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      Efficacy and Cytokine Modulating Effects of Tacrolimus in Systemic Lupus Erythematosus: A Review

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      Journal: Journal of Biomedicine and Biotechnology
      Publisher: Hindawi Publishing Corporation

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          Abstract

          Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with involvement of both B cells and cytotoxic T lymphocytes and several cytokines aberrations. Standard therapy for SLE has its limitations. Tacrolimus, a novel calcineurin inhibitor with potent immunosuppressive effects, has been shown in the recent years to be effective in SLE therapy. This paper serves to collate the experimental and clinical data on the efficacy of tacrolimus in the treatment of SLE and lupus nephritis. Tacrolimus as a key component of multitarget therapy in SLE is also discussed. The immunocytokine modulatory effects of tacrolimus are also reviewed with reference to SLE. It can be concluded that tacrolimus has an established role in the management of SLE.

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          Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus.

          Jean-Luc Taupin, Vincent Pitard, Jean-François Moreau … (2004)
          Cytotoxic T lymphocyte-mediated killing using granzyme B has recently been proposed to be a preferential and selective source of autoantigens in systemic autoimmune diseases, including systemic lupus erythematosus (SLE), while other reports have indicated that cytolytic activity in SLE patients was decreased. The aim of this study was to examine the phenotypic and functional status of the CD8+ T cells in SLE patients. Phenotype analysis of CD8+ T cells was carried out using flow cytometry. The cytotoxic potential of CD8+ T cells and its consequences were examined in redirected-killing experiments. SLE patients with quiescent disease (n = 41) were compared with SLE patients with active disease (n = 20), normal individuals (n = 36), and control patients with vasculitis (n = 14). Cytotoxic CD8+ T cell differentiation was examined by coculture with differentiated dendritic cells (DCs) in the presence of SLE patient sera. Patients with disease flares were characterized by higher proportions of perforin- and/or granzyme B-positive lymphocytes with a differentiated effector phenotype (CCR7- and CD45RA+). The frequency of these cells in peripheral blood correlated with clinical disease activity as assessed by the SLE Disease Activity Index. These cells generated high amounts of soluble nucleosomes as well as granzyme B-dependent unique autoantigen fragments. Finally, the activation of DCs with serum from a patient with active lupus induced granzyme B expression in CD8+ T lymphocytes. DCs generated in the presence of sera from SLE patients with active disease could promote the differentiation of CD8+ effector T lymphocytes that are fully functional and able to generate SLE autoantigens. Our data disclose a new and pivotal role of activated CD8+ T lymphocytes in SLE pathogenesis.
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            Successful treatment of class V+IV lupus nephritis with multitarget therapy.

            Xin Hu, Zhi Liu, Tao Zhang … (2008)
            Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.
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              Cytokine production, serum levels and disease activity in systemic lupus erythematosus.

              G Gröndal, I Gunnarsson, J Rönnelid … (2015)
              T cell abnormalities, B cell hyperactivity and abnormal cytokine production have been implicated to be of pathogenic importance in systemic lupus erythematosus (SLE). The aim of this study was to investigate if ongoing production and serum levels of type 1 and 2 cytokines reflect disease activity and the presence of organ manifestations. Fifty-two SLE patients and 29 healthy individuals were investigated. Blood samples were collected for assessment of anti-ds DNA antibodies, cytokine production and serum cytokine levels. Disease activity was simultaneously assessed using the Systemic Lupus Activity Measure (SLAM) index and SLE Disease Activity Index (SLEDAI). ELISPOT analysis of freshly isolated peripheral blood mononuclear cells (PBMC) was used to estimate the production of cytokines (gamma-interferon (IFN-gamma), interleukin-4 (IL-4), IL-6 and IL-10) using both unstimulated cells and cells stimulated with the T cell mitogen phytohaemagglutinin (PHA). Serum levels of IL-10 were determined using an ELISA method, serum levels of IL-6 were determined using a bioassay and anti-ds DNA antibodies were analysed by immunofluorescence. The SLE patient group had significantly increased numbers of cells spontaneously producing IL-10 and IL-6 as compared to healthy controls (P = 0.01 and 0.03, respectively). The number of cells producing IL-10 and IL-6 after PHA-stimulation was also increased in SLE patients (P = 0.01 and < 0.0004, respectively). Serum IL-10 and IL-6 levels were also significantly increased in SLE patients (P < 0.0004 and 0.0005, respectively). Serum IL-10 levels correlated with the titre of anti-ds DNA antibodies in the patients. No correlation was found between disease activity or clinical profiles and the production or serum levels of cytokines except for a weak correlation (not statistically significant) between levels of IL-10 in the sera and disease activity as measured by the SLEDAI but not by the SLAM index. Our results confirm earlier reports that SLE patients have an increased production as well as increased serum levels of the type 2 cytokines IL-10 and IL-6. We found no significant correlation between IL-6 and IL-10 and disease activity or clinical profiles. Serum IL-10 levels correlated with the titre of anti-ds DNA antibodies in the SLE patients. In summary, our result indicate that the increased IL-10 production in SLE could be constitutive.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Biotechnol
                Journal ID (publisher-id): JBB
                Title: Journal of Biomedicine and Biotechnology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1110-7243
                ISSN (Electronic): 1110-7251
                Publication date (Print): 2010
                Publication date (Electronic): 28 June 2010
                Volume: 2010
                Electronic Location Identifier: 686480
                Affiliations
                El Shaddai Arthritis and Rheumatism Specialist Medical Centre, Block 102, #01-258, Towner Road, Singapore 322102
                Author notes

                Academic Editor: Brian Poole

                Article
                DOI: 10.1155/2010/686480
                PMC ID: 2896715
                PubMed ID: 20625508
                SO-VID: 38065f82-3f68-4d06-8752-dfcec612c7e1
                Copyright © Copyright © 2010 Kam Hon Yoon.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 February 2010
                Date accepted : 31 March 2010
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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