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PubMed2000

Immunosuppressive agents in transplantation: mechanisms of action and current anti-rejection strategies.

Over the past century, the concept of interfering with the immune response at various sites by blocking the formation, stimulation, proliferation, and differentiation of lymphocytes has led to relentless development of new immunosuppressive drugs. These agents are associated with reduced risk of short- and long-term toxicity and have dramatically improved allograft and patient survival, especially in recipients of solid organ transplants. Current protocols in such patients are nearly all calcineurin-inhibitor based, using cyclosporine or tacrolimus, as part of dual, triple, or sequential therapy. This review focuses on agents currently in clinical use at transplant centers in United States. The drugs are described in terms of their basic mechanisms of action, therapeutic uses, clinical studies, and adverse effects. In addition, the efficacy and toxicity of a few promising new therapeutic approaches are examined. Finally, important challenges regarding pharmacological immunosuppression as it relates to solid organ and composite tissue allotransplantation are discussed.

Drug Therapy, Combination↗
PubMed1993

Treatment of life-threatening autoimmune diseases with myeloablative doses of immunosuppressive agents: experimental background and rationale for ABMT.

We describe a case of autoimmune-mediated mixed cryoglobulinemia with vasculitis and nephritis that was successfully treated with acute myeloablative immunosuppressive treatment. The case suggests that elimination of autoreactive lymphocytes followed by de novo regeneration of lymphocytes from autologous stem cells that re-acquire unresponsiveness towards self may be successfully accomplished in life-threatening autoimmune diseases. The combination of acute myeloablative immunosuppression followed by syngeneic stem cell transplantation may be an effective treatment for severe autoimmune diseases.

Adult↗
PubMed1998

Hepatitis viruses under immunosuppressive agents.

Clinical and experimental studies have shown that T cell-mediated immune mechanisms are involved in the pathogenesis of hepatitis B virus (HBV) and hepatitis C virus infection. Immunosuppressants may impair T cell function and thereby reduce immune-mediated hepatocytolysis and virus clearance. In addition, corticosteroid may activate the glucocorticoid responsive element in the HBV genome to enhance HBV replication and gene expression. These combined effects result in an increase of viraemia in association with a decrease of serum aminotransferase and hepatic necroinflammation. In acute infection, use of immunosuppressants will increase the incidence of chronic evolution. In chronic infection, withdrawal of immunosuppressants will be followed by a clinical flare due to a rebound of immune attack to hepatocytes with increased viral load. This may lead to a subsequent decrease of the viraemia. Therefore, short-term use of immunosuppressant before antiviral therapy may be beneficial in the treatment of chronic viral hepatitis. However, the clinical rebound may be extremely severe and lead to hepatitis failure; thus, the patients should be monitored closely upon tapering and after the withdrawal of immunosuppressants. Long-term use of immunosuppressants in patients with hepatitis virus infection is usually deleterious, particularly in patients after organ transplantation. These findings suggest that clinicians should be cautious in the use of immunosuppressants in patients with hepatitis virus infection.

Animals↗
PubMed2000

Sirolimus, a new potent immunosuppressant agent for refractory cardiac transplantation rejection: two case reports.

Rejection remains a major cause of both early and late morbidity and mortality following heart transplantation despite major advances in immunosuppressive therapy. A major hurdle in the successful management of patients who have undergone heart transplantation is preventing and treating graft rejection. Cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus (FK506) and OKT3 are well documented, effective immunosuppressive medications that prevent and treat acute or chronic rejection following heart transplantation. One of the macrolide antibiotics, sirolimus, is known to have immunosuppressant activity. In two patients with chronic rejection of cardiac grafts refractory to usual antirejection medications, sirolimus was successfully used to suppress graft rejection. Both patients continued to be rejection free after 10 months of sirolimus treatment despite significant decreases in doses of other immunosuppressants.

Administration, Oral↗
PubMed1998

In vitro and in vivo mechanisms of action of the antiproliferative and immunosuppressive agent, brequinar sodium.

Intracellular pyrimidine nucleotides (PyN) can be synthesized de novo from glutamine, CO2, and ATP, or they can be salvaged from preformed pyrimidine nucleosides. The antiproliferative and immunosuppressive activities of brequinar sodium (BQR) are thought to be due to the inhibition of the activity of dihydroorotate dehydrogenase, which results in a suppression of de novo pyrimidine synthesis. Here we describe the effects of the pyrimidine nucleoSide, uridine, on the antiproliferative and immunosuppressive activities of BQR. In vitro reduction of PyN levels in Con A-stimulated T cells and inhibition of cell proliferation by low concentrations of BQR (< or =65 microM) are reversed by uridine. However, uridine is unable to reverse the effects of high concentrations of BQR (> or =65 microM). The ability of BQR to induce anemia in BALB/c mice is prevented by the coadministration of uridine. In contrast, the immunosuppressive activity of BQR is unaffected by similar doses of uridine. PyN levels in the bone marrow, but not in the spleen, are depressed in mice treated with BQR. These observations suggest that the induction of anemia by BQR is due to depletion of intracellular PyN in hemopoietic stem cells located in the bone marrow. They also suggest that the mechanism of immunosuppression by BQR may be only marginally dependent on depletion of intracellular PyN in lymphocytes located in the periphery. We report a novel activity of BQR: inhibition of tyrosine phosphorylation, and hypothesize that the immunosuppressive activity may be due, in part, to this unsuspected ability of BQR to inhibit tyrosine phosphorylation in lymphocytes.

Animals↗