Rhipicephalus sanguineus salivary gland extract as a source of immunomodulatory molecules.

Rhipicephalus sanguineus sensu lato (s.l.), popularly known as 'brown dog tick', is the primary vector of pathogens affecting dogs worldwide. To enter the host's organism, these pathogens utilise the anticoagulant, antiplatelet, anti-inflammatory and immunomodulatory actions of compounds present in the tick's saliva; such compounds are released by the ectoparasite in order to attach and feed on dogs. Nitric oxide (NO) is one of the regulatory factors in inflammation, apoptosis and immunomodulation. Here, we evaluated the in vitro activity of salivary gland extract of female dog ticks on the macrophage-derived J774 cell line, with and without lipopolysaccharide (LPS) stimulation. Cultures were evaluated for possible morphological alterations caused by exposure to the extract. There was no apparent in vitro cytotoxicity of the extract. Also, the NO secretory response in the non-LPS-stimulated cells was not inhibited. On the other hand, the extract presented modulatory action in the cultures of LPS-stimulated cells at a concentration of 0.1 µg/mL, possibly through macrophage activation, and induced a significant decrease in NO secretion. These results confirm the modulatory potential of bioactive molecules in the salivary glands of R. sanguineus ticks.

Immunomodulatory and morphophysiological effects of Rhipicephalus sanguineus s. l. (Acari: Ixodidae) salivary gland extracts.

Rhipicephalus sanguineus s. l. is popularly known as the "brown dog tick" since dogs are its preferential hosts, but the species has been reported to parasitize other mammals, including humans, with significant medical-veterinary importance since it transmits several important pathogenic agents during the feeding period. The tick saliva is a complex mixture that has several functions, including the capability to modulate the hemostatic, inflammatory and immunologic systems of the host, allowing pathogens to settle. Despite knowledge about the immunosuppressive action of tick saliva, little is known about the mechanisms involved in this process and the morphophysiological effects caused by exposure to the salivary gland extract, taking into consideration the different periods of the glandular cycle. Thus, the objective of this study was to analyze the in vitro effects of salivary gland extracts obtained from R. sanguineus s. l. females fed on host rabbits for two (SGE2 - Salivary Gland Extracts of 2 days) and four days (SGE4 - Salivary Gland Extracts of 4 days) on J774 cells (monocyte macrophage cell line) and verify the occurrence of morphological and immunomodulatory alterations in these cells when exposed to different concentrations of these extracts. The results showed that: (i) SGE2 and SGE4 at the concentration of 4 µg/mL presented cytotoxicity to the J774 cells exposed for 24 and 48 hours; (ii) SGE2 at the concentrations of 2 µg/mL(48-hour exposure) and 1 µg/mL (24-hour exposure) and SGE4 at the concentrations of 2 and 1 µg/mL (48-hour exposure) showed proinflammatory activity, confirmed by the increased secretion of NO and proinflammatory cytokine (IL-2), and the presence of morphological characteristics detected by microscopy; and (iii) SGE2 and SGE4 at the concentrations of 0.5 and 0.1 µg/mL had immunomodulatory activity, demonstrated by decreases in the secretion of NO and proinflammatory cytokines (IL2, IL-6 and TNF-α) and increase in the synthesis of IL-10, confirmed by the morphophysiological analysis. These unprecedented data are extremely relevant for future research to identify the processes involved in the ectoparasite-host relationship, as well to develop more efficient tick control strategies.

Tolerogenic Dendritic Cells on Transplantation: Immunotherapy Based on Second Signal Blockage.

Dendritic cells (DCs), the most important professional antigen-presenting cells (APC), play crucial role in both immunity and tolerance. It is well known that DCs are able to mount immune responses against foreign antigens and simultaneously tolerate self-antigens. Since DCs can be modulated depending on the surrounding microenvironment, they can act as a bridge between innate and adaptive immunity. However, the mechanisms that support this dual role are not entirely clear. Recent studies have shown that DCs can be manipulated ex vivo in order to trigger their tolerogenic profile, what can be a tool to be used in clinical trials aiming the treatment of various diseases and the prevention of transplant rejection. In this sense, the blockage of costimulatory molecules on DC, in the attempt of inhibiting the second signal in the immunological synapse, can be considered as one of the main strategies under development. This review brings an update on current therapies using tolerogenic dendritic cells modulated with costimulatory blockers with the aim of reducing transplant rejection. However, although there are current clinical trials using tolerogenic DC to treat allograft rejection, the actual challenge is to modulate these cells in order to maintain a permanent tolerogenic profile.

Inflammatory Bowel Disease: An Overview of Immune Mechanisms and Biological Treatments.

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal tract associated with an imbalance of the intestinal microbiota. Crohn's disease (CD) and ulcerative colitis (UC) are the most widely known types of IBD and have been the focus of attention due to their increasing incidence. Recent studies have pointed out genes associated with IBD susceptibility that, together with environment factors, may contribute to the outcome of the disease. In ulcerative colitis, there are several therapies available, depending on the stage of the disease. Aminosalicylates, corticosteroids, and cyclosporine are used to treat mild, moderate, and severe disease, respectively. In Crohn's disease, drug choices are dependent on both location and behavior of the disease. Nowadays, advances in treatments for IBD have included biological therapies, based mainly on monoclonal antibodies or fusion proteins, such as anti-TNF drugs. Notwithstanding the high cost involved, these biological therapies show a high index of remission, enabling a significant reduction in cases of surgery and hospitalization. Furthermore, migration inhibitors and new cytokine blockers are also a promising alternative for treating patients with IBD. In this review, an analysis of literature data on biological treatments for IBD is approached, with the main focus on therapies based on emerging recombinant biomolecules.