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Immunopharmacology

Immunopharmacology. Fen-Fei Gao. Elements of the Immune System. Normal Immune Responses The innate immune system : The first line of defense Including physical (eg, skin), biochemical (eg, complement( 补体 ), lysozyme( 溶菌酶 ) ), and cellular (macrophages, neutrophils) components

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Immunopharmacology

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  1. Immunopharmacology Fen-Fei Gao

  2. Elements of the Immune System • Normal Immune Responses • The innate immune system: • The first line of defense • Including physical (eg, skin), biochemical (eg, complement(补体), lysozyme(溶菌酶)), and cellular (macrophages, neutrophils) components • The adaptive immune system: • Humoral immunity – B lymphocytes: antibodies • Cell-mediated immunity – T lymphocytes

  3. Abnormal Immune Responses • Hypersensitivity: • Immediate hypersensitivity: usually antibody-mediated. • Type Ⅰ: cross-linking of membrane-bound IgE on blood basophils(嗜碱细胞) or tissue mast cells(肥大细胞) by antigen. • Type Ⅱ: the formation of antigen-antibody complexes between foreign antigen and IgM or IgG immunoglobulins(免疫球蛋白). eg, blood transfusion reactions and hemolytic disease of the newborn. • Type Ⅲ: the presence of elevated levels of antigen-antibody complexes that cause tissue damage. • Delayed hypersensitivity: cell-mediated. Induces a local inflammatory response and causes extensive tissue damage characterized by the influx of antigen-nonspecific inflammatory cells. • Autoimmunity: an immune response against itself due to failure to distinguish self tissues and cells from foreign (nonself) antigens. • Immunodeficiency diseases:

  4. Immunosuppressive Drugs • Common characteristic: • Deficiency in specific or selectivity: • More effective in the first immume response action than in that of the second. • Action related to the time of administration of drugs, the interval of antigen stimulation and subsequence. • Non-specific anti-inflammatory effect.

  5. Cyclosporin • Fat-soluble peptide antibiotic • Pharmacokinetics • Slowly and incompletely absorbed after oral administration. • Almost totally metabolized and excreted in the bile. • Pharmacological Effects: • Act at an early stage in the antigen receptor-induced differentiation of T cells and block their activation. • Inhibit the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells, but it does not block the effect of such factors on primed T cells nor does it block interaction with antigen.

  6. Mechanisms • cyclosporin + cyclophilin → complex → calcineurin(钙调磷酸酶)↓→ dephosphorylation of nuclear factors of activated T cells↓ → gene transcription↓ → IL-2,3,4↓, TNF-α↓, IFN-γ↓ • cyclosporin → TGF-β↑ → proliferation of T cells induced by IL-2 ↓, cytotoxic T cells↓ • Clinical Uses • Organ transplantation • Autoimmune disorders • Adverse Effects and Cautions • Nephrotoxicity(中毒性肾损害), • Transient liver dysfunction • secondary infection: viral infection • Lymphoma and other cancers (Kaposi’s sarcoma, skin cancer)

  7. Tacrolimus (FK506) • Macrolide(大环内酯) antibiotic produced by streptomyces tsukubaensis(链霉菌属). • It is not chemically related to cyclosporine, but their machanisms of action are similar, both bind to cytoplasmic peptidyl(肽基)-prolyl(脯氨酰) isomerases(异构酶). • For liver, kidney, heart, pancreas, and bone marrow transplant applications. • Toxic effects: nephrotoxicity, neurotoxicity, hyperglycemia (requiring insulin therapy), gastrointestinal dysfunction. • Some studies suggested the higher efficacy and the higher incidence of serious toxicities of tacrolimus than cyclosporine in the management of of liver transplant patients.

  8. Adrenocortical Hormones • Lympholytic(淋巴细胞溶解) properties • Interfere with the cell cycle of activated lymphoid cells. • Their immunologic effects are due to their ability to modify cellular functions rather than to direct cytotoxicity. • Immunosuppressive and anti- inflammatory properties. • Indications include organ transplantation and autoimmune disorders.

  9. Antimetabolite • Including Aza, MTX, 6-MP, et al. • Aza is an imidazolyl(咪唑) derivative of 6-MP. • Aza is the purine analog that interferes with nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation which follows antigenic stimulation. • T cells is more sensitive than B cells. • Benefit in maintaining renal allograft(同种异基因移植物) • Treatment of autoimmune disorders: rheumatoid arthritis(类风湿关节炎), systemic lupus erythematosus(系统性红斑狼疮), et al. • Adverse reactions: bone marrow suppression, gastrointestinal symptoms, hepatic dysfunction.

  10. Alkylating(烷化) agent • Cyclophosphamide (CTX) destroys proliferating lymphoid cells but also appears to alkylate some resting cells. • B cells is more sensitive than T cells. • Organ transplants, autoimmune disorders. • Adverse reactions: bone marrow suppression, gastrointestinal symptoms, hemorrhagic cystitis(出血性膀胱炎).

  11. Antilymphocyte Globulin (ALG) • Antiserum is usually obtained by immunization of large animals with human lymphoid cells or by the hybridoma(杂交瘤) technique for monoclonal antibody generation. • Antithymocyte(抗胸腺细胞的) globulin(ATG). • Destruction or inactivation of the T cells. • primary immune response＞secondary immune response • Adverse reactions are mostly those associated with injection of a foreign protein obtained from heterologous serum.

  12. Mycophenolate Mofetil (RS-61443) • A semisynthetic derivative of mycophenolic acid (MPA), isolated from the mold Penicillium glaucum. • MPA is the inhibitor of IMPDH. Inhibit the de novo(重新) pathway of purine synthesis. • Inhibit a series of T and B lymphocyte responses. • Kidney and liver transplant, et al. • Adverse reactions are mainly gastrointestinal .

  13. Leflunomide • A prodrug of an inhibitor of pyrimidine synthesis rather than purine synthesis. • Inhibit DHODH through A771726. • It is orally active, and the active metabolite has a long half-life of several weeks.– should be started with a loading dose. • Mainly for rheumatoid arthritis. • Toxicities: liver damage, renal impairment, teratogenic(致畸) effects.

  14. Immunostimulants • Increase the immune responsiveness of patients who have either selective or generalized immunodeficiency. • Use for immunodeficiency disorders, chronic infectious diseases, and cancer.

  15. Immune Adjuvant • Bacillus Calmette-Guerin-Vaccine (BCG) is a viable(可培育的) strain of Mycobacterium(分支杆菌) bovis(牛型) that has been used for immunization against tuberculosis. • Also been employed as a nonspecific adjuvant or immunostimulant in cancer therapy.

  16. Cytokines • Interferon (INF): INF-α,β,γ • Antiviral, anticancer, immunomodulating effects. • Antiviral effects : INF-α,β＞ INF-γ • immunomodulating effects: INF-γ • Adverse Effects: flu-like symptoms, fatigue(疲乏), malaise(不适) • Interleukin-2 (IL-2) • T cell proliferation, TH, NK, LAK cell activation • Treatment of malignant melanoma(恶性黑素瘤), renal cell carcinoma, Hodgkin disease • Adverse Effects: fever, anorexia(食欲缺乏), et al.

  17. Other Immunomodulators • Entanercept • Transfer Factor (TF) • Thymosin • Levamisole (LSM) • Isoprinosine

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