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PubMed1995

Immunosuppressive agents and endothelial repair. Prednisolone delays migration and cytoskeletal rearrangement in wounded porcine aortic monolayers.

Endothelial denudation at areas of predilection to atherosclerosis is balanced by an active repair process that may be inhibited under conditions of accelerated atherosclerosis. After cardiac transplantation, the accelerated atherosclerotic process that develops may be enhanced by immunosuppressive agents that have nonspecific effects on cell signaling, proliferation, and response to injury. To study subtle effects of cyclosporine A, azathioprine, and 6 alpha-methylprednisolone on normal endothelial repair processes, confluent porcine endothelial monolayers were denuded in the presence of clinically relevant concentrations of these agents. The rate of endothelial wound repair was compared and the effects on cell spreading, proliferation, and the cytoskeleton assessed. 6 alpha-Methylprednisolone at concentrations of 1.25 to 50 mumol/L was associated with a transient 30% to 60% inhibition of endothelial wound repair. This was associated with increased cell size at the wound edge and a delay in centrosomal reorientation toward the wound, without any effect on cell proliferation. Cyclosporine and azathioprine in clinically relevant concentrations did not affect endothelial repair. Thus, corticosteroids transiently inhibit endothelial cytoskeletal alterations that are important in endothelial repair after a denuding injury.

Animals↗

PubMed2000

Autoimmune cholangitis with features of autoimmune hepatitis: successful treatment with immunosuppressive agents and ursodeoxycholic acid.

We report a 42-year-old Chinese female with elevated serum levels of liver aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase, cholesterol and immunoglobulin M. Serum antimitochondrial antibody was negative, but antinuclear antibody was strongly positive. Liver histology showed features of both autoimmune cholangitis and autoimmune hepatitis. Combination therapy with immunosuppressive (prednisone and azathioprine) and choleuretic agents (ursodeoxycholic acid) was given. Serum aminotransferases and biliary enzymes showed much improvement after treatment. A follow-up liver biopsy showed improvement of both hepatic necroinflammation and bile duct damage. Biliary enzymes rose after withdrawal of the immunosuppressive agents and declined again with reinstitution of prednisone. This case demonstrates that a combination of immunosuppressive agents and ursodeoxycholic acid may effectively treat patients with features of both autoimmune cholangitis and autoimmune hepatitis.

Adult↗

PubMed1993

FK506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Histologic and immunopathologic observations.

We investigated possible explanations for the common occurrence of perivenular lesions in liver allografts of patients on FK506 within a few weeks to several months after OLT. Hematoxylin and eosin-stained sections of pre- and postperfusion biopsy specimens and day 7 post-transplant protocol biopsy specimens from 31 patients, randomly assigned to either FK506 or CsA as primary immunosuppressive agent, were reviewed, and immunohistochemical stains for HLA-DR antigen and S-100 protein were performed by the avidin-biotin peroxidase complex method. The histologic features of cellular rejection in the portal tracts of day 7 posttransplant allograft biopsy specimens from patients on FK506 were milder than those from patients on CsA. Immunohistochemical stains for HLA-DR showed intense positivity in a variety of cell types in day 7 posttransplant specimens from both groups, including sinusoidal-lining cells, bile duct epithelial cells, vascular endothelial cells, inflammatory cells, and occasional injured hepatocytes. Although diffuse lobular staining was seen in the majority of cases in both groups, either with or without rejection, liver biopsy specimens from patients on FK506 showed concentration of positively stained cells in perivenular regions more often, and at a lower overall histologic grade of rejection, than specimens from patients on CsA. There were no differences in the number and distribution of S-100 protein-positive dendritic APC between biopsy specimens from FK506 versus CsA-treated patients, or between specimens with and without cellular rejection in either group. It is suggested that the development of perivenular injury, which is seen frequently in allograft biopsy specimens from patients on FK506 obtained at various intervals after transplantation, may be related to drug toxicity rather than to the process of allograft rejection.

Cyclosporine↗

PubMedDate not supplied

Effect of a new immunosuppressive agent, FTY720, on survival of islet allografts.

A newly developed immunosuppressant, FTY720, has a unique mechanism that is quite different from those of conventional immunosuppressants, and is presumed to be mediated through decreases in the number of peripheral lymphocytes, especially helper T cells. This study was performed to ascertain whether this innovative drug could prolong islet allograft survival. The donors were inbred Lewis rats and the recipients were ACI rats rendered hyperglycemic with intravenous streptozotocin. In the study group, FTY720 dissolved in distilled water was orally administered at a dose of 5 mg/kg to the recipient ACI rats 1 day before and on the day of grafting. In the control group, only distilled water was orally administered to the recipient ACI rats on the day before and the day of grafting. Two thousand islets were transplanted into the portal vein of the recipient rats in the study and control groups immediately after isolation. The graft survival time in the study group was significantly longer than that in the control group, indicating that FTY720 retains a potent effect on the prolongation of islet allograft survival. FTY720 could become a useful immunosuppressant for future clinical islet allotransplantation.

Animals↗

PubMed1999

Immunosuppressive agents in organ transplantation.

This article reviews current and future immunosuppressive strategies in organ transplantation. Recently introduced drugs are lowering the rates of acute rejection and allowing more individualized management of transplanted patients.

Calcineurin Inhibitors↗

PubMed2003

The emerging matrix of immunosuppressive agents.

In recent years, significant milestones have been reached in the field of transplantation through the development of immunosuppressive drugs that inhibit lymphocyte activation, cytokine signal transduction, and cellular proliferation. However, the widespread tissue distribution of the molecular targets exploited to date-calcineurin, mammalian target of rapamycin (mTOR), and inosine monophosphate dehydrogenase-produces an array of collateral toxicities. Avoiding these side effects requires new strategies that selectively block destructive immune responses: a fifth generation of immunosuppressants. These agents must target molecules that are critical for and specific to the adaptive immune response.

Animals↗

PubMed1991

Triple agent immunosuppression in serpiginous choroiditis.

Serpiginous choroidopathy is a progressive choroidal inflammatory disorder that typically has a variable saltatory course. Response to steroids is uncertain. By using azathioprine, cyclosporine, and prednisone in combination, the authors have observed rapid remission of active disease in five patients. Remissions have been maintained for periods up to 18 months. Because of the synergistic effects of this combination, doses could rapidly be reduced to maintenance levels without reactivation. Disease in two patients recurred immediately after discontinuation of low-dose therapy but was arrested when therapy resumed. Triple agent immunosuppressive therapy is well tolerated and appears to be effective.

Adult↗

PubMed1988

[The effects of various cell growth factors and cyclosporin A, an immunosuppressive agent, on cloned osteoblastic cell line, MC3T3-E1 cells].

Cloned MC3T3-E1 cells which have retained several osteoblast-like characteristics were derived from newborn mouse calvaria. In order to elucidate the function of osteoblasts, the effects of 1,25(OH)2D3, interleukin (IL)-1 beta, IL-3, interferon(INF)-gamma and epidermal growth factor(EGF) on the activity of alkaline phosphatase(Al-P'ase), DNA synthesis and the production of prostaglandin E2(PGE2) in MC3T3-E1 cells were studied. The influence of cyclosporin A(CSA), a potent immunosuppressive agent, was also studied. The following results were obtained: 1. 1,25(OH)2D3 increased the incorporation of [45Ca]Cl2 into matrix and accelerated the calcification of MC3T3-E1 cells. 2. Al-P'ase activity and the incorporation of [3H]-thymidine into MC3T3-E1 cells were increased by 1,25(OH)2D3 but decreased by IL-1 beta, INF-gamma, IL-3 and EGF. 3. IL-1 beta increased and INF-gamma decreased PG-E2 production by MC3T3-E1 cells. 4. CSA decreased either Al-P'ase activity or incorporation of [3H]-thymidine, and increased PG-E2 production in MC3T3-E1 cells. CSA which was simultaneously incubated with these various cell growth factors, showed a similar effect to that of CSA alone. These results suggest that cytokines produced from immune cells, could affect osteoblasts besides that of calcium regulating hormones like parathyroid hormone and 1,25(OH)2D3, implying a probability for the participation of immunocompetent cells in the regulation of bone metabolism.

Alkaline Phosphatase↗

PubMed1978

Effect of immunosuppressive agents on the blastogenic response of mouse spleen T and B lymphocytes. I. Culture conditions and the evaluation system.

A microplate culture system has been standardized for blastic transformation of lymphocytes, using various mitogens more or less specific to T lymphocytes (concanavalin A, phytohaemagglutinin, erythrogenic toxin) or B lymphocytes (lipopolysaccharides and their lipids A, pokeweed mitogen). The mitogen-stimulated lymphocyte activation was examined by the use of the nucleolar test determining the state of nucleolar RNA synthesis by morphologic criteria. In this introductory paper to a series of papers analyzing the specificity of action of the various chemical and biological immunosuppressive agents on the blastogenic responses of T and B lymphocytes, optimal concentrations of cells and blastogenic substances and other parameters were tested, and the kinetics of transformation was investigated in detail.

Animals↗

PubMedDate not supplied

Effects of immunosuppressive agents and particularly of cyclophosphamide on lymphocytes subsets in treated multiple sclerosis patients.

Immune treatments have been used in multiple sclerosis (MS) since 20 years, but it is still difficult to estimate their clinical efficacy as well as their precise immunological effects. The development of the monoclonal antibodies techniques makes it possible to appreciate certain immune effects of these treatments in MS patients and to correlate them with clinical results. It appears that Cyclophosphamide is able to correct the CD4/CD8 ratio imbalance observed in most MS patients and that this correction is generally associated with a beneficial effect on the disease. Other immunosuppressive agents appear less effective both on the CD4/CD8 ratio and on the progression of MS.

Cyclophosphamide↗

PubMed2005