Immunosuppressive Adverse Effects Research Articles

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Genetic Testing in Crohn Disease

Inflammatory bowel disease (IBD), with its two subforms of Crohn disease and ulcerative colitis, is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition. The first risk gene underlying susceptibility to Crohn disease has been identified as CARD15 (located on chromosome 16q12, encoding NOD2). Three single nucleotide polymorphisms in the leucine rich region (LRR) of this gene are strongly and independently associated with Crohn disease susceptibility and explain up to 20% of the total genetic predisposition for Crohn disease. These variants have been consistently replicated as associated with a particular sub-phenotype characterized by small bowel (ileum) involvement and early age at onset. Presently, genetic testing for the CARD15 variants has only a modest relevance in clinical practice. The most attractive use of genetic testing is for the prediction of response to therapy. Most therapies only show efficacy in subgroups of patients and no clinical parameters are available to distinguish, prior to therapy, whether the patients will be responders or non-responders, or if the patients will experience adverse effects. The pharmacogenetic basis of toxicity is well known for azathioprine: several thiopurine methyltransferase (TPMT) polymorphisms that are associated with reduced activity of this thiopurine drug metabolizing enzyme result in cytotoxic and immunosuppressive adverse effects of azathioprine. Genetic screening, which has found its way into routine clinical diagnostics, allows the identification of the patients who will not tolerate a standard dose of the drug. The extensive search for genetic predictors of response to the anti-tumor necrosis factor treatment with infliximab, which results in a remission rate of 30-40%, has, however, failed to identify a variation associated with a differential response.