Mycophenolate mofetil and its mechanisms of action.

Mycophenolate mofetil (MMF, CellCept(R)) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. T- and B-lymphocytes are more dependent on this pathway than other cell types are. Moreover, MPA is a fivefold more potent inhibitor of the type II isoform of IMPDH, which is expressed in activated lymphocytes, than of the type I isoform of IMPDH, which is expressed in most cell types. MPA has therefore a more potent cytostatic effect on lymphocytes than on other cell types. This is the principal mechanism by which MPA exerts immunosuppressive effects. Three other mechanisms may also contribute to the efficacy of MPA in preventing allograft rejection and other applications. First, MPA can induce apoptosis of activated T-lymphocytes, which may eliminate clones of cells responding to antigenic stimulation. Second, by depleting guanosine nucleotides, MPA suppresses glycosylation and the expression of some adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into sites of inflammation and graft rejection. Third, by depleting guanosine nucleotides MPA also depletes tetrahydrobiopterin, a co-factor for the inducible form of nitric oxide synthase (iNOS). MPA therefore suppresses the production by iNOS of NO, and consequent tissue damage mediated by peroxynitrite. CellCept(R) suppresses T-lymphocytic responses to allogeneic cells and other antigens. The drug also suppresses primary, but not secondary, antibody responses. The efficacy of regimes including CellCept(R) in preventing allograft rejection, and in the treatment of rejection, is now firmly established. CellCept(R) is also efficacious in several experimental animal models of chronic rejection, and it is hoped that the drug will have the same effect in humans.

[Present and future of immunosuppressive therapy]. / Presente y futuro de la terapia inmunosupresora.

Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.

Presente y futuro de la terapia inmunosupresora. / [Present and future of immunosuppressive therapy]

Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.

Presente y futuro de la terapia inmunosupresora / [Present and future of immunosuppressive therapy]

Immunosuppressive drugs make possible the acceptance of organ allografts among individuals with differences in Major Histocompatibility Antigens (HLA). Transplantation of vital organs prolongs the survival of patients with terminal diseases, and this procedure has become a routine practice in the clinic, mainly because of advances in immunosuppressive therapy. Some immunosuppressive drugs, such as glucocorticosteroids and azathioprine, have been used for the past 30 years. More recently, newly discovered agents with a better ratio of efficacy to toxicity have been added to the armamentarium of anti-rejection therapies. Progress in understanding T cell activation in response to alloantigens has contributed to the development of new and more selective strategies to control the immune response and prevent acute rejection. The use of drugs in combination, with or without monoclonal antibodies, has also improved the efficacy and reduced the toxicity of immunosuppressive therapies. The new agents include drugs that interfere with calcineurin, inhibitors of de novo purine biosynthesis, kinase inhibitors, as well as monoclonal antibodies that block activation signals on the surface of T cells or co-stimulatory signals between T cells and antigen-presenting cells. In this review the modes of action of commonly used immunosuppressive drugs are described. Successful new strategies are also being developed to establish tolerance to allografts in rodents and non-human primates. The progress in these approaches, although still in the experimental stages, offers promising alternatives for these patients in the future. Treatment protocols using combinations of drugs with antibodies that might produce tolerance in humans are also discussed.

Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid.

Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.

Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF).

Mycophenolate mofetil (MMF) is a novel immunosuppressive drug that shows promise in preventing the rejection of organ allografts and in the treatment of ongoing rejection. Orally administered MMF is hydrolyzed by esterases in the intestine and blood to release mycophenolic acid (MPA), a potent, selective, noncompetitive inhibitor of the type 2 isoform of inosine monophosphate dehydroxygenase (IMPDH) expressed in activated human T and B lymphocytes. By inhibiting IMPDH, MPA depletes the pool of dGTP required for DNA synthesis. MPA has a more potent cytostatic effect on lymphocytes than on other cell types, and this is the principal mechanism by which immunosuppressive activity is exerted. MPA also depletes pools of GTP in human lymphocytes and monocytes, thereby inhibiting the synthesis of fucose- and mannose-containing saccharide components of membrane glycoproteins. These are recognized by the family of adhesion molecules termed selectins. By this mechanism, MPA could decrease the recruitment of lymphocytes and monocytes into sites of graft rejection. In addition to preventing allograft rejection, MMF suppresses graft-versus-host reactions in lethal and nonlethal murine models. MMF inhibits primary antibody responses more efficiently than secondary responses. MPA inhibits the proliferation of human B lymphocytes transformed by Epstein-Barr virus and is not mutagenic. Clinically attainable concentrations of MPA suppress the proliferation of human arterial smooth muscle cells. These two properties of MPA may decrease the risk of lymphoma development and proliferative arteriopathy in long-term recipients of MMF.

Some antioxidants inhibit, in a co-ordinate fashion, the production of tumor necrosis factor-alpha, IL-beta, and IL-6 by human peripheral blood mononuclear cells.

Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydropapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyaporphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1 beta, and IL-6 by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS) (IC50s in the low micromolar range). Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis. Inhibition of cytokine production by PBMC was observed also when other inducers were used (staphylococci, silica, zymosan). Much higher concentrations of other antioxidants--including ascorbic acid, trolox, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton--did not affect the production of these cytokines. The active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs. Nuclear run-on experiments showed that THP inhibited transcription of the IL-1 beta gene. THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL-1 beta in the circulation of mice following LPS injection. Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines. Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.

Effects of sarcoma 180 growth on interleukin-1 and circulating immune complexes.

Cultured splenic mononuclear adherent cells (SMAc) from normal BALB/c mice as well as those from mice bearing 10-day sarcoma 180 (S180), exhibited a marked increase in Escherichia coli lipopolysaccharide-stimulated interleukin-1 (IL-1) production, when compared to spontaneous values. On days 20 and 30 following S180 challenge, a decrease in this effect on IL-1 production in treated and untreated SMAc was observed. Concomitantly with the alterations in the regulation of IL-1 production during tumor growth, an increase in the levels of prostaglandin E2 and serum immune complexes could be detected. These data suggest that the immunosuppression associated with later stages of tumor development may be due to direct effects on monocytes, by means of a down-regulation of IL-1 production.