Wei-Ping Zhang, Ph.D. weiping601@zju

1. Immunomodulator Wei-Ping Zhang, Ph.D. weiping601@zju.edu.cn Department of pharmacology, School of medicine, Zhejiang University 2012.10.31

2. Immunomodulator，免疫调节药 • Immunosuppressive agents，免疫抑制药 • Immunopotentiating agents，免疫增强药

3. Functions of the immune system • Immunological defense (免疫防御) • Immunological homeostasis (免疫稳定) • Immunological surveillance (免疫监视)

4. Disorders of the immune system 1. Autoimmune diseases (in which the body's own immune system attacks its own tissue as foreign matter) 2. Hypersensitivity (in which the immune system overreacts in response to an antigen) 3. Immunoproliferative diseases (Cancers of the immune system) 4. Immunodeficiency diseases (primary or acquired) 5. Graft rejection 6. Tumors

5. Immunosuppressive agents 1. Glucocorticoids 2. Calcineurin inhibitors 3. Cytotoxic agents (anti-metabolism/anti-proliferation agents) 4. Antibodies 5. Cytokine inhibitors 6. TCM: Tripterygium glycosides 雷公藤总苷

6. Properties of Immunosuppressive agents • Low specificity • More potent on primary immune response than the secondary immune response • The sensitivity of immune disorders to immunosuppressive agents is various • The therapeutic window are different according to the immunosuppressive agents • Most immunosuppressive agents posses anti-inflammatory effects

7. 1. Glucocorticoids Commonly used drugs • Short-acting:hydrocortisone (cortisol) 氢化可的松 cortisone 可的松 • Intermediate-acting:prednisone泼尼松, 强的松 prednisolone 泼尼松龙, 强的松龙 • Long-acting:dexamethasone 地塞米松 • Topical:fluocinolone 氟轻松

8. 1. Glucocorticoids 1. Immunosupressive effects 1)Inhibiting the functions of tissue macrophages and other antigen-presenting cells. 2)Inhibiting lymphocyte cell proliferation and destroying lymphocyte cell 3) Reducing production of antibody and release of cytokines. 2. Clinical uses 1) autoimmune diseases/allergic diseases:rheumatic fever, rheumatic carditis, rheumatic arthritis, rheumatoid arthritis osteoarthritis, systemic lupus erythematosus (SLE), polyarthritis nodosa, nephritic syndrome, etc. 2) rejection of organ transplantation

9. 3. Adverse effects The toxicity of high-dose, long-term glucocorticoid therapy can be severe and will be discuss later. 4 Contraindications Psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc.

10. 2. calcineurin inhibitors Cyclosporine (11 AA peptide) 环孢素 Tacrolimus (FK506) 他克莫司，属23元大环内酯类

11. Cyclosporine CsA: cyclosporin CpN: cyclophylin 亲环蛋白 CaN: calcineurin 钙依赖磷酸酶 NF-ATc: nuclear factor of activated T cells FKBP: FK506 binding protein

12. Cyclosporine 1. Pharmacological effect 1) Byblocking the function of the enzyme calcineurin(CaN), inhibit the expression of interleukin 2 2) Suppressing immune IFN- and other macrophage growth factors 2. Clinical uses 1) Human organ transplantation, It has been used successfully as the sole immunosuppressant for cadaveric transplants of the kidney, pancreas, and liver, and heart. 2) Graft-versus-host disease（移植块抗宿主 病） 3) Autoimmune disorders, including uveitis （眼色素膜炎） and rheumatoid arthritis.

13. Cyclosporine 3. Adverse effects 1) Major side effects: nephrotoxicity, hepatic injury, neurotoxicity and hirsutism (多毛症). 2) A increased incidence of lymphoma and other cancers, infection 3) Very little bone marrow toxicity 4. Drug interactions Cyclosporine is able to inhibit the hepatic cytochrome P450 pathway, and there is a potential for many drug interactions.

14. Tacrolimus (FK506) 1. Pharmacological effect Byblocking the function of the enzyme calcineurin(CaN), inhibit the expression of IL-2 and IL-3 and INF- and IL-2 receptor. Inhibit T cell-dependent activation of B cell. 2. Clinical uses It is 10–100 times more potent than cyclosporine and utilized for the same indications as cyclosporine,

15. 3 Adverse effects Nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints. 4. Drug interactions Tacrolimusis metabolized primarily by P450 enzymes in the liver, and there is a potential for drug interactions.

16. 3. Cytotoxic agents Azathioprine 巯唑嘌呤 Methotrexate 甲氨蝶呤

17. Azathioprine/methotrexate • Pharmacological effects • Byinhibiting the purine synthesis, inhibit the proliferation of T cells and B cells. • 2. Clinical uses • 1) Benefit in maintaining renal all grafts and may be of value in transplantation of other tissue • 2) Acute glomerulonephritis and in the renal component of systemic lupus erythematosus (SLE).

18. 3. Adverse effects • Bone marrow suppression • 2) Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur • 3) Hepatic dysfunction, • 4. Drug interactions • Since much of the drug’s inactivation depends on xanthine oxidase (黄嘌呤氧化酶), patients who are also receiving allopurinol (别嘌呤醇) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity

19. 3. Anti-proliferation and anti-metabolism agents Mycophenolate Mofetil 霉酚酸酯

20. Mycophenolate mofetil mycophenolic acid，霉酚酸

21. Mycophenolate mofetil 次黄(嘌呤核)苷酸 鸟苷一磷酸 鸟苷酸 次黄嘌呤单核苷酸脱氢酶

22. Mycophenolate mofetil 1. Pharmacological effect 1) By inhibiting the purine synthesis (guanine), inhibit the proliferative capability of T cells and B cells; 2) Inhibiting phagocytosis by macrophages, which enhances their antigen-presenting capability. 2. Clinical uses 1) Solid organ transplant patients for refractory rejections 2) Steroid-refractory graft-versus-host disease in hematopoietic stem cell transplant patients.

23. Mycophenolate mofetil 3. Adverse effects Diarrhea, leukopenia, cytomegalovirus infection, bacterial infections and an increased incidence of lymphomas and other malignacies. Low toxicity to liver and kidney MPAG  MPA MPA  MPAG 霉酚酸-葡萄糖醛酸酐 Kidney enterohepatic circulation

24. Rapamycin，雷帕霉素 • 1. Pharmacological effect • 1) By binding FKBP12, inhibit the activity of mTOR/P70 S60, thus inhibit the activation of T cells and B cells; • 2) Inhibiting the synthesis of IL-2 and IFN-. Inhibit IL-2 and IL-4 induced proliferation • 2. Clinical uses • Synergistic with CsA and FK506, inhibit rejection after organ graft, esp. for long term usage. • 3. Adverse effects • GI responses, peptic ulcer, interstitial pneumonia

25. 4. Antibodies • Antilymphocyte antibodies • Antithymocyte antibodies • Monoclonal antibodies directed against specific antigens such as CD3, CD4, CD20, IL-2 receptor

26. Immunological molecule in the cellular membrane • TCR: T cell receptor • BCR: B cell receptor • IgFcR: IgFc receptor • CR: complement receptor • CKR: cytokine receptor • AM: adhesive molecular receptor • MHC • CD

27. Antilymphocyte antibodies • 1. Pharmacological effect • Acting primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and the lymph. • Inhibiting delayed hypersensitivity and cellular immunity • 2. Clinical uses • Renal transplant rejection

28. Antilymphocyte antibodies 3. Adverse effects 1) Local pain and erythema （红斑）often occur at the injection site. 2) Anaphylacticreaction and serum sickness 3) lymphoma as well as other forms of cancer

29. Antithymocyte antibodies • 1. Pharmacological effect • Bind to T cell and kill cell with the assistance of complements. Reducing the number of T cells. • Non-specifically inhibit cell immune response and inhibit thymus-dependent antibody formation. • 2. Clinical uses • Primarily used in patients undergoing kidney transplants. • 3. Adverse effects • Fever, chill, thrombocytopenia, arthralgia, serum disease, allergic shock etc.

30. Monoclonal antibodies Anti-CD3 antibodies: muromonabCD3(OKT3) 莫罗单抗-CD3 • Pharmacological effects and clinical uses: • Specifically block the surface CD3 • Given weekly by intravenous injection and in combination with cyclosporine, significantly inhibits the formation of cytotoxic T lymphocytes • Effectively prevents acute rejection in renal transplant recipient. • Remove T cells from donor

31. Monoclonal antibodies Anti-CD20 drugs: rituximab (利妥昔单抗) Pharmacological effects and clinical uses: Blocking the specific function of the surfaceofCD20 molecule on pre-B and B cells Used for non-Hodgkins lymphoma and chemotherapy-resistant advanced follicular lymphoma（滤泡性淋巴瘤）

32. Adverse effects Infusion-related side effects including fever, chills, nausea, vomiting, allergic reactions, flushing, and tumor pain. Patients should be given an analgesic and an antihistamine before each dose of rituximab to reduce these effects.

33. Monoclonal antibodies Basiliximab (巴利昔单抗): a chimeric murine monoclonal antibody against the human IL-2 receptor  submit of activated T cells Pharmacological effects and clinical uses: Effectively blocking T-cell activation and inhibiting colonel expansion of T cells. In combination with immunosuppressants, prolong the life of transplanted organs.

34. Monoclonal antibodies Infliximab(英夫利昔单抗，Remicade): a chimeric human/murine anti-tumour necrosis(TNF) monoclonal antibody

35. Pharmacological effects and clinical uses: • Effectively blocking TNF binding to its receptor and thus down-regulate the inflammatory effects of TNF • Used for rheumatoidarthritis and chronic inflammatory bowel disease

36. Immunopotentiating agents • Used in immunodeficiency disorders, chronic infections and cancer. 1) Originate from microorgans（vaccines） — Bacillus calmette-guerin vaccine, BCG 2) Immunological products — Interleukins （IL-2）, interferons （INF-, , ）, transfer factors, thymosin 1 3) Synthesized agents — levamisole（左旋咪唑）, isoprinosine（异丙基苷） Poly I:C（聚肌胞苷酸） 4) Biological polysachride（生物多糖） — Krestin（云芝多糖）， achyranthan（牛膝多糖） 5) Others — TCM, PHA（植物血凝素）

37. Thanks!