Inflammation & Allergy-Drug Targets (Discontinued) - Volume 7, Issue 2, 2008

HLA-G antigens are non classical HLA-class I molecules characterized by a low allelic polymorphism, a limited tissue distribution and the presence of membrane bound and soluble isoforms. The HLA-G antigens were firstly detected in cytotrophoblast cells at the feto-maternal interface where they maintain a tolerogenic status between the mother and the semiallogenic fetus. Recently a variable expression of HLA-G molecules has been documented in several autoimmune diseases, viral infections, cancer diseases and transplantation. Overall the presence of HLA-G molecules in both membranes bound and soluble isoforms was associated with tolerogenic functions against innate and adaptative cellular responses. HLA-G antigens are able to affect the cytotoxicity of natural killer and CD8+ T cells, CD4+ T lymphocyte functions and dendritic cell maturation. In addition to the allelic polymorphism the HLA-G gene shows a deletion/insertion polymorphism of a 14 base pairs sequence (14bp) in the exon 8 at the 3' untranslated region. Several reports have associated the presence of the 14bp insertion allele (+14bp) to an unstable mRNA and a lower sHLA-G protein production, suggesting a different ability to counteract inflammation between genotypes. We reviewed the literature on the expression of HLA-G antigens in autoimmune and allergic diseases and the possible functional role of these molecules in counteracting inflammation.

Intravenous immunoglobulin (IVIG) is sterilized and purified human plasma which contains supra-physiologic levels of immunoglobulin G. IVIG is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Although numerous immunomodulatory mechanisms have been suggested, the exact mechanisms of action are poorly understood. There is also accumulating evidence that high-dose IVIG is efficacious in the treatment of some skin diseases, despite the lack of evidence from randomized, double-blind, placebo-controlled trials. Though in most cases, IVIG is only effective in combination with other immunomodulating strategies, it offers new hope for the treatment of many severe dermatologic conditions. This article focuses on the efficacy and safety of IVIG therapy in skin diseases.

Leukocyte migration into the tissues represents a key process in the pathogenesis of inflammatory diseases. Data obtained in clinical trials have convincingly shown that inhibition of leukocyte migration into the target organs represents an effective therapeutic approach for diseases in which inflammation has a noxious effect. Leukocyte tethering and rolling are the earliest steps of leukocyte adhesion cascade in inflamed vessels. Selectins are type I transmembrane glycoproteins that bind sialylated carbohydrate structures in a calcium-dependent manner and are involved in the tethering and rolling of leukocytes under physiological and pathological conditions. Three selectins have been identified: L-, P- and Eselectin. Current understanding of the glycosylation-dependent selectin function reveals a complex role for selectins and their ligands during inflammatory diseases. Among selectin ligands, mucin P-selectin glycoprotein ligand-1 (PSGL-1) binds all three selectins and has a well-documented role in organ targeting during inflammation in animal models. However, although inhibition of selectins and their ligands in animal models of inflammatory diseases has proven the validity of this approach in vivo, only a limited number of anti-selectin drugs have been tested in humans. Recent results obtained in clinical trials for asthma and psoriasis show that, although very challenging, the development of selectin antagonists holds concrete promise for the therapy of inflammatory diseases.

The development of colorectal carcinoma (CRC) has been hypothesized to be raised mostly from the precancerous lesion of colorectal adenoma (CRA) through a multistep process and defined as the adenoma-carcinoma sequence. In response to the tumorigenesis, host cellular immunity acts as the most important defense factor with cytokines as the main regulator molecules. Therefore, changes of cytokines of the T helper 1 (Th1)/T helper 2 (Th2) type immune responses along this sequence may therefore reflect a functional switch of host anti-tumor immunity. This minireview focused on the recent knowledge of the Th1/Th2 balance in the adenoma-carcinoma sequence and its potential clinical and therapeutical significance.

HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a systemic immune-mediated inflammatory disease and tissues other than nervous can be damaged, mainly ocular, rheumatic and dermatologic. Over 90% of HTLV-1-infected individuals remain lifelong asymptomatic and this retrovirus persists indefinitely in their CD4+ T-lymphocytes. The infection is maintained due to the proliferation of lymphocytes that harbor a provirus and express HTLV-1 proteins, particularly Tax, promoting an active and selective expansion of infected T cells. High proviral load is related to disease progression, which is correlated to disequilibrium between host and virus. Cytotoxic T lymphocytes are abundant and chronically activated in asymptomatic carriers and in HAM/TSP patients. The asymptomatic carriers were shown to have a high frequency of pro-inflammatory monocytes and anti-inflammatory IL-10+CD4+ and IL-10+CD8+ Tcells, as an immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha. A putative immunomodulatory event would be the key to control their overall immunological status. In HAM/TSP, a pro-inflammatory microenvironment is the hallmark of the immunological profile. Enhanced frequency of activated CD8+ T-cells (HLA-DR+) in combination with high CD18 surface expression has been seen. In blood and cerebrospinal fluid, increased levels of Type- 1 cytokines, as interferon-(IFN)-gamma, Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-2, and pro-inflammatory IL-6, can be found. Concerning the progression, HLA polymorphisms may influence HAM/TSP and the allele HLA-A*2 has been associated with protection. The authors showed that HAM/TSP is strongly associated with a decreased percentage of B-cells, with enhanced T/B-cell ratio and activated CD8+ T-cells. These immunological parameters have been proposed as a prognostic biomarker for HAM/TSP.

ADAM (a disintegrin and metalloprotease) family members are membrane-anchored proteins with wide ranging functions, including proteolytic cleavage of cell surface molecules, cell fusion, cell adhesion and intracellular signaling. ADAM8, also known as CD156a, is expressed mainly in cells of the immune system, such as monocytes, neutrophils, eosinophils, dendritic cells, and B cells. It can cleave a variety of substrates and is a sheddase for CD23 and L-selectin. ADAM8 has an important role in allergic inflammation. ADAM8 mRNA expression is increased with disease progression in asthma. ADAM8 is strongly induced by allergens and Th2 cytokines in the lung in experimental asthma. Soluble ADAM8 is elevated in the bronchoalveolar lavage fluid of patients with eosinophilic pneumonia and has a physiologic role in protecting against allergic pulmonary disease in experimental murine asthma. Together, these findings support the view that ADAM8 might be a therapeutic target for allergic respiratory diseases. This review discusses novel strategies for immune intervention in allergic respiratory disease.

Helminths secrete several molecules that can modulate the immune responses, favoring their evasion and perpetuate their survival in the host. These molecules interfere with antigen presentation, cell proliferation and activation, antibody production, cause cell death, and stimulate regulatory responses. Here, we focus on some helminth products and address their immunomodulatory effects in the host immune system and, also, we describe some anti-inflammatory properties of an Ascaris suum-derived immunomodulatory molecule, named PAS-1. This protein is a 200-kDa molecule isolated by affinity chromatography using MAIP-1 (monoclonal antibody which recognizes PAS-1), coupled to Sepharose 4B. It suppresses the inflammatory responses in murine models of delayed-type hypersensitivity, lung allergic inflammation and LPS-induced inflammation into air pouches. PAS-1 also stimulates the secretion of regulatory cytokines such as IL-10 and TGF-β and primes IFN-γ-secreting CD8+ and IL-10/ TGF-β-secreting CD4+CD25+ cell clones that avoid the lung inflammation. Thus, this protein is a potent immunomodulatory component that may be used for therapeutic interventions in inflammatory diseases.

Asthma is a chronic disease characterised by airways hyperresponsiveness, airways inflammation, airways remodelling and reversible airways obstruction. Airway structural cells, recruited inflammatory cells and many mediators such as cytokines, chemokines and adhesion molecules are involved in the pathogenesis of asthma. Although asthma is treatable in most, but not all patients by currently available drugs, no treatment is preventive or curative and the disease has reached epidemic proportions worldwide and its incidence is continuing to increase. Many thousands have chronic, severe asthma and suffer daily symptoms making it imperative that we continue to improve our understanding of the mechanisms of asthma particularly related to airway inflammation and remodelling, the hallmarks of asthma, and to identify new therapeutic targets. In this review we will discuss current drugs and potential targets in the treatment of asthma.