLs) in vivo. Whereas CTLs given a 4-h stimulus underwent an abortive clonal expansion with transient surface CD25 expression, those given a 20-h stimulus sustained CD25 up-regulation, proliferated extensively, and efficiently mediated destruction of peripheral target tissues.