We report two cases of gingival plasma cell granuloma in a 34-yr-old and 40-yr-old two male renal transplant recipients with cyclosporine A (CsA)-induced gingival overgrowth (GO). Histologically, these lesions were composed of mature plasma cells, showing polyclonality for both lambda and kappa light chains and fibrovascular connective tissue stroma. In addition to the fact that CsA-induced plasma cell granuloma is rare, the salient features of our cases were the secretion of interleukin-6 and overexpression of phospholipase C-gamma1 of the tumor cells, which may explain the mechanisms of CsA- induced GO.
Cyclosporine/adverse effects ; Female ; Gingival Diseases/*chemically induced/enzymology/immunology/pathology ; Granuloma, Plasma Cell/*chemically induced/enzymology/immunology/pathology ; Humans ; Immunohistochemistry ; Immunosuppressive Agents/adverse effects ; Interleukin-6/metabolism ; Kidney Transplantation ; Male ; Middle Aged ; Phospholipase C gamma ; Type C Phospholipases/metabolism

Cyclosporine (CsA) has improved patient and graft survival rates following solid-organ transplantation and has shown significant clinical benefits in the management of autoimmune diseases. However, the clinical use of CsA is often limited by acute or chronic nephropathy, which remains a major problem. Acute nephropathy depends on the dosage of CsA and appears to be caused by a reduction in renal blood flow related to afferent arteriolar vasoconstriction. However, the mechanisms underlying chronic CsA nephropathy are not completely understood. Activation of the intrarenal renin-angiotensin system (RAS), increased release of endothelin-1, dysregulation of nitric oxide (NO) and NO synthase, up-regulation of transforming growth factor-beta1 (TGF-beta1), inappropriate apoptosis, stimulation of inflammatory mediators, enhanced innate immunity, endoplasmic reticulum stress, and autophagy have all been implicated in the pathogenesis of chronic CsA nephropathy. Reducing the CsA dosage or using other renoprotective drugs (angiotensin II receptor antagonist, mycophenolate mofetil, and statins, etc.) may ameliorate chronic CsA-induced renal injury. This review discusses old and new concepts in CsA nephropathy and preventive strategies for this clinical dilemma
Animals ; Chronic Disease ; Cyclosporine/*adverse effects ; Humans ; Immunosuppressive Agents/*adverse effects ; Kidney/*drug effects/immunology/metabolism/pathology ; Kidney Diseases/*chemically induced/immunology/metabolism/pathology/prevention & control ; Risk Factors ; Signal Transduction/*drug effects

Three kinds of networks were summarily described in this review including the small intracellular molecular networks, the middle-scale networks of hypothalamus-pituitary-adrenal-thymus (HPAT) axis and the large network, neuroendocrine-immune (NEI) network, covering the whole organism and linking multiple systems together. The hypothesis was expressed that the "disease" or "syndrome" formed in the human body by the intervention from outside world is based on the changes of multi-molecular network. In this paper, the pattern and ability of signal transduction channel and the methods of studying changes in it were also described, and raised, herefrom, "to determine syndrome by drug effects (DSDE)" is the intervention means for studying syndrome in the light of systemic biological methods. We found Kidney-yang deficiency syndrome covered the NEI network and the regulating center located in hypothamus with Compound Bushen Recipe (CBR, Kidney-tonifying recipe). By intervention with EF, an effective component of CBR, it was found that EF can activate the immune system and the three networks, including growth axis, sex hormone axis and lymphocyte apoptosis network in HPAT axis through the downward pathway of NEI network to play its efficiency of molecular network. There are many regulation patterns of EF on networks. For example, in the network mechanism of lymphocyte apoptosis and proliferation, EF can reconstruct the balance of the opposite apoptosis related genes and proliferation related genes; EF can assemble and integrate co-stimulating molecules, transform growth factors (TGF), and several oncogenes to form an upstream factor network for initiating the proliferation and anti-apoptosis promotion; EF can simultaneously up-regulate the two opposite genes expression of IkappaB and NFkappaB in NIK/IKK/IkappaB/Rel/NFkappaB signal transduction channel, which could not only control the rising of NFkappaB in a moderate range, but also guarantee its predominant status to exert its hinge role in molecule regulating network, by which gene network regulation atlas in HPAT axis of Kidney-deficiency syndrome was observed.
Animals ; Apoptosis ; genetics ; physiology ; Diagnosis, Differential ; Drugs, Chinese Herbal ; pharmacology ; Gene Expression ; Humans ; Hypothalamo-Hypophyseal System ; drug effects ; metabolism ; Kidney Diseases ; chemically induced ; genetics ; metabolism ; Lymphocytes ; metabolism ; pathology ; Medicine, Chinese Traditional ; Neurosecretory Systems ; immunology ; metabolism ; Pituitary-Adrenal System ; metabolism ; Rats ; Signal Transduction ; Yang Deficiency ; chemically induced ; genetics ; metabolism

PURPOSE: Local activation of the complement system plays a role in target organ damage. The aim of our study was to investigate the influence of cyclosporine (CsA)- induced renal injury on the complement system in the kidney. MATERIALS AND METHODS: Mice fed a low salt (0.01%) diet were treated with vehicle (VH, olive oil, 1mL/kg/day) or CsA (30mg/kg/day) for one or four weeks. Induction of chronic CsA nephrotoxicity was evaluated with renal function and histomorphology. Activation of the complement system was assessed through analysis of the expression of C3, C4d, and membrane attack complex (MAC), and the regulatory proteins, CD46 and CD55. CsA treatment induced renal dysfunction and typical morphology (tubulointerstitial inflammation and fibrosis) at four weeks. RESULTS: CsA-induced renal injury was associated with increased the expression of C3, C4d, and MAC (C9 and upregulation of complement regulatory proteins (CD 46 and CD55). Immunohistochemistry revealed that the activated complement components were mainly confined to the injured tubulointerstitium. CONCLUSION: CsA-induced renal injury is associated with activation of the intrarenal complement system.
Animals ; Antigens, CD45/analysis ; Antigens, CD46/analysis ; Antigens, CD55/analysis ; Complement C3/analysis ; Complement C4b/analysis ; Complement Membrane Attack Complex/analysis ; Complement System Proteins/*analysis ; Cyclosporine/*toxicity ; Disease Models, Animal ; Immunity, Innate/drug effects ; Immunoblotting ; Immunohistochemistry ; Immunosuppressive Agents/toxicity ; Kidney/*drug effects/immunology/pathology ; Kidney Diseases/*chemically induced/immunology ; Mice ; Microscopy, Confocal ; Peptide Fragments/analysis