sirolimus and mizoribine

Amelioration of podocyte injury, which can lead to podocyte detachment, is the target of therapeutic intervention in glomerular diseases. Since podocytes are terminally differentiated cells with little or no proliferative ability, their loss results in permanent glomerular dysfunction. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression, which indirectly ameliorates podocyte injury by interrupting the input of immunological stress. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data now suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. Indeed, the therapeutic efficacy of immunomodulatory agents is, at least in part, derived by the direct action on podocytes. In this review, we discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance.

Topics: Abatacept; Adjuvants, Immunologic; Calcineurin Inhibitors; Everolimus; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Levamisole; Mycophenolic Acid; Nephrosis, Lipoid; Nephrotic Syndrome; Podocytes; Ribonucleosides; Rituximab; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.

Topics: Antimalarials; Azathioprine; Biological Products; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lupus Nephritis; Mycophenolic Acid; Ribonucleosides; Severity of Illness Index; Sirolimus; Tacrolimus

Topics: Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Models, Biological; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation Immunology

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B i

Topics: Amino Acid Isomerases; B-Lymphocytes; Biphenyl Compounds; Calcineurin; Calmodulin-Binding Proteins; Carrier Proteins; Cyclosporine; Enzyme Inhibitors; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Isoxazoles; Leflunomide; Mycophenolic Acid; Oxidoreductases; Peptidylprolyl Isomerase; Phosphoprotein Phosphatases; Polyenes; Purines; Pyrimidines; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; T-Lymphocytes; Tacrolimus

Topics: Biphenyl Compounds; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus; Transplantation Immunology

Topics: Animals; Antimetabolites; Azathioprine; Biphenyl Compounds; Cell Differentiation; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lymphocytes; Lymphokines; Oligonucleotides, Antisense; Polyenes; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; Tacrolimus

Topics: Animals; Biphenyl Compounds; Cyclosporine; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Tacrolimus; Xenobiotics

Topics: Animals; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus

Topics: Cell Line; Cells, Cultured; Cyclosporine; Humans; Immunosuppressive Agents; Kinetics; Lymphocyte Activation; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; T-Lymphocytes; Tacrolimus