Oxidative Phosphorylation

Serious infections were fewer in the abatacept group (1

Serious infections were fewer in the abatacept group (1.3%) than in the placebo (2.7%) and infliximab (4.2%) groups. MalignancyThe initial phase III/LTE study [21] included one case of bladder cancer, two cases of basal cell carcinoma and one neoplasm in the 10 mg/kg abatacept group, and one case each of endometrial cancer, squamous cell carcinoma and malignant melanoma in the placebo group. trials. Introduction The role of T cells in rheumatoid arthritis (RA) pathogenesis has regained central importance in recent years. Several observations over the years support a fundamental role for T cells in RA: the association of RA susceptibility with HLA-DR allele on major histocompatibility complex (MHC) class II [1,2]; the induction of an inflammatory arthritis by transfer of CD4+ T cells from affected animals into healthy syngeneic recipients [3,4]; and the induction of clinical features of RA in human synovium-severe combined immunodeficient mice [5]. In addition, RA synovium contains a rich infiltrate of activated CD4+ cells and MHC class II [6], with correlation seen between synovial T-cell numbers and severity of joint damage [7]. During the 1990s, the widely accepted concept of cytokine networks perpetuating disease, with tumor necrosis factor (TNF)- assuming a hierarchical role [8], was supported by the success of TNF- blocking treatments [9,10]. The lack of universal benefit from TNF- blocking therapies [11], however, has focused attention on alternative immunological mediators, including T cells. The relative lack of success of T-cell-directed therapies stimulated research into alternative methods of targeting T-cell biology, including T-cell co-stimulation; of the multiple co-stimulatory pathways that can upregulate or downregulate T-cell activation, one of the best characterized is that between CD28 and CD80/CD86 (B7 molecules). Both CD80 and CD86 bind to cytotoxic T-lymphocyte antigen (CTLA)4-immunoglobulin (Ig) complex (CD152), which shares 30% homology with CD28 but has a 10 to 20 times greater binding affinity to the B7 molecules [12]. CTLA4 expression and binding therefore competitively inhibit T-cell activation in both na? ve and primed CD4+ and CD8+ T cells, disrupting CD28-dependent T-cell responses [13]. Advances in drug development and protein engineering have facilitated creation of targeted therapies, in this case to interrupt the T-cell-activation pathway. The role of T cells in RA and, in particular, the biology of co-stimulation is the subject of more detailed discussion in other articles included in this supplement. This review concentrates on the outcomes of CTLA4-directed therapies in RA. Co-stimulation signal blockade Abatacept (CTLA4-Ig) is a soluble fusion protein that consists of the extracellular domain of human CTLA4 linked to the modified Fc (hinge, CH2 and CH3 regions) portion of human IgG1. Like native CTLA4, the fusion protein binds more avidly to CD80/86 than to CD28. Belatacept (LEA29Y) is a second-generation CTLA4-Ig, which is currently in Impurity C of Alfacalcidol phase III trials in transplantation. Therapeutic inhibition with CTLA4-Ig A CTLA4-Ig fusion protein was initially applied in rodent models of transplantation [14], in which graft survival was prolonged. Subsequent application in nonhuman primate organ transplantation studies, however, was unsuccessful. In contrast, slowing of disease progression was observed in several experimental animal models of autoimmune disease, including lupus and glomerulonephritis [15,16]. CTLA4-Ig prevented development of collagen-induced arthritis if it was administered at the time of immunization, and it ameliorated arthritis if it was given after the onset of disease [17]. Abatacept was therefore developed for application in autoimmune disease, with a Impurity C of Alfacalcidol number of clinical studies conducted to evaluate its use in RA (the focus of this supplement). To address the poor outcomes in transplantation studies, further development of CTLA4-Ig concentrated on improving its binding to CD86 in particular (owing to its importance in initiation of the immune reaction in primates), in order to confer the more potent immunosuppressive action needed. This led to the development of belatacept, a second-generation CTLA4-Ig that exhibits superior binding to CD80 Impurity C of Alfacalcidol and CD86 as compared with the parent CTLA4-Ig. Abatacept in initial clinical studies The cumulative biological and experimental data provided the basis for targeting CD28-mediated T-cell activation in human disease with abatacept. The first clinical study to evaluate the efficacy of Hs.76067 abatacept was conducted in patients with psoriasis; 46% of patients exhibited greater than 50% sustained improvement in disease activity [18]. Abatacept in rheumatoid arthritis Abatacept was subsequently applied in patients with RA. A summary of the clinical efficacy data from each of Impurity C of Alfacalcidol the main phase II and III trials of abatacept in RA is first presented, followed by cumulative quality of life and safety data. Phase II studies Abatacept monotherapy in patients with rheumatoid arthritis and a history of DMARD failureAn initial dose-ranging study provided preliminary clinical data and has been the only study to assess safety and efficacy of abatacept monotherapy in patients with active RA who had previously failed disease-modifying antirheumatic drug.

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