Ximwi Wu, Dept. of Pharmacology, School of Medicine, Zhejiang University

1. Immunomodulator Ximwi Wu, Dept. of Pharmacology, School of Medicine, Zhejiang University

2. Background knowledge The immune system Disorders of the immune system Immunosuppressive agents Immunopotentiating agents

4. Disorders of the immune system 1. Autoimmune disorders (in which the body's own immune system attacks its own tissue as foreign matter) 2. Allergic disorders (in which the immune system overreacts in response to an antigen) 3. Cancers of the immune system 4.Immunodeficiency disorders (primary or acquired)

5. Organ transplants and rejection

6. Immunosuppressive agents 1. Glucocorticoids 2. Calcineurin inhibitors 3. Cytotoxic agents 4. Antibodies

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 Prednisone

9. 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 disorders:reumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc. • 2) rejection of organ transplantation

10. 3. Adverse effects The toxicity of high-dose, long-term glucocorticoid therapy can be severe and is discussed in previous chapter 4 Contraindications Psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc.

11. 2. calcineurin inhibitors Cyclosporine Tacrolimus (FK506)

12. Cyclosporine

13. Cyclosporine CsA: cyclosporin CpN: cyclophylin CaN: calcineurin

14. Cyclosporine 1. Pharmacological effect 1) Byblocking the function of the enzyme calcineurin(CaN), inhibit the expression of interleukin 2 2) Suppressing immune IFN-γ 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 3) Autoimmune disorders, including uveitis and rheumatoid arthritis.

15. 3. Adverse effects 1) Major side effects: nephrotoxicity, neurotoxicity and hirsutism. 2 A increased incidence of lymphoma and other cancers 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

16. Tacrolimus (FK506)

17. Tacrolimus (FK506)

18. Tacrolimus (FK506) 1. Pharmacological effect Byblocking the function of the enzyme calcineurin(CaN), inhibit the expression of interleukins-2 and -3 and γ-interferon and interleukin-2 receptor. 2. Clinical uses It is 10–100 times more potent than cyclosporine and utilized for the same indications as cyclosporine,

19. 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.

20. 3. Cytotoxic agents Azathioprine Mycophenolate Mofetil

21. Azathioprine

22. Azathioprine Mechanisms of action

23. Azathioprine • Pharmacological effects • Byinhibiting the purine synthesis, inhibit the proliferation of T 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

24. 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, patients who are also receiving allopurinol for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity

25. Mycophenolate mofetil

26. Mycophenolate mofetil

27. Mycophenolate mofetil 1. Pharmacological effect 1)By inhibiting the purine sythesis, inhibit the proliferative capbility of T cells and B cells; 2)Stimulating 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.

28. Mycophenolate mofetil 3. Adverse effects Diarrhea, leukopenia, cytomegalovirus infection, bacterial infections and an increased incidence of lymphomas and other malignacies

29. 4. Antibodies 1. Antilymphocyte antibodies 2. Antithymocyte antibodies 3. Monoclonal antibodies directed against specific antigens such as CD3, CD4, CD20, IL-2 receptor

30. 1. 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

31. 3. Adverse effects 1) Local pain and erythema often occur at the injection site. 2) Anaphylactic and serum sickness reactions 3) lymphoma as well as other forms of cancer

32. Antithymocyte antibodies 1. Pharmacological effect Reducing the number of T cells in the thymus-dependent areas of the spleen and lymph nodes 2. Clinical uses Primarily used in patients undergoing kidney transplants.

33. Monoclonal antibodies Anti-CD3 antibodies: muromonabCD3(OKT3) Pharmacological effects and clinical uses: Block the specific function of the surface CD3 Given weekly by intravenous injection and in conjunction with cyclosporine, significantly inhibits the formation of cytotoxic T lymphocytes and effectively prevents acute rejection in renal transplant recipient

34. Monoclonal antibodies Anti-CD20 drugs:rituximab Pharmacological effects and clinical uses: Blocking the specific function of the surface ofCD20 molecule on pre-B and B cells Used for non-Hodgkins lymphoma and chemotherapy-resistant advanced follicular lymphoma

35. 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 rituxmab to reduce these effects.

36. Monoclonal antibodies Basiliximab: a chimeric murine monoclonal antibody against the human IL-2 receptor alpha submit of activated T cells Pharmacological effects and clinical uses: Effectively blocking T-cell activation and inhibiting clonal expansion of T cells. In combination with immunosuppressants, prolong the life of transplanted organs

37. Monoclonal antibodies Infliximab( Remicade): a chimeric human/murine anti-tumour necrosis(TNF) monoclonal antibody

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

39. Immunopotentiating agents • Used in immunodeficiency disorders, chronic infections and cancer. 1) Cytokines like INF-alpha, INF-beta, INF-gamma IL-2: metastatic RCC and malignant melanoma. TNF alpha:malignant melanoma and soft tissue sarcoma of extremity. 2) Levamisole – anti-helminthic. Used to treat immunodeficiency associated with Hodgkins disease. Causes severe agranulocytosis. 3) BCG Used as intravesical therapy for superficial bladder cancer. It causes activation of macrophages to make them more effective killer cells. 4) Other drugs inosiplex, azimexon, imexon, thymosin, methylinosine monophosphate…….