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PubMed1999

Sjögren's syndrome in mice carrying the Ipr(cg) gene and the therapeutic efficacy of an immunosuppressive agent FK506.

The influence of the Ipr(cg) gene on the development of Sjögren's syndrome was followed up to 5 months of age in male and female mice of MRL, CBA and C3H strains. In MRL-Ipr(cg) mice, focal mononuclear cell infiltration started at 2 months and became conspicuous after 3 months of age in the lacrimal and submandibular glands but was minimal in the parotid and sublingual glands, even at 5 months of age, without any apparent sex effects found. In CBA and C3H mice carrying the Ipr(cg) gene, this manifestation of Sjögren's syndrome was much less prominent, indicating that the participation of some genes of the MRL strain may be indispensable for the development of Sjögren's syndrome in mice carrying this gene. In MRL-Ipr(cg) mice, an immunosuppressive agent, FK506, improved the serological abnormalities (decreased levels of anti-double-stranded DNA antibody of IgG2a and IgG3 subclasses) and proteinuria. It also reduced the manifestations of Sjögren's syndrome when it was intraperitoneally administered three times weekly at a dose of 2 mg/kg from 6 weeks (before disease onset) until 5 months of age (the termination of the experiment). Although VP8.2+ T cells have been demonstrated to be responsible for causing several autoimmune diseases, the selective deletion of Vp8.2+ T cells with the superantigen encoded by mouse mammary tumor virus did not affect the disease severity at all, suggesting that this T cell repertoire may not play a crucial role in induction of Sjögren's syndrome.

Animals↗

PubMed1984

Studies on antinephritic effect of mizoribine (p-INN, Bredinin), a new immunosuppressive agent, and azathioprine. (2) Effect on crescentic-type anti-GBM nephritis in rats.

Crescentic-type nephritis was induced in rats by immunizing with rabbit gamma-globulin following i.v. injection of rabbit anti-rat glomerular basement membrane (anti-GBM) serum. The antinephritic effect of mizoribine was compared to that of azathioprine by administration from the 2nd day after the injection of anti-GBM serum to the 23rd day (Experiment I) and from the 15th to the 38th day (Experiment II). The experiment I assessment on the 24th day revealed that mizoribine at a dose of 7.5 mg/kg/day p.o. remarkably reduced plasma cholesterol level, wet kidney weight and glomerular histopathological changes (i.e., crescent formation and fibrinoid deposition). In addition, mizoribine at this dose also tended to reduce urinary protein excretion and the adhesion of capillary walls to Bowman's capsule. At a dose of 5 mg/kg/day p.o., mizoribine significantly reduced kidney weight and crescent formation. On the other hand, azathioprine at a dose of 20 mg/kg/day p.o. had a tendency to reduce these biochemical and histopathological parameters. In the experiment II assessment on the 39th day, the effects of both drugs were somewhat diminished compared to those in experiment I. Mizoribine strikingly inhibited the crescent formation with 5 and 7.5 mg/kg/day p.o. and inhibited the fibrinoid deposition with a dose of 7.5 mg/kg/day p.o. Azathioprine at a dose of 20 mg/kg/day p.o. was prone to reduce histopathological parameters. The above data indicate that mizoribine may be a useful new immunosuppressive agent for rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesion with the extensive formation of crescents.

Animals↗

PubMed1994

The benefit of early treatment with immunosuppressive agents in lupus nephritis.

OBJECTIVE: In a cohort of 87 patients with lupus nephritis, delay between the detection of the onset of renal disease and renal biopsy was a significant predictor at the time of a first renal biopsy for subsequent renal insufficiency (relative risk - 4.9; 95% confidence interval = 1.7 to 14.5; p < 0.001) and death due to lupus renal involvement (relative risk = 6.7; 95% confidence interval = 2.1 to 21.2; p < 0.001). We evaluated the role of lead time bias, 2 variants of prognostic selection bias (length biased sampling), and the benefit of early treatment as explanations for this effect. METHODS AND RESULTS: Evaluation using the time of renal onset rather than the time of renal biopsy for the analysis suggested that lead time bias was unlikely to be an explanation for the effect of duration on renal insufficiency or death due to renal involvement. Identical values of age, serum creatinine and 24 hour urinary protein excretion at renal onset for those with a long duration versus short duration prior to biopsy, suggested that differences in prognostic selection were unlikely to explain the observed results. A 2nd type of prognostic selection bias arising from the failure to include patients who did not undergo a renal biopsy was further assessed by statistical simulation. The results of this approach indicated that prognostic selection bias was not solely responsible for the significant associations. Because treatment with high dose prednisone and immunosuppressive drugs was not instituted until a renal biopsy had been performed, delay in instituting these therapies remained a possible explanation for the increased frequency of renal insufficiency and death due to renal involvement observed in those with longer delays before renal biopsy. In addition, there was significant deterioration in serum creatinine (median change 0.6 mg/dl) and 24 hour urinary protein excretion (median change 2.5 gm) over the period from renal onset to renal biopsy, and significantly higher scores for the activity, chronicity and tubulointerstitial indices on renal biopsy in those in whom therapy was delayed. CONCLUSION: Prompt therapy with prednisone and immunosuppressive agents in lupus nephritis has a beneficial effect on longterm prognosis.

Adult↗

PubMed1989

Lymphocytic myocarditis and dilated cardiomyopathy: treatment with immunosuppressive agents.

Thirty-four patients with history of congestive heart failure, dilated cardiomyopathy, and biopsy-proven lymphocytic myocarditis were treated for six months with immunosuppressive agents (prednisone and azathioprine) in addition to standard therapy for congestive heart failure. Seventy-three percent had improvement or resolution of the lymphocytic infiltrate, whereas 27% had persistent infiltrates. Improvement in myocardial histologic findings was unpredictable and did not correlate with age, gender, duration of symptoms, initial functional class, severity of left ventricular dysfunction, intensity of initial inflammatory infiltrate, or degree of myocardial cell injury. Histologic response was associated with significant improvement in left ventricular ejection fraction, but not cardiothoracic ratio, left ventricular dimensions, or survival. Functional class improved equally whether patients' disease did or did not respond to the treatment, and was not necessarily associated with objective improvement in cardiac function. Immunosuppressive therapy resulted in serious or fatal side effects in 24% of patients. Overall long-term survival was 79% at one year and 76% at two years. Poor survival was related to left ventricular ejection fraction less than 20%, male sex, age less than 50 years, and marked left ventricular dilation, but not to myocardial histologic findings. These findings indicate that the potential benefits nu the risks of immunosuppressive therapy must be weighed carefully in the individual patient.

Adult↗

PubMed1992

Possible enhancing effect of the immunosuppressive agent, 6-mercaptopurine(6-MP) on focal lesion development in cirrhotic liver induced by carbon tetrachloride but not furfural in F344 rats.

The modifying effects of an immunosuppressive agent, 6-mercaptopurine (6-MP), on development of focal lesions in liver cirrhosis models induced by carbon tetrachloride (CCl4) or furfural were studied in male F344 rats. Feeding of 6-MP at 50 p.p.m. for 20 weeks to animals with pre-existing liver cirrhosis caused immunosuppression, and significantly enhanced the induction of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the CCl4 but not furfural case. Glutathione S-transferase P (GST-P)-positive preneoplastic lesions were not affected. Moreover, phenobarbital (PB) also enhanced the induction of GGT-positive hepatocellular lesions only in the CCl4-induced liver cirrhosis model, no promotion influence being exerted after treatment with the non-carcinogenic furfural. This study, therefore, suggests that 6-MP can enhance the induction of one type of preneoplastic foci and nodules and that essential differences exist between focal lesions arising in cirrhotic livers caused by CCl4 as opposed to furfural.

Alkaline Phosphatase↗

PubMed2000

[Withdrawal of prednisone from a triple combination of immunosuppressive agents after kidney transplantation].

BACKGROUND: Triple-drug immunosuppression may not be necessary in a majority of stabilized patients over 1 year after kidney transplantation. In contrary steroid withdrawal may be beneficial for the patient by elimination of side-effects. The primary aim of this study was assessment of the risk of rejection after the prednisone withdrawal. METHODS AND RESULTS: 88 patients 1 year after the first renal transplantation with stable graft function and serum creatinine < 160 mumol/l treated with cyclosporine-A, azathioprine and prednisone were randomized into group A (n = 46) with a prednisone withdrawal and group B (n = 42) on triple-drug therapy without change. At the time of randomization, fine-needle biopsy was carried out in all of the patients. In group A, the dose of prednisone was gradually reduced to zero in the course of six months and the patients were followed up for the next 12 months. In the group B, patients on triple-drug therapy were followed for the corresponding period of time. 3 patients (6.6%) in group A, and 2 (4.8%) in group B experienced rejection (NS). Mean values of serum creatinine were in the course of follow-up in both groups without any statistical difference. Suspect immunological activity or proved immunological activity in aspiration biopsy was present in 4 patients in each group, but one of them rejected the graft. In comparison with group B, a significant decrease of cholesterol and leukocytes was observed in group A. Prednisone withdrawal had no influence on hypertension and triglyceride. CONCLUSIONS: Gradual withdrawal of steroids is not associated with higher risks of rejection and has a beneficial effect on cholesterol levels. Aspiration biopsy was of no use for the prediction of rejection.

Azathioprine↗

PubMed2003

Transplant immunosuppressant agents and their role in autoimmune rheumatic diseases.

This article examines immunosuppressant transplant agents used to treat the various rheumatic diseases. The older drugs of this type have been used in this dual role for decades. There is a new generation of immunosuppressant drugs with established use in the arena of transplantation medicine. Only recently have the potential rheumatologic applications for these agents been investigated. The authors review in depth the published experience with the newer agents. The authors also discuss novel rheumatologic uses for the older agents that have been described within the past year.

Autoimmune Diseases↗

PubMed1991

The immunosuppressive agent FK506 inhibits in vitro expression of membrane-bound and soluble interleukin-2 receptors on resting but not on activated human lymphocytes.

FK506 is a recently introduced immunosuppressive agent synthesised by the microorganism Streptomyces tskubaensis. It has been found to be more potent than Cyclosporin A in inhibiting T cell activation. We investigated its effects on the expression of membrane bound as well as soluble interleukin-2 receptors on human lymphocytes. The membrane-bound IL-2 receptor expression was inhibited by FK506 in resting lymphocytes at a concentration of 1 pmol/l. At 10 nmol/l no further inhibition was seen. In activated lymphocytes FK506 exerted no inhibitory effect on the IL-2 receptor expression. The release of soluble IL-2 receptor showed a pronounced decline in the concentration interval between 10 pmol/l and 0.1 nmol/l. Above a concentration of 10 nmol/l, no further decrease was seen. In activated lymphocytes the expression of soluble IL-2 receptors was unaffected by FK506 incubated up to 72 h. Pretreatment of the lymphocytes with the compound did not further depress the expression of the membrane-bound or the soluble receptor. Our results also indicate that the expression of the membrane-bound receptor is more sensitive to the drug than the soluble form of the receptor.

Enzyme-Linked Immunosorbent Assay↗

PubMed2001

Clinical course of patients with IgA nephropathy between combined treatment of immunosuppressive agents and ACE inhibitor and ACE inhibitor alone.

BACKGROUND: It has not been clear whether immunosuppressive therapy favorably influences renal function and proteinuria in IgA nephropathy (IgAN). Angiotensin converting enzyme inhibitor (ACEi) has an anti-proteinuric effect in IgAN. A retrospective study was done to see whether the addition of immunosuppressive therapy to ACEi produces a more excellent anti-proteinuric effect and preserves better renal function than ACEi alone. METHODS: A total of 49 patients with proteinuria > 1.0 g/day and serum creatinine concentrations < 1.5 mg/dL were followed-up from at least 1 year to 9 years. Among them, 25 patients were treated with the combination of cyclophosphamide, prednisolone and ACEi while the other 24 were treated with ACEi alone. RESULTS: The combination therapy or ACEi alone both reduced proteinuria with significant value (the combination group: from 5.74 +/- 5.08 to 2.29 +/- 2.77 g/day, ACEi group: from 3.85 +/- 2.54 to 1.68 +/- 1.91 g/day), while no significant differences in reduction of proteinuria were noticed between the two groups. There was no significant elevation of serum creatinine in both groups during follow-up (the combination group: from 0.91 +/- 0.20 to 1.03 +/- 0.38 mg/dL, ACEi group: from 0.93 +/- 0.27 to 0.99 +/- 0.37 mg/dL). This study showed no significant differences in the change in slope of 1/serum creatinine levels during the follow-up period between the two groups. CONCLUSION: We conclude that immunosuppressive therapy may not be beneficial in patients with proteinuric IgAN. ACEi may be a valuable therapeutic agent avoiding serious side effects of immunosuppressive agents.

Adolescent↗

PubMed1995

Important interactions of drugs with immunosuppressive agents used in transplant recipients.

Solid organ transplant recipients depend on multiple immunosuppressive drugs, given in combination, to prevent rejection of their allografts. These patients often require many other therapeutic agents to treat underlying illnesses or concurrent diseases. Whenever a new medication is administered to a transplant patient, the potential exists for increasing or decreasing the tissue concentrations of immunosuppressive agents. This can lead to serious complications, such as over-immunosuppression and infection, under-immunosuppression and acute rejection, or additive toxicities, including nephrotoxicity. New immunosuppressants are under development and in clinical use, such as FK506, deoxyspergualin, OG 37-325, rapamycin, brequinar, and mycophenolate mofetil, thereby creating the possibility of many new drug-drug interactions.

Azathioprine↗

PubMed1994