In-depth review
Immunosuppressants: Cellular and molecular mechanisms of action

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Abstract

The basic immunosuppressive protocol used in most transplant centers involves the use of multiple drugs, each directed at a discrete site in the T-cell activation cascade and each with distinct side effects. Cyclosporine, azathioprine, corticosteroids, FK506 (tacrolimus), and RS61443 (mycophenolate mofetil) have been approved by the Food and Drug Administration, and the clinical efficacy of rapamycin (sirolimus), mizoribine, 15-deoxyspergualin, and leflunomide is being explored. Based on their primary site of action, the immunosuppressants can be classified as inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine, leflunomide), inhibitors of growth factor signal transduction (sirolimus, leflunomide), and inhibitors of differentiation (15-deoxyspergualin). Polyclonal antilymphocyte antibodies, monoclonal antibodies directed at the T-cell antigen receptor complex (OKT3, TIOB9), and monoclonal antibodies directed at additional cell surface antigens, including interleukin-2 receptor alpha, afford cell-specific regulation of the immune response and are being used in the clinical setting as induction therapy and/or antirejection drugs. Clearly, the transplant clinician now has a greater choice in the selection and application of immunosuppressants in the clinic for the fine regulation of the antiallograft repertory. The prevailing paradigm regarding the mechanisms of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. One hypothesis, albeit provocative, is that some of the immunosuppressants might function by stimulating the expression of immunosuppressive molecules and/or cells.

References (109)

  • RA Williamson et al.

    Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound

    J Biol Chem

    (1995)
  • S Greene et al.

    Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide

    Biochem Pharmacol

    (1995)
  • X Xu et al.

    Inhibition of protein tyrosine phosphorylation in T cells by a novel immnosuppressive agent, leflunomide

    J Biol Chem

    (1995)
  • RV Nair et al.

    Inhibition of smooth muscle cell proliferation in vitro by leflunomide, a new immunosuppressant, is antagonized by uridine

    Immunol Lett

    (1995)
  • ER Unanue et al.

    Antigen presentation

    FASEB J

    (1989)
  • M Suthanthiran et al.

    Renal transplantation

    N Engl J Med

    (1994)
  • A Weiss et al.

    Signal transduction by lymphocyte antigen receptors

    Cell

    (1994)
  • H Clevers et al.

    The T-cell receptor/CD3 complex: A dynamic protein ensemble

    Annu Rev Immunol

    (1988)
  • MC Miceli et al.

    The role of CD4 and CD8 in T-cell activation

    Semin Immunol

    (1991)
  • M Suthanthiran

    A novel model for antigen-dependent activation of normal human T-cells

  • MH Brown et al.

    The CD2 antigen associates with the T-cell antigen receptor/CD3/antigen complex on the surface of human T lymphocytes

    Nature

    (1989)
  • AD Beyers et al.

    Molecular associations between the T-lymphocyte antigen receptor complex and the surface antigens CD2, CD4, or CD8 and CD5

  • Y Nishizuka

    Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C

    Science

    (1992)
  • SJ O'Keefe et al.

    FK 506- and CsA-sensitive activation of the interleukin2 promoter by calcineurin

    Nature

    (1992)
  • NA Clipstone et al.

    Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation

    Nature

    (1992)
  • DA Fruman et al.

    Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A

  • RH Schwartz

    T-cell anergy

    Sci Am

    (1993)
  • M Suthanthiran

    Signaling features of T-cells: Implications for the regulation of the anti-allograft response

    Kidney Int

    (1993)
  • ML Dustin et al.

    T-cell receptor crosslinking transiently stimulates adhesiveness through LFA-1

    Nature

    (1989)
  • PS Linsley et al.

    CTLA-4 is a second receptor for the B-cell activation antigen B7

    J Exp Med

    (1991)
  • CB Thompson et al.

    CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines

  • JP Allison et al.

    The yin and yang of T cell costimulation

    Science

    (1995)
  • M Isobe et al.

    Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1

    Science

    (1992)
  • J Lenschow et al.

    Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA-41g

    Science

    (1992)
  • JM Williams et al.

    The events of primary T-cell activation can be staged by use of sepharose-bound anti-T3 [64.1] monoclonal antibody and purified interleukin1

    J Immunol

    (1985)
  • P Bretcher et al.

    A theory of self-nonself discrimination: Paralysis and induction involve the recognition of one and two determinants on an antigen, respectively

    Science

    (1970)
  • EA Clark et al.

    How B- and T-cells talk to each other

    Nature

    (1994)
  • AB Roberts et al.

    Physiological actions and clinical applications of transforming growth factor-β (TGF-β)

    Growth Factors

    (1993)
  • B Li et al.

    Differential regulation of transforming growth factor beta and interleukin-2 genes in human T-cells: Demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction

    J Exp Med

    (1991)
  • A Khanna et al.

    Regulation of new DNA synthesis in mammalian cells by cyclosporine

  • PJ Knudsen et al.

    Glucocorticoids inhibit transcription and post-transcriptional expression of interleukin-1

    J Immunol

    (1987)
  • B Zanker et al.

    Evidence that glucocorticosteroids block expression of the human interleukin-6 gene by accessory cells

    Transplantation

    (1990)
  • SK Arya et al.

    Dexamethasone mediated inhibition of T-cell growth factor and gamma interferon messenger RNA

    J Immunol

    (1984)
  • WY Almawi et al.

    Abrogation of glucocorticosteroid-mediated inhibition of T-cell proliferation by the synergistic action of IL-1, IL-6, and IFN

    J Immunol

    (1991)
  • A Vacca et al.

    Glucocorticoid receptor-mediated suppression of the interleukin-2 gene expression through impairment of the cooperativity between nuclear factor of activated T-cells and AP-1 enhancer elements

    J Exp Med

    (1992)
  • HF Yang-Yee et al.

    Transcriptional interference between cp-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction

    Cell

    (1990)
  • F Palvogianni et al.

    Negative transcriptional regulation of human interleukin-2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT

    J Clin Invest

    (1993)
  • RI Scheinman et al.

    Role of transcriptional activation of IKBa in mediation of immunosuppression by glucocorticoids

    Science

    (1995)
  • N Auphan et al.

    Immunosuppression by glucocorticoids: Inhibition of NFKB activity through induction of IKB synthesis

    Science

    (1995)
  • GB Elion

    Biochemistry and pharmacology of purine analogues

    Fed Proc

    (1967)
  • Cited by (0)

    Supported in part by grants no. A126982 and DK44626 from the National Institutes of Health, Bethesda, MD.

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