With growing evidence of its use, many adaptations have been made, including modified shorter courses or prolongation of treatment at fixed-dose intervals [6]

With growing evidence of its use, many adaptations have been made, including modified shorter courses or prolongation of treatment at fixed-dose intervals [6]. to be important for the desensitization protocols for highly sensitized patients as well as for the preconditioning of ABO-incompatible recipients and the treatment of antibody-mediated rejection, will also be addressed. strong class=”kwd-title” Key Words?: B cell depletion, Rituximab, Membranous nephropathy, Lupus nephritis, ANCA-associated vasculitis, Transplantation? Introduction B cells occupy a central role in normal immunity. They interact with antigen-presenting cells, act as antigen-presenting cells themselves, provide co-stimulatory support to T cells, differ from plasma cells and produce antibodies. B cells have the ability to expand and HS-10296 hydrochloride clonally proliferate. As expected, abnormal B cell function plays a major role in immune dysregulation such as autoimmunity [1]. Furthermore, B cells are implicated in the pathogenesis of T cell autoreactivity. Abnormal B and T cell interactions may be amplified by T cell-derived cytokines such as the B lymphocyte stimulator and a proliferation-inducing ligand [2]. Additionally, B cells have been found in affected tissues from nasal biopsies of patients with ANCA-associated vasculitis (AASV) [3] or from renal biopsies of patients with membranous nephropathy [4]. B Cell-Directed Therapies B cell-directed therapies include those that deplete B cells and those HS-10296 hydrochloride that alter B cell function. B cell depletion HS-10296 hydrochloride can be achieved by using monoclonal antibodies against B cell-specific antigens such as CD20, CD19 and CD22. Most monoclonal antibodies currently in use are against the anti-CD20 receptor. B cell modulation comprises the blockade of the following cytokines: B cell-activating factor/B lymphocyte stimulator, proliferation-inducing ligand and their receptors, as well as co-stimulation blockade [2]. Rituximab is a mouse/human IgG1k chimeric monoclonal antibody against the CD20 cell surface receptor of the B cell. CD20 is expressed on immature, mature and activated B cells but not on long-lived plasma cells. Rituximab depletes B cells by three mechanisms: antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. One course of rituximab effectively depletes B cells for 6-9 months in over 80% of the patients [5]. Rituximab has first been licensed for the treatment of non-Hodgkin’s lymphoma in the 1990s and has been approved for the treatment of rheumatoid arthritis in 2006. Thereafter, it has been used increasingly in autoimmune diseases. At first, the standard dosing regimens were either the so-called lymphoma protocol (four weekly doses of 375 mg/m2) or the rheumatoid arthritis protocol (two doses of 1 1 g, 2 weeks apart). With growing evidence of its use, many adaptations have been made, including modified shorter courses or prolongation of treatment at fixed-dose intervals [6]. Rituximab has been widely used and is considered a safe drug. Most adverse events include minor infusion reactions that only rarely limit its use. According to the literature, up to 8% of all lymphoma patients experience a delayed neutropenia that may be profound but finally resolves [7]. True estimates about the incidence of infections after rituximab treatment are difficult because most patients receive concomitant immunosuppression. Rituximab use is not associated with an increased risk neither for common nor for opportunistic infections [1]. Concern has been raised about the relation of rituximab with progressive multifocal leukoencephalopathy. However, no definite conclusion can be drawn, since such patients also received intensive immunosuppression. On the other hand, the syndrome occurred also in patients who had never received rituximab [8]. Since rituximab does not deplete long-lived plasma cells, ITGAV there is no decrease in immunoglobulin levels. However, a slight decrease in IgG occurs after repeated dosing. Human antichimeric antibodies develop in 5-30% of the patients. They may shorten the time of effective B cell depletion, but the true incidence and importance of these antibodies are unknown [1]. Rituximab has been used in idiopathic and secondary glomerulonephritides and in renal transplantation. Specifically in idiopathic glomerulonephritides, most of the available data concern the use of rituximab in idiopathic membranous nephropathy (IMN) and steroid-resistant nephrotic syndrome (NS). Secondary forms of glomerulonephritis include systemic lupus erythematosus (SLE) and AASV. In renal transplantation, rituximab has been used for the desensitization of highly sensitized patients before transplantation and as part of the preconditioning of the recipient before ABO-incompatible transplantations. Furthermore, it is used in severe immune-mediated, antibody-associated rejection. Idiopathic Membranous Nephropathy Since HS-10296 hydrochloride IMN is characterized HS-10296 hydrochloride by autoantibody formation and immune complex deposition, from the pathogenetic point of view, the use of rituximab is reasonable. Ruggenenti et al. [9] were the first who used rituximab as first-line therapy in 8 patients with IMN. Sustained remission with maximal reduction of proteinuria by 66% occurred after 12 months. In the meantime, several case series and small prospective trials reporting that rituximab is efficacious in IMN have been published. A meta-analysis published in 2009 2009 [10] summarized.