Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. blocking the complement cascade, including new monoclonal antibodies, Sabinene recombinant proteins, small molecules, and small interfering RNA (siRNA) agents. Validation of these new drugs as effective treatments for kidney diseases faces several challenges. Many complement-mediated kidney diseases are rare, so it is not feasible to test all of the new drugs in numerous different rare diseases. The onset and course of the diseases are heterogeneous and many of these diseases also carry a Sabinene life-long risk of recurrence, and it is not Rabbit Polyclonal to PARP (Cleaved-Gly215) clear how long complement inhibition must be maintained. In spite of these challenges, new therapeutic options for targeting the complement system will likely become available in the near future and may prove useful for treating patients with kidney disease. Keywords:complement, glomerulonephritis, inflammation == Introduction == The kidney is a common target of immune-mediated injury. Several kidney diseases are caused by autoimmunity against antigens expressed within the glomeruli, and the innate immune system also frequently causes renal injury. Furthermore, kidney failure causes dysregulation of the immune system. Chronic kidney disease (CKD) is associated with a reduced ability to fight infection, for example, yet patients with CKD also have evidence of chronic systemic inflammation.1Thus, there is a delicate interrelationship between the kidney and the immune system (Figure 1), and immunomodulatory drugs may be beneficial for treating a many different kidney diseases and their complications. == Figure 1. The Complement System and Kidney Disease. == Complement activation contributes to the pathogenesis of acute and chronic kidney injury. Damage to the kidney, in turn, increases local and systemic complement activation. The complement cascade may link kidney disease with an increased susceptibility to infection and systemic inflammation. Complement inhibitory drugs hold the promise of blocking many forms of immune-mediated kidney injury and reducing the systemic effects of kidney disease. The complement cascade is a vital component of both the innate and adaptive immune systems, making it an important therapeutic target. Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. Although the specific mechanisms vary, complement activation contributes to the pathogenesis of almost every kidney disease.2This protein cascade is amenable to many different pharmacologic approaches, and anti-complement drugs could play a larger role in the treatment of kidney disease in the years to come. == The complement system == The complement system is comprised of more than 30 plasma and membrane-bound proteins. Activation of the system proceeds in a cascade fashion via three initiation pathways: the classical (CP), lectin (LP), and alternative (AP). During activation the proteins C2, C4, C3, and C5 are cleaved. The resultant protein fragments bind to nearby tissues or enter the systemic circulation, eliciting both local and systemic responses. The complement system mediates detection and removal of pathogens, local inflammatory reactions, the recruitment and activation of phagocytes, direct cell lysis, and the removal of apoptotic cells and immune-complexes. These downstream effects are primarily mediated by C3a, C5a, C3b, and C5b-9 (Figure 2). C3a and C5a (the anaphylatoxins) are small peptides released during complement activation that bind to transmembrane spanning G protein coupled receptors Sabinene (C3aR Sabinene and C5aR). C5a also binds to a non-G protein coupled receptor (C5L2). The anaphylatoxin receptors are expressed on myeloid and non-myeloid cells. They induce vasodilation, cytokine and chemokine release, the recruitment of immune cells, and they induce an Sabinene oxidative burst by macrophages, eosinophils and neutrophils. C5a also contributes to T-cell and antigen-presenting cell activation, expansion, and survival. == Figure 2. Overview of drugs that target the complement cascade. == Complement activation is initiated through three pathways: the classical pathway, alternative pathway, and lectin pathway. Full activation leads to the generation of several biologically active fragments, namely C3a, C5a, C3b, and C5b-9. Drugs are currently being developed to selectively block the classical pathway, the alternative pathway,.
