Current treatment practice in immunosuppression

Ciancio, Gaetano; Burke, George W.; Miller, Joshua

doi:10.1517/14656566.1.7.1307

Cited by 24 publications

(7 citation statements)

References 174 publications

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“…This strategy has been employed in the field of transplantation medicine for decades by using drugs such as cyclosporin and tacrolimus. 91 These agents inhibit the synthesis and release of cytokines and prevent the differentiation of CD4 cells, thereby blocking an immune response. Unfortunately, this therapy works in a nonspecific manner and thus leaves the patient highly susceptible to infections.…”

Section: Removing the "Danger"mentioning

confidence: 99%

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Brown

Lillicrap

2002

Blood

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Section: Removing the "Danger"mentioning

confidence: 99%

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Brown

Lillicrap

2002

Blood

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“…Besides the potent immunosuppressive drugs CsA and FK506, glucocorticoids and cytotoxic compounds, such as azathioprine or mycophenolate mofetil, are widely used in the prevention of graft-versus-host reactions and in the therapy of serious autoimmune diseases (44). However, these immunosuppressive agents have many serious side effects such as nephrotoxicity (7), hypertension (45), hyperlipidemia (46), neuropathies (47), and an increased risk for diabetes mellitus type II (48).…”

Section: Discussionmentioning

confidence: 99%

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

Erdmann

Weiwad

Kilka

et al. 2010

Journal of Biological Chemistry

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The Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin is a key mediator in antigen-specific T cell activation. Thus, inhibitors of calcineurin, such as cyclosporin A or FK506, can block T cell activation and are used as immunosuppressive drugs to prevent graft-versus-host reactions and autoimmune diseases. In this study we describe the identification of 2,6-diaryl-substituted pyrimidine derivatives as a new class of calcineurin inhibitors, obtained by screening of a substance library. By rational design of the parent compound we have attained the derivative 6-(3,4-dichloro-phenyl)-4-(N,N-dimethylaminoethylthio)-2-phenyl-pyrimidine (CN585) that noncompetitively and reversibly inhibits calcineurin activity with a K i value of 3.8 M. This derivative specifically inhibits calcineurin without affecting other Ser/Thr protein phosphatases or peptidyl prolyl cis/trans isomerases. CN585 shows potent immunosuppressive effects by inhibiting NFAT nuclear translocation and transactivation, cytokine production, and T cell proliferation. Moreover, the calcineurin inhibitor exhibits no cytotoxicity in the effective concentration range. Therefore, calcineurin inhibition by CN585 may represent a novel promising strategy for immune intervention.The activation and the precise interplay between signaling pathways are crucial for the successful initiation and progression of the immune response as a reaction of an antigen contact. In T cells the stimulation of the T cell receptor by a specific antigen leads to a calcium release from the intracellular stores and to a calcium release-activated Ca 2ϩ channel-mediated calcium influx into the cytoplasm which activates calmodulin and thereby the Ser/Thr-protein phosphatase calcineurin (1). Consequently, calcineurin represents a bottleneck in T cell receptor signaling and allows the modulation of T cell activation by low molecular compounds, such as cyclosporin A (CsA) 2 or tacrolimus (FK506) (2). The cyclic undecapeptide CsA and the macrolid FK506 bind to and inhibit the phosphatase activity of calcineurin only after interaction with their respective peptidyl prolyl cis/trans isomerases (PPIases), cyclophilins (Cyp), and FK506-binding proteins (FKBP) through a gain-of-function mechanism (3, 4). Based on their particular characteristic to bind the immunosuppressive drugs CsA and FK506, members of the Cyp and FKBP family of PPIases were also termed immunophilins (5). Among the many known PPIases, the most abundant isoforms, Cyp18 and FKBP12, were identified as major intracellular acceptor proteins for CsA and FK506, respectively. The PPIase activity of both enzymes is strongly inhibited by the immunosuppressive drugs (6), leading to many of serious side effects (e.g. nephrotoxicity, neurotoxicity, hypertension, fibrosis) that were observed in the prevention and therapy of graftversus-host reactions or autoimmune diseases (7-10). Therefore, CsA derivatives, such as [DAT-Sar] 3 CsA, were synthesized to obtain cyclophilin-independent calcineurin inhibitors (11). However, [DAT-Sar] ...

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“…Transplant recipients require life-long immunosuppressant therapy to treat and prevent rejection events that would otherwise jeopardise the performance and longevity of their newly acquired graft [1,2]. Immunosuppressant medicines are used in 3 treatment stages; induction, as maintenance therapy and for acute treatment of organ rejection [3].…”

Section: Introductionmentioning

confidence: 99%

Multinational Evaluation of Mycophenolic Acid, Tacrolimus, Cyclosporin, Sirolimus, and Everolimus Utilization

2016

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Current treatment practice in immunosuppression

Cited by 24 publications

References 174 publications

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

Multinational Evaluation of Mycophenolic Acid, Tacrolimus, Cyclosporin, Sirolimus, and Everolimus Utilization

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