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    • PND-1186 Controlling the immune dysfunctions and overcoming

    2018-10-30

    Controlling the immune dysfunctions and overcoming the shortage of islet β PND-1186 are two critical steps for the treatment of T1D. Conventional immunotherapies (e.g., CD3 and CD20 mAb treatments) targeting the general immune cell compartment usually leads to the absolute decline of cell numbers due to their broad cytotoxicity. These approaches may make patients more vulnerable to pathogens and certainly raise concerns about clinical safety and tolerability. SCE therapy modifies rather than destroys the cells responsible for autoimmune responses. Current clinical data demonstrated the safety and efficacy of the SCE therapy for the immune modulation of Caucasian T1D subjects of European background. Due to the plasticity of human T cells, the induction of differentiation of T cells into different functional subsets and the correction of functional defects of TEM can be efficiently achieved through SCE therapy in T1D subjects. SCE therapy provides lasting reversal of autoimmunity that allows the native improvement of islet β-cell function in T1D subjects with residual β cell function. A better understanding of the molecular disparities of islet β cells between Caucasian and Chinese populations will provide insight into possible methods for improving treatment efficacy and β cell recovery in Caucasians with T1D who do not have residual β cell function prior to treatment. SCE therapy may revolutionize the clinical treatment of diabetes without the safety and ethical concerns associated with conventional approaches.
    Competing Interests
    Authors\' Contributions
    Acknowledgments We appreciate Dr. Robert Korngold for helpful discussion and review of this manuscript. The authors are grateful to Dr. Catalina Plaza and the nurses at the Gynecology and Obstetric Service, Hospital Universitario Central de Asturias, Oviedo, Spain for their help in Cord Blood collection, as well as the nurses at the Hematology and Hemotherapy Service Hospital Universitario Central de Asturias for their help in apheresis. Clinical trial was supported by the grants from the Instituto de Salud Carlos III (PI12/02587), Red de Investigación Renal (REDiNREN RD12/0021/0021), European Union FEDER funds, Principado de Asturias (Plan de Ciencia, Tecnologia e Innovacion), FICYT (GRUPIN 14-069), and Hackensack University Medical Center Foundation. Sponsors had no role in conception, design, or conduct of the study; collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. The researchers worked independently of the funders.
    Introduction Rheumatoid Arthritis (RA) is an autoimmune disease and a systemic inflammatory disorder affecting joints and internal organs. It is one of the main causes of disability in the western world. The etiology and the triggers of autoimmunity and in particular of RA have been ascribed to different factors: genetic and environment. The humoral and cell-mediated immune responses in which self-reactivity plays an important role are key points in the pathophysiology of RA. The chronic synovial inflammation involved in joint destruction and disability is mediated by the infiltration of the activated immune cells: CD4+ T cells, B cells, dendritic cells and macrophages (Cooles and Isaacs, 2011; van der Woude et al., 2010; Willemze et al., 2012; Michelutti et al., 2011; Tolusso et al., 2009). Family-based and twin-based studies have shown that the heritability of RA accounts for about 60% of the developmental risk, one third of which has been linked to two particular major histocompatibility antigens (human leukocyte antigens) namely HLA-DRB1*04 and 01 (Deighton et al., 1989). The genome-wide association studies (GWAS) and meta-analyses identified and combined a number of single nucleotide polymorphisms (SNPs) related to RA, both in HLA and non-HLA genes (Chatzikyriakidou et al., 2013; Mesko et al., 2010). Several studies about the amino-acids motifs at the position 70–74 of the third hyper-variable region of HLA-DRB1 molecules associated not only with RA susceptibility (RR-QK-QRRAA as in DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001 and *1402) or protection (DERAA as in *0103, *0402, *1102, *1103, *1301, *1302 and *1304) (Feitsma et al., 2008), but also to disease severity and progression (Gonzalez-Gay et al., 2002) with variations among different ethnicities and populations, also demonstrated in Kapitany et al. (Kapitany et al., 2005).