mycophenolic-acid and Aortic-Diseases

Cardiovascular involvement occurring in 20-30% patients is the second most common cause of mortality in patients with relapsing polychondritis. Aortic insufficiency occurs as a result of aortic root dilatation rather than primary valvular involvement. We are reporting a patient of relapsing polychondritis with aortic root dilatation, in whom institution of early and aggressive therapy successfully prevented the progression of aortic insufficiency.

Topics: Aorta; Aortic Diseases; Aortic Valve Insufficiency; Azathioprine; Cyclophosphamide; Dilatation, Pathologic; Drug Substitution; Drug Therapy, Combination; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Polychondritis, Relapsing; Prednisolone

Small series and case reports suggest that a combination of mycophenolate mofetil and prednisone is an efficatious and safe treatment for patients with retroperitoneal fibrosis.. To describe the outcomes of patients with retroperitoneal fibrosis treated with a combination of prednisone and mycophenolate mofetil.. Prospective, case series.. 31 patients with retroperitoneal fibrosis.. Single-center tertiary care facility.. Prednisone 40 mg administered daily and tapered over 6 months and mycophenolate mofetil 1,000 mg given twice daily.. Clinical course, laboratory assessment, measurement of periaortic mass.. Systemic symptoms resolved in all patients. Eighty-nine percent of patients had a 25% or greater reduction in periaortic mass. Eighteen patients had 32 obstructed ureters. Thirty of these ureters were free of obstruction after an average of 513 days of therapy. Laboratory abnormalities of elevated erythrocyte sedimentation rate and serum creatinine and decreased hemoglobin levels normalized in all patients. Recurrent disease occurred in 2 of 28 patients.. Combined prednisone and mycophenolate mofetil appears to be an effective therapeutic option for patients with retroperitoneal fibrosis.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Aortic Diseases; Disease Management; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Retroperitoneal Fibrosis; Retrospective Studies; Tertiary Care Centers; Treatment Outcome; Ureteral Obstruction

This study tested whether immunosuppression with mycophenolate mofetil (MMF) inhibits atherosclerosis development in apolipoprotein-E-deficient (Apoe(-/-)) mice and investigated the mechanism.. Chronic vascular inflammation involving both innate and adaptive immunity is central in the development of atherosclerosis, but immunosuppressive treatment is not uniformly beneficial. The immunosuppressive MMF targets lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase.. Young and aged Apoe(-/-) mice were treated with 30 mg/kg daily MMF during 12 and 3 weeks of a high-fat diet, respectively. Aortic lesion size and composition was investigated by histology and flow cytometry; soluble inflammatory mediators were investigated by enzyme-linked immunosorbent assay.. Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in both MMF-treated groups. While systemic immunoglobulin G directed against low-density lipoproteins was not significantly altered, the T-cell cytokine interleukin (IL)-17 was significantly reduced in plasma of MMF-treated mice and supernatants from their aortas after T-cell stimulation. The MMF treatment decreased aortic αβ T-cell receptor(+) lymphocyte proliferation and cell numbers. Also, aortic contents of CD11b(+)CD11c(+) cells and their proliferation were reduced in MMF-treated Apoe(-/-) mice. The IL-17 supplementation restored the number of proliferating aortic CD11b(+)CD11c(+) cells in MMF-treated mice. The IL-17 receptor A was highly expressed on circulating monocytes that are macrophage progenitors. Genetic deletion of IL-17 receptor A or IL-17A reduced inflammatory peritoneal CD11b(+)CD11c(+) macrophage accumulation.. The lymphocyte-directed immunosuppressant MMF that curbs IL-17 production was a successful antiatherosclerotic treatment. Our data delineate a role for IL-17 in CD11b(+)CD11c(+) cell accumulation.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Female; Immunosuppressive Agents; Interleukin-17; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycophenolic Acid; T-Lymphocytes

Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity.. Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically.. Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft.. Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

Topics: Animals; Aorta; Aortic Diseases; Arterial Occlusive Diseases; Blood Cell Count; Cyclosporine; Drug Therapy, Combination; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Inbred Strains; Receptors, Lysosphingolipid; Retreatment; Sulfhydryl Compounds; T-Lymphocytes; Transplantation, Homologous; Tunica Intima

BACKGROUND.: Transplant arteriosclerosis is one of the main features of chronic graft failure in organ transplantation. In this article, the authors investigate mechanisms of mycophenolate mofetil (MMF) on prevention of transplant arteriosclerosis in a rat aortic allograft model.. Orthotopic rat abdominal aortic transplantation was performed from Brown Norway (RT1) to Lewis (RT1) rats. The recipients were divided into three oral treatment groups: (1). vehicle; (2). MMF40 (40 mg/kg); and (3). MMF20 (20 mg/kg). The authors histologically and immunohistochemically evaluated neointima formation; infiltration of macrophages and T cells; and expression of endothelin (ET)-1, platelet-derived growth factor (PDGF)-B, PDGF receptor-beta (Rbeta), transforming growth factor (TGF) beta 1, and osteopontin (OPN). Using cultured rat vascular smooth muscle cells (VSMC), effects of mycophenolic acid (MPA) on ET-1-induced proliferation and ERK1/2 activation were also examined in vitro.. In the vehicle group, marked neointima formation was observed, with massive macrophages and T-cell infiltration in neointima, media, and adventitia. Marked expression of ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN were also observed in neointima. In the MMF40 and MMF20 groups, neointima formation was halted, but macrophages and T cells were infiltrated in the adventitia and adhered to the endothelium. In the MMF40 group, medial infiltration by macrophages and T cells and intimal expression of ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN was inhibited compared with the vehicle and MMF20 groups. Furthermore, MPA inhibited ET-1-induced VSMC proliferation but failed to inhibit its ERK1/2 activation.. MMF treatment might have preventive potential in transplant patients with chronic vasculopathy through inhibition of VSMC proliferation.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Arteriosclerosis; Body Weight; Cell Division; Cells, Cultured; Endothelin-1; Growth Substances; Immunosuppressive Agents; Macrophages; Male; Muscle, Smooth, Vascular; Mycophenolic Acid; Myocytes, Smooth Muscle; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rats, Sprague-Dawley; T-Lymphocytes; Tunica Intima