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Abstract:

A number of natural and synthetic substances are used in the treatment of immunological disorders. The immunosuppressive drugs are widely utilized in clinical treatments of autoimmune disorders, in the prevention of transplant rejection as well as in non-autoimmune diseases such as allergy. The design of immunosuppressive therapies is based on the control of the exacerbated immune response. The pathophysiologic mean of this concept is to modulate the action of mononuclear cells, being T cells the main targets. Immunosuppressive agents have different molecular targets, and an important drawback in their use is that they also inhibit the normal immune system response. Depending on their mode of action, immunosuppressive drugs can be classified in four different groups: antinflammatory drugs of the corticosteroid family, inhibitors of the calcineurin pathway, cytototoxic or antiproliferative drugs and specific antibodies. In this article, we focus on the molecular action of immunosuppressive drugs such as steroids, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, sirolimus, mycophenolate mofetil, leflunomide and specific antibodies, providing data to characterize and improve the use of these agents.

Registro:

Documento: Artículo
Título:Molecular mechanisms of action of some immunosuppresive drugs
Autor:Liberman, A.C.; Druker, J.; Refojo, D.; Arzt, E.
Filiación:Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Palabras clave:Corticosteroids; Immunosuppressive drugs; T cells; antibody; antiinflammatory agent; azathioprine; basiliximab; calcineurin inhibitor; corticosteroid; cyclophosphamide; cyclosporin A; cytotoxic agent; daclizumab; immunosuppressive agent; leflunomide; mycophenolic acid 2 morpholinoethyl ester; OKT 3; rapamycin; steroid; tacrolimus; antiinflammatory agent; corticosteroid; immunosuppressive agent; allergy; article; autoimmune disease; drug mechanism; drug targeting; graft rejection; human; immune response; immunomodulation; immunopathology; molecular mechanics; mononuclear cell; pathophysiology; T lymphocyte; animal; autoimmune disease; drug effect; immune system; Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Humans; Immune System; Immunosuppressive Agents
Año:2008
Volumen:68
Número:6
Página de inicio:455
Página de fin:464
Título revista:Medicina
Título revista abreviado:Medicina (Argentina)
ISSN:00257680
CODEN:MEDCA
CAS:azathioprine, 446-86-6; cyclophosphamide, 50-18-0; cyclosporin A, 59865-13-3, 63798-73-2; leflunomide, 75706-12-6; mycophenolic acid 2 morpholinoethyl ester, 116680-01-4, 128794-94-5; OKT 3, 140608-64-6; rapamycin, 53123-88-9; tacrolimus, 104987-11-3; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Immunosuppressive Agents
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_00257680_v68_n6_p455_Liberman.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257680_v68_n6_p455_Liberman

Referencias:

  • Fischereder, M., Kretzler, M., New immunosuppressive strategies in renal transplant recipients (2004) J Nephrol, 17, pp. 9-16
  • Dambrin, C., Klupp, J., Morris, R.E., Pharmacodynamics of immunosuppressive drugs (2000) Curr Opin Immunol, 12, pp. 557-562
  • Armstrong, V.W., Oellerich, M., New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine (2001) Clin Biochem, 34, pp. 9-16
  • Myers, B.D., Sibley, R., Newton, L., Tomlanovich, S.J., Boshkos, C., Stinson, E., The long-term course of cyclosporine-associated chronic nephropathy (1988) Kidney Int, 33, pp. 590-600
  • Kasiske, B.L., Tortorice, K.L., Heim-Duthoy, K.L., Awni, W.M., Rao, K.V., The adverse impact of cyclosporine on serum lipids in renal transplant recipients (1991) Am J Kidney Dis, 17, pp. 700-707
  • Del Tacca, M., Prospects for personalized immunosuppression: Pharmacologic tools-a review (2004) Transplant Proc, 36, pp. 687-689
  • Swartz, S.L., Dluhy, R.G., Corticosteroids: Clinical pharmacology and therapeutic use (1978) Drugs, 16, pp. 238-255
  • Barnes, P.J., Adcock, I.M., Transcription factors and asthma (1998) Eur Respir J, 12, pp. 221-234
  • Boumpas, D.T., Chrousos, G.P., Wilder, R.L., Cupps, T.R., Balow, J.E., Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates (1993) Ann Intern Med, 119, pp. 1198-1208
  • Ashwell, J.D., Lu, F.W., Vacchio, M.S., Glucocorticoids in T cell development and function (2000) Annu Rev Immunol, 18, pp. 309-345
  • Sapolsky, R.M., Romero, L.M., Munck, A.U., How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions (2000) Endocr Rev, 21, pp. 55-89
  • Refojo, D., Liberman, A.C., Giacomini, D., Carbia Nagashima, A., Graciarena, M., Echenique, C., Integrating systemic information at the molecular level: Cross-talk between steroid receptors and cytokine signaling on different target cells (2003) Ann N Y Acad Sci, 992, pp. 196-204
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G., Mechanisms of anti-inflammatory action and of immunosuppression by gluococorticoids: Negative interference of activated glucocorticoid receptor with transcription factors (2000) J Neuroimmunol, 109, pp. 16-22
  • Liberman, A.C., Druker, J., Perone, M.J., Arzt, E., Glucocorticoids in the regulation of transcription factors that control cytokine synthesis (2007) Cytokine Growth Factor Rev, 18, pp. 45-56
  • Beato, M., Gene regulation by steroid hormones (1989) Cell, 56, pp. 335-344
  • Schoenmakers, E., Verrijdt, G., Peeters, B., Verhoeven, G., Rombauts, W., Claessens, F., Differences in ADN binding characteristics of the androgen and glucocorticoid receptors can determine hormone-specific responses (2000) J Biol Chem, 275, pp. 12290-12297
  • Pratt, W.B., Toft, D.O., Steroid receptor interactions with heat shock protein and immunophilin chaperones (1997) Endocr Rev, 18, pp. 306-360
  • Dittmar, K.D., Demady, D.R., Stancato, L.F., Krishna, P., Pratt, W.B., Folding of the glucocorticoid receptor by the heat shock protein (hsp) 90-based chaperone machinery. The role of p23 is to stabilize receptor.hsp90 heterocomplexes formed by hsp90.p60.hsp70 (1997) J Biol Chem, 272, pp. 21213-21220
  • Davies, T.H., Ning, Y.M., Sanchez, E.R., A new first step in activation of steroid receptors: Hormone-induced switching of FKBP51 and FKBP52 immunophilins (2002) J Biol Chem, 277, pp. 4597-4600
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G., The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-l: Molecular mechanisms for gene repression (2003) Endocr Rev, 24, pp. 488-522
  • Beato, M., Chalepakis, G., Schauer, M., Slater, E.P., ADN regulatory elements for steroid hormones (1989) J Steroid Biochem, 32, pp. 737-747
  • Geserick, C., Meyer, H.A., Haendler, B., The role of ADN response elements as allosteric modulators of steroid receptor function (2005) Mol Cell Endocrinol, 236, pp. 1-7
  • Auphan, N., DiDonato, J.A., Rosette, C., Helmberg, A., Karin, M., Immunosuppression by glucocorticoids: Inhibition of NF-kappa B activity through induction of I kappa B synthesis (1995) Science, 270, pp. 286-290
  • Scheinman, R.I., Gualberto, A., Jewell, C.M., Cidlowski, J.A., Baldwin Jr., A.S., Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors (1995) Mol Cell Biol, 15, pp. 943-953
  • Drouin, J., Maira, M., Philips, A., Novel mechanism of action for Nur77 and antagonism by glucocorticoids: A convergent mechanism for CRH activation and glucocorticoid repression of POMC gene transcription (1998) J Steroid Biochem Mol Biol, 65, pp. 59-63
  • Novac, N., Baus, D., Dostert, A., Heinzel, T., Competition between glucocorticoid receptor and NFkappaB for control of the human FasL promoter (2006) Faseb J, 20, pp. 1074-1081
  • Ray, A., Prefontaine, K.E., Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor (1994) Proc Natl Acad Sci USA, 91, pp. 752-756
  • Wissink, S., van Heerde, E.C., vand der, Burg, B., van der, Saag, P.T., A dual mechanism mediates repression of NF-kappaB activity by glucocorticoids (1998) Mol Endocrinol, 12, pp. 355-363
  • Caldenhoven, E., Liden, J., Wissink, S., Van de Stolpe, A., Raaijmakers, J., Koenderman, L., Negative cross-talk between RelA and the glucocorticoid receptor: A possible mechanism for the antiinflammatory action of glucocorticoids (1995) Mol Endocrinol, 9, pp. 401-412
  • Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F., The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction (2007) Faseb J, 21, pp. 1177-1188
  • Helmberg, A., Auphan, N., Caelles, C., Karin, M., Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor (1995) Embo J, 14, pp. 452-460
  • Jonat, C., Rahmsdorf, H.J., Park, K.K., Cato, A.C., Gebel, S., Ponta, H., Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/ Jun) activity by glucocorticoid hormone (1990) Cell, 62, pp. 1189-1204
  • Schule, R., Rangarajan, P., Kliewer, S., Ransone, L.J., Bolado, J., Yang, N., Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor (1990) Cell, 62, pp. 1217-1226
  • Nissen, R.M., Yamamoto, K.R., The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain (2000) Genes Dev, 14, pp. 2314-2329
  • Shaw, A.S., Dustin, M.L., Making the T cell receptor go the distance: A topological view of T cell activation (1997) Immunity, 6, pp. 361-369
  • Stoddard, B.L., Flick, K.E., Calcineurin-immunosuppressor complexes (1996) Curr Opin Struct Biol, 6, pp. 770-775
  • Handschumacher, R.E., Harding, M.W., Rice, J., Drugge, R.J., Speicher, D.W., Cyclophilin: A specific cytosolic binding protein for cyclosporin A (1984) Science, 226, pp. 544-547
  • Liu, J., Farmer Jr., J.D., Lane, W.S., Friedman, J., Weissman, I., Schreiber, S.L., Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes (1991) Cell, 66, pp. 807-815
  • Reynolds, N.J., Al-Daraji, W.I., Calcineurin inhibitors and sirolimus: Mechanisms of action and applications in dermatology (2002) Clin Exp Dermatol, 27, pp. 555-561
  • Hoffmann, M., Rychlewski, J., Chrzanowska, M., Hermann, T., Mechanism of activation of an immunosuppressive drug, azathioprine. Quantum chemical study on the reaction of azathioprine with cysteine (2001) J Am Chem Soc, 123, pp. 6404-6409
  • Poppe, D., Tiede, I., Fritz, G., Becker, C., Bartsch, B., Wirtz, S., Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins (2006) J Immunol, 176, pp. 640-651
  • Tiede, I., Fritz, G., Strand, S., Poppe, D., Dvorsky, R., Strand, D., CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes (2003) J Clin Invest, 111, pp. 1133-1145
  • Murata, M., Suzuki, T., Midorikawa, K., Oikawa, S., Kawanishi, S., Oxidative ADN damage induced by a hydroperoxide derivative of cyclophosphamide (2004) Free Radio Biol Med, 37, pp. 793-802
  • Chen, C.S., Jounaidi, Y., Su, T., Waxman, D.J., Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model (2007) Cancer Gene Ther
  • Chen, L., Yu, L.J., Waxman, D.J., Potentiation of cytochrome P450/ cyclophosphamide-based cancer gene therapy by coexpression of the P450 reductase gene (1997) Cancer Res, 57, pp. 4830-4837
  • Schwartz, P.S., Waxman, D.J., Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells (2001) Mol Pharmacol, 60, pp. 1268-1279
  • Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., Snyder, S.H., RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs (1994) Cell, 78, pp. 35-43
  • Lorenz, M.C., Heitman, J., TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin (1995) J Biol Chem, 270, pp. 27531-27537
  • Alarcon, C.M., Heitman, J., Cardenas, M.E., Protein kinase activity and identification of a toxic effector domain of the target of rapamycin TOR proteins in yeast (1999) Mol Biol Cell, 10, pp. 2531-2546
  • Allison, A.C., Eugui, E.M., Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF) (1996) Clin Transplant, 10, pp. 77-84
  • Allison, A.C., Eugui, E.M., Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection (2005) Transplantation, 80, pp. S181-S190
  • Breedveld, F.C., Dayer, J.M., Leflunomide: Mode of action in the treatment of rheumatoid arthritis (2000) Ann Rheum Dis, 59, pp. 841-849
  • Manna, S.K., Aggarwal, B.B., Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression (1999) J Immunol, 162, pp. 2095-2102
  • Yao, H.W., Li, J., Chen, J.Q., Xu, S.Y., A 771726, the active metabolite of leflunomide, inhibits TNF-alpha and IL-1 from Kupffer cells (2004) Inflammation, 28, pp. 97-103
  • Pietra, B.A., Boucek, M.M., Immunosuppression for pediatric cardiac transplantation in the modern era (2000) Prog Pediatr Cardiol, 11, pp. 115-129
  • Alegre, M.L., Peterson, L.J., Xu, D., Sattar, H.A., Jeyarajah, D.R., Kowalkowski, K., A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo (1994) Transplantation, 57, pp. 1537-1543
  • Xu, D., Alegre, M.L., Varga, S.S., Rothermel, A.L., Collins, A.M., Pulito, V.L., In vitro characterization of five humanized OKT3 effector function variant antibodies (2000) Cell Immunol, 200, pp. 16-26
  • Kuus-Reichel, K., Grauer, L.S., Karavodin, L.M., Knott, C., Krusemeier, M., Kay, N.E., Will immunogenicity limit the use, efficacy, and future development of therapeutic monoclonal antibodies? (1994) Clin Diagn Lab Immunol, 1, pp. 365-372
  • Tsurushita, N., Hinton, P.R., Kumar, S., Design of humanized antibodies: From anti-Tac to Zenapax (2005) Methods, 36, pp. 69-83
  • Kanda, H., Mori, K., Koga, H., Taniguchi, K., Kobayashi, H., Sakahara, H., Construction and expression of chimeric antibodies by a simple replacement of heavy and light chain V genes into a single cassette vector (1994) Hybridoma, 13, pp. 359-366
  • Chapman, T.M., Keating, G.M., Basiliximab: A review of its use as induction therapy in renal transplantation (2003) Drugs, 63, pp. 2803-2835
  • Waldmann, T.A., Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: A 25-year personal odyssey (2007) J Clin Immunol, 27, pp. 1-18

Citas:

---------- APA ----------
Liberman, A.C., Druker, J., Refojo, D. & Arzt, E. (2008) . Molecular mechanisms of action of some immunosuppresive drugs . Medicina, 68(6), 455-464.
Recuperado de https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257680_v68_n6_p455_Liberman [ ]
---------- CHICAGO ----------
Liberman, A.C., Druker, J., Refojo, D., Arzt, E. "Molecular mechanisms of action of some immunosuppresive drugs " . Medicina 68, no. 6 (2008) : 455-464.
Recuperado de https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257680_v68_n6_p455_Liberman [ ]
---------- MLA ----------
Liberman, A.C., Druker, J., Refojo, D., Arzt, E. "Molecular mechanisms of action of some immunosuppresive drugs " . Medicina, vol. 68, no. 6, 2008, pp. 455-464.
Recuperado de https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257680_v68_n6_p455_Liberman [ ]
---------- VANCOUVER ----------
Liberman, A.C., Druker, J., Refojo, D., Arzt, E. Molecular mechanisms of action of some immunosuppresive drugs . Medicina (Argentina). 2008;68(6):455-464.
Available from: https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00257680_v68_n6_p455_Liberman [ ]