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      Renal tuberculosis in an imatinib-treated chronic myeloid leukemia Translated title: Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

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          ABSTRACT

          Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

          RESUMO

          O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

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          Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner.

          The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor (TCR)-mediated activation of human T cells. Following stimulation with the anti-CD3 antibody 12F6, proliferation of activated T cells was almost completely inhibited by 10 microM imatinib. Furthermore, antigen-triggered expansion of CD8+ T cells in response to immunodominant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) peptides was significantly reduced. Up-regulation of the activation markers CD25 and CD69 in response to TCR cross-linking was suppressed by imatinib at a mean inhibitory concentration 50% (IC50) of 5.4 microM and 7.3 microM, respectively; interleukin 2 (IL-2) production was also impaired. Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the adenosine triphosphate (ATP) binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib. The IC50 for LCK inhibition by imatinib was 0.6 microM to 0.8 microM in an in vitro tyrosine kinase assay. In summary, imatinib can interfere with T-cell activation in vitro, and its impact on the frequency of opportunistic infections and graft-versus-host or graft-versus-leukemia reactions after transplantation should be investigated in clinical trials.
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            Renal tuberculosis in the modern era.

            Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis. The disease remains as an important public health problem in developing countries. Extrapulmonary TB became more common with the advent of infection with human immunodeficiency virus and by the increase in the number of organ transplantation, which also leads to immunosuppression of thousand of persons. Urogenital TB represents 27% of extrapulmonary cases. Renal involvement in TB can be part of a disseminated infection or a localized genitourinary disease. Renal involvement by TB infection is underdiagnosed in most health care centers. Most patients with renal TB have sterile pyuria, which can be accompanied by microscopic hematuria. The diagnosis of urinary tract TB is based on the finding of pyuria in the absence of common bacterial infection. The first choice drugs include isoniazide, rifampicin, pirazinamide, ethambutol, and streptomycin. Awareness of renal TB is urgently needed by physicians for suspecting this disease in patients with unexplained urinary tract abnormalities, mainly in those with any immunosuppression and those coming from TB-endemic areas.
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              Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo.

              Imatinib mesylate (STI571, imatinib) inhibited DNA synthesis in primary human T cells stimulated with allogeneic mature dendritic cells or phytohemagglutinin (PHA) but did not induce apoptosis. The values for the concentration that inhibits 50% (IC50) of T-cell proliferation stimulated by dendritic cells and PHA were 3.9 microM and 2.9 microM, respectively, that is, within the concentration range found in patients treated with imatinib mesylate. Interestingly, imatinib mesylate did not inhibit expression of T-cell activation markers CD25 and CD69, although it reduced the levels of activated nuclear factor-kappaB (NF-kappaB) and changed phosphorylation or protein levels of Lck, ERK1/2, retinoblastoma protein, and cyclin D3. When T cells were washed free of imatinib mesylate, they proliferated in response to PHA, demonstrating that inhibition is reversible. Treatment with imatinib mesylate led to accumulation of the cells in G0/G1 phase of the cell cycle. The in vitro observations were confirmed in vivo in a murine model of delayed-type hypersensitivity (DTH). In mice treated with imatinib mesylate, DTH was reduced in comparison to sham-injected controls. However, the number of splenic T cells was not reduced showing that, similarly to in vitro observations, imatinib mesylate inhibited T-cell response, but did not cause apoptosis. These findings indicate that long-term administration of high-dose imatinib mesylate might affect immunity.
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                Author and article information

                Journal
                J Bras Nefrol
                J Bras Nefrol
                jbn
                Jornal Brasileiro de Nefrologia
                Sociedade Brasileira de Nefrologia
                0101-2800
                2175-8239
                27 April 2020
                Jul-Sep 2020
                : 42
                : 3
                : 366-369
                Affiliations
                [1 ]Dr.RMLIMS, Department of Nephrology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.
                [2 ] Dr.RMLIMS, Department of Pathology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.
                Author notes
                Correspondence to: Namrata Rao. E-mail: namrata.sarvepalli@ 123456gmail.com

                CONFLICT OF INTEREST

                This project did not receive financial support from anywhere. Authors have no conflict of interest to declare.

                AUTHORS’ CONTRIBUTION

                All authors have contributed in the manuscript preparation as per International Committee of Medical Journal Editors (ICMJE) recommendations.

                Author information
                http://orcid.org/0000-0002-9055-4351
                http://orcid.org/0000-0002-5733-4218
                http://orcid.org/0000-0002-4400-9168
                Article
                10.1590/2175-8239-JBN-2019-0123
                7657051
                32353102
                8f4720cb-735c-4f41-b0c9-bf92160e0dd4

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

                History
                : 05 July 2019
                : 27 January 2020
                Categories
                Case Report

                imatinib mesylate,tuberculosis,leukemia, myelogenous, chronic, bcr-abl positive,mesilato de imatinib,tuberculose,leucemia mielogênica crônica bcr-abl positiva

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