Current Immunology Reviews (Discontinued) - Volume 8, Issue 2, 2012

Disease modifying, anti-inflammatory strategies often target pathogenic cells once they are localized within the site of inflammation. The prototypes of biologic drugs such as anti-TNFα or anti-p40 (IL-12 and IL-23) therapies act on cytokines produced by tissue macrophages for example in the synovium in Rheumatoid Arthritis (RA) or in the intestinal mucosa in Intestinal Bowel Disease (IBD). Furthermore, immuno Read More

Leucocyte recruitment from the bloodstream into tissues depends on a coordinated sequence of adhesive interactions between leucocytes and the vascular wall. It is tightly regulated, both spatially and temporally, such that leucocyte recruitment is efficient and the integrity of the vascular wall is not impaired. Although the cell adhesion molecules and chemokines that mediate adhesion have been identified, the signalling events Read More

The α4β7 integrin is a leukocyte homing receptor with selective tissue tropism for the gastrointestinal tract through its interaction with MAdCAM-1, an adhesion receptor expressed on the endothelium of the gut mucosa. Crohn’s disease (CD) and ulcerative colitis (UC), two inflammatory bowel diseases resulting from intestinal immunedysregulation, are associated with pronounced infiltration of α4β7 positive lymphocytes. This h Read More

Blocking the action of alpha4 integrin would be expected to be of therapeutic benefit in the management of autoimmune diseases. Although this has been successfully demonstrated in the clinic with a monoclonal antibody for the treatment of multiple sclerosis, there are no small molecule alpha4 integrin antagonists on the market despite significant endeavour over the last 15-20 years. We review our efforts in this area, sta Read More

Chemokines cannot be easily antagonized by low molecular weight (LMW) compounds and are therefore more suitable for targeting clinically via ‘biologics’. Significant beneficial features of mAbs as compared to LMW compounds include a high selectivity for their target, reducing the risk of off-target side effects, as well as the prolonged pharmacokinetics, with half-lives ranging from days to weeks, necessitating less frequent Read More

Monoclonal antibodies (mAbs) serve as research reagents, for dissecting the biology of chemokine and chemoattractant receptors. However mAbs are also an attractive class of therapeutic, because they are able to block large protein-protein interactions, and are generally easier and more predictable for clinical development. mAbs are also capable of depleting leukocyte subsets, such as pathogenic cell types, through proce Read More

Phosphoinositide 3-kinase (PI3K) has been positioned at the heart of an evolutionarily conserved cellular compass and/or the biochemical mechanisms that facilitate cell migration. PI3K has therefore, become a popular drug target for inhibition of leukocyte migration in response to inflammatory chemoattractant mediators including members of the chemokine family. PI3K has also been implicated as a key regulator Read More

The chemokine system is now recognized as a key element in cancer-related inflammation because it can affect tumor progression acting on tumor-stroma and also directly on tumor cells. Chemokines are produced by both tumor cells and the tumor microenvironment and modulate not only leukocyte infiltration and angiogenesis but also senescence, cell survival and metastasis. Here, we review available information in p Read More

FTY720 (fingolimod, Gilenya®) is a sphingosine analog prodrug that induces lymphocyte sequestration in secondary lymphoid organs, resulting in peripheral lymphopenia. Lymphopenia by FTY720 is characterized by a dosedependent and sustained reduction of circulating T and B lymphocytes within hours of administration, accounting for a 70% reduction of CD4+ T cells, 90% reduction of CD8+ T-cells, and >50% reduction of C Read More

Aberrant cell recruitment is a hallmark of inflammatory responses, a complex process orchestrated by a unique interplay of adhesion, chemotactic and pro-inflammatory molecules. To date there are only two marketed drugs that block cell migration, interestingly both for Multiple Sclerosis (MS). Tysabri/Natalizumab, a humanized monoclonal antibody against the cellular adhesion molecule VLA-4 was the first to be approved for th Read More