Immunosuppressive drugs

Immunosuppressants are a pharmacologically and pharmacodynamically heterogeneous group of drugs that target specific structures or signaling pathways of immunocompetent cells. They suppress the reactions of the immune system in order to prevent or attenuate harmful immune reactions such as those occurring in allergic reactions, autoimmune diseases and transplant rejections. By its very nature, this also affects natural and thus beneficial immune reactions. The consequences are a reduced resistance to infections and, under long-term treatment, an increased risk of malignant tumours. Since immunosuppressants exert their effects in different ways, a distinction is made between different groups:

Cytotoxic immunosuppressants

• Cyclophosphamide (DNA synthesis inhibitors)
• Azathioprine (purine analogues)
• Methotrexate (folic acid antagonist, very specifically inhibits the enzyme dihydrofolate reductase)

Immunosuppressants with inhibitory effect on antigen-induced T-cell activation

• Ciclosporin (T-cell-specific calcineurin inhibitor; binds to the cytosolic receptor protein cicliphilin)
• Tacrolimus (also acts as a T-cell-specific calcineurin inhibitor; the cytosolic protein FK506-binding protein acts as a reeptor)

• Sirolimus (a local therapeutic Tacrolimus derivative inhibits the protein kinase mTOR)

• Everolimus (synthetic derivative of sirolimus, inhibits protein kinase mTOR)

• Glucocorticoids(Glucocorticoids (inhaled, glucocorticoids, topical, glucocorticoids, systemic, glucocorticoids bind to the cytosolic GK receptor (GKR). The resulting FK-GKR complex leads to a broad immunosuppressive-antiphlogistic-antiproliferative effect: hydrocortisone, methylprednisolone, prednisolone, prednisone ,dexamethasone).
• Abatacept (recombinant fusion protein; consisting of a modified Fc fragment of human IgG and the extracellular domain of human cytotoxic T lymphocyte antigen 4 CTLA4).

Immunosuppressants with inhibitory effects on the IL-2 receptor and its signal transduction: These agents block the IL-2 receptor or antagonize early (sirolimus/evrolimus) or late (e.g., mycophenolate) steps in the signal transduction pathway of the IL-2 receptor on T cells.

• Basiliximab (CD25 antibody; CD25 = alpha subunit of the IL-2 receptor)
• Daclizumab (CD25 antibody; CD25 = alpha subunit of the IL-2 receptor)
• Mycophenolate mofetil (inhibitor of inosine monophosphate dehydrogenase)
• Leflunomide (inhibits mitochondrial dihydroorotate dehydrogenase via its active metabolite teriflunomide)

Immunosuppressants with unclear mechanism of action

• D-penicillamine and organic gold compounds (less common today)
• Sulfasalazine
• Chloroquine
• Hydrochloroquine
• Dimethyl fumarate (fumaric acid dimethyl ester)
• Fingolimod (sphingosine-1-phosphate analogue)

Immunologically acting immunosuppressants. This small group of pharmaceuticals includes:

• Anti-RhD immunoglobulin (this antibody causes lysis of Rh+ erythrocytes in the maternal circulation, preventing sensitization of the mother.
• Anti-lymphocyte globulins (polyclonal antibodies against a variety of antigens on T-lymphocytes).
• Muromonab (monoclonal mouse antibody against the CD3 antibody of human T cells).
• Rituximab (monoclonal chimeric human-mouse antibody against the CD20 antigen expressed by immature and mature B cells, but not by plasma cells)

Glucocorticoids: Their action is mainly based on inhibition of the genes of proinflammatory cytokines. They suppress the humoral and cellular immune response. Less pro-inflammatory interleukins, interferons and TNF-α are released. B cells and thus plasma cell antibody production are inhibited. Glucocorticoids are used as part of immunosuppressive combination therapy.

Antiproliferatives (azathioprine, cyclophosphamide, mycophenolate mofetil): This group of immunosuppressants exerts its effect by curbing purine synthesis. In this way, it inhibits lymphocyte proliferation after antigen contact. The preparations are mainly administered as additional drugs to the basic immunosuppressants. This group includes: Azathioprine (Imurek), which has been used in transplant medicine for about 40 years.

Mycophenolate mofetil (MMF, CellCept®). It is converted in the body to mycophenolic acid, which inhibits lymphocyte proliferation and antibody formation. Mycophenolic acid and mycophenolate mofetil specifically inhibit activated B and T lymphocytes. Intercalants (e.g., mitoxantrone) bind noncovalently to DNA and prevent binding of the polymerases that serve to replicate and transcribe the genetic material.

Antibodies. The CD3 antibody muromonab is a monoclonal antibody that specifically binds to and deactivates the CD3 antigen of T-cell receptors. Partial T-cell lysis also occurs. CD20 antibodies (rituximab) CD25 antibodies (basiliximab and daclizumab) block the interleukin-2 receptor on activated T lymphocytes. These antibodies are used prophylactically in combination with other immunosuppressants in kidney transplantation. TNF-α antibodies (infliximab and adalimumab) neutralize TNF-α and thus prevent the release of IL-1 and IL-6. They are used to treat chronic diseases such as psoriasis vulgaris, psoriasis arthropathica, rheumatoid arthritis, Crohn's disease. Cytokine antibody (ustekinomab) human monoclonal antibody against cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23).

Macrolides:

Calcineurin inhibitors (ciclosporin and tacrolimus); Calcineurin is an enzyme in various cells of the body, including cells of the immune system. It is important for signal transduction in special immune defence cells (T-lymphocytes) when they are activated. Calcineurin inhibitors prevent this signal transduction and thus the activation of the immune system: Ciclosporin The polypeptide ciclosporin, derived from the fungus Tolypocladium inflatum, specifically and reversibly blocks the resting lymphocytes in the G0 or G1 phase of the cell cycle. The substance inhibits the production and release of lymphokines including interleukin-2 or T-cell growth factor. Pimecrolimus: Lipophilic macrolacatam derivative of ascomycin with anti-inflammatory properties. It is a cell-selective inhibitor of the production and release of pro-inflammatory cytokines. Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calicium-dependent phosphatase calcineurin. As a result, the synthesis of inflammatory cytokines in T cells is blocked. Tacrolimus: metabolite of the fungus Streptomyces tsukubaensis, structurally unrelated to ciclosporin. The substance influences the cellular and humoral immune response. Like ciclosporin, tacrolimus inhibits T-cell activation through high-affinity binding to the cytosolic protein FKBP12 (macrophilin-12). Tacrolimus inhibits the release of inflammatory mediators from mast cells of the skin and from basophilic and eosinophilic granulocytes. Tacrolimus is used for prophylaxis and treatment of transplant rejection (kidney, liver) and topically for atopic eczema. Sirolimus Sirolimus (rapamycin) is a macrolide produced by the actinobacterium Streptomyces hygroscopicus. Unlike ciclosporin and tacrolimus, which interfere with the first phase of activation of T lymphocytes, sirolimus inhibits the second step, namely signal transduction and cell proliferation. Other interferons IFN-β decreases TH1 cytokine production and monocyte activation. IFN-γ can induce apoptosis in lymphocytes. Antilymphocyte globulins: Animal polyclonal antibodies are obtained by immunizing animals with cells from the human lymphatic system. A single injection causes marked lymphopenia. Therefore, they are mainly used for the therapy of rejection reactions.

In contrast to conventional, non-specific immunosuppressants , biologics specifically target certain components of the immune system that are involved in the pathophysiological processes of the disease.

Glucocorticoids: Their action is mainly based on inhibition of the genes of proinflammatory cytokines. They suppress the humoral and cellular immune response. Less pro-inflammatory interleukins, interferons and TNF-α are released. B cells and thus plasma cell antibody production is inhibited. Glucocorticoids are used as part of immunosuppressive combination therapy.

Antiproliferatives (azathioprine, cyclophosphamide, methotrxate and, in an extended sense, mycophenolate mofetil): This group of immunosuppressants exerts its effect by curbing purine synthesis. Thereby it inhibits the lymphocyte proliferation after antigen contact. The preparations are mainly administered as additional drugs to the basic immunosuppressants. This group includes:Glucocorticoids: Their action is mainly based on inhibition of the genes of proinflammatory cytokines. They suppress the humoral and cellular immune response. Less pro-inflammatory interleukins, interferons and TNF-α are released. B cells and thus plasma cell antibody production is inhibited. Glucocorticoids are used as part of immunosuppressive combination therapy.

Antiproliferatives (azathioprine, cyclophosphamide, mycophenolate mofetil): This group of immunosuppressants exerts its effect by curbing purine synthesis. In this way, it inhibits lymphocyte proliferation after antigen contact. The preparations are mainly administered as additional drugs to the basic immunosuppressants. This group includes:

• Azathioprine (Imurek), which has been used in transplant medicine for about 40 years.
• Cyclophosphamide (Endoxan®)
• Methotrexate (inhibits in high potency the enzyme dihydrofolate reductase.
• Mycophenolate mofetil (MMF, CellCept®). It is converted in the body to mycophenolic acid, which inhibits lymphocyte proliferation and antibody formation. Mycophenolic acid and mycophenolate mofetil specifically inhibit activated B and T lymphocytes.

Antibodies: The CD3 antibody muromonab is a monoclonal antibody that specifically binds to and deactivates the CD3 antigen of T-cell receptors. Partial T cell lysis also occurs. CD20 antibodies (rituximab) CD25 antibodies (basiliximab and daclizumab) block the interleukin-2 receptor on activated T lymphocytes. These antibodies are used prophylactically in combination with other immunosuppressants in kidney transplantation. TNF-α antibodies (infliximab and adalimumab) neutralize TNF-α and thus prevent the release of IL-1 and IL-6. They are used to treat chronic diseases such as psoriasis vulgaris, psoriasis arthropathica, rheumatoid arthritis, Crohn's disease. Cytokine antibody (ustekinomab); Ustekinomab is a human monoclonal antibody that targets cytokines interleukin-12 (IL-12) and interleukin-23. (IL-23). Macrolides

Calcineurin inhibitors (ciclosporin and tacrolimus); Calcineurin is an enzyme in various cells of the body, including cells of the immune system. It is important for signal transduction in special immune defence cells (T-lymphocytes) when they are activated. Calcineurin inhibitors prevent this signal transmission and thus the activation of the immune system:

Ciclosporin: The polypeptide ciclosporin, derived from the fungus Tolypocladium inflatum, specifically and reversibly blocks resting lymphocytes in the G0 or G1 phase of the cell cycle. The substance inhibits the production and release of lymphokines including interleukin-2 or T-cell growth factor. Pimecrolimus: Lipophilic macrolacatam derivative of ascomycin with anti-inflammatory properties. It is a cell-selective inhibitor of the production and release of pro-inflammatory cytokines. Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calicium-dependent phosphatase calcineurin. As a result, the synthesis of inflammatory cytokines in T cells is blocked.
Tacrolimus: metabolite of the fungus Streptomyces tsukubaensis, structurally unrelated to ciclosporin. The substance influences the cellular and humoral immune response. Like ciclosporin, tacrolimus inhibits T-cell activation through high-affinity binding to the cytosolic protein FKBP12 (macrophilin-12). Tacrolimus inhibits the release of inflammatory mediators from mast cells of the skin and from basophilic and eosinophilic granulocytes. Tacrolimus is used for prophylaxis and treatment of transplant rejection (kidney, liver) and topically for atopic eczema.

Sirolimus (Rapamycin) is a macrolide produced by the actinobacterium Streptomyces hygroscopicus. Unlike ciclosporin and tacrolimus, which interfere with the first phase of activation of T lymphocytes, sirolimus inhibits the second step, namely signal transduction and cell proliferation.

Antilymphocyte globulins: Animal polyclonal antibodies are obtained by immunizing animals with cells from the human lymphatic system. A single injection results in pronounced lymphopenia. Therefore, they are mainly used for the therapy of rejection reactions.

1. Rangwala S et al (2011) Roles of the immune system in skin cancer. Br J Dermatol 165:953-965