Drugs affecting immune function

1. Drugs affecting immune function Immunopharmacology

2. Immunomodulating agents- Classification - • Immunosuppressive agents (immunosuppressants) • Immunopotentiating agents (immunostimulants) • Immunization (prophylaxis) • Vaccines;Immune globulin

3. Immunosuppressants • 1.Glucocorticoids(糖皮质激素类)： • prednisolone (泼尼松龙) , methylprednisolone (甲泼尼松龙) • 2. Calcineurin inhibitors (钙调磷酸酶抑制剂)： • cyclosporine (CsA, 环孢素),tacrolimus(FK506, 他克莫司) • 3. Antiproliferative and antimetabolic drugs (抗增殖/抗代谢类)： • rapamycin (雷帕霉素, sirolimus 西罗莫司), mycophenolate mofetil (MMF, 霉酚酸酯), azathioprine (Aza, 硫唑嘌呤) , cyclophosphamide (CTX, 环磷酰胺) • 4. Antibodies (抗体类)： • antithymocyte globulin (ATG, 抗胸腺细胞球蛋白) • 5. Active TCM components (中药有效成分)： • tripterygium glycosides(雷公藤总苷)

4. Immunosuppressants- application - • 1.Organ transplantation therapy • Multitiered approach to immunosuppressive drug therapy • Established rejection:blocking activated T lymphocytes, such as high dose glucocorticoids, polyclonal antilymphocyte antibodies, or muromonab-CD3 mAb • Maintenance immunotherapy:such as calcineurin inhibitors, glucocorticoids and mycophenolate mofetil • Intensive induction and lower-dose maintenance • 2. Autoimmune diseases • Rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc. • 3. Others hypersensitivity

5. Immunostimulants • 1. Microbial products: • Bacillus Calmette-Guerin (BCG,卡介苗) • 2. Immunological products from human or animals: • interferons (干扰素), interleukin-2 (IL-2, 白介素-2) • 3. Chemical drugs: • levamisole (左旋咪唑 ) • 4. Others: • polysaccharides (多糖类), active TCM components

6. Immunostimulants- application - • 1. Immunodeficient diseases • 2. Chronic refractoryinfections • 3. Tumors • - Adjuvant therapy -

7. Immunosuppressants

8. Cell-mediated and humoral immune responses

9. Immune responses and the actions of immunomodulating agents

10. 1. Glucocorticoid drugs Prednisone 泼尼松 Prednisolone 泼尼松龙 H

11. 1. Glucocorticoid drugs • Effects on immune • Suppressing immunological functions and allergy • a) inhibiting all stages of immune responses • b) inducing apoptosis of T and B lymphocytes • c) inhibiting transcription factor －such asnuclear factor B (NF-B) or activating protein-1 (AP-1)activity

13. 1. Glucocorticoid drugs One of glucocorticoids’ actions: Inhibition of gene transcription (AP-1 and NFB)

14. 1. Glucocorticoid drugs • 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 • (3) Allergic diseases:urticaria, serum sicknss, contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc.

15. 2. Calcineurin inhibitors 他克莫司 (FK506) 环孢素

16. 2. Calcineurin inhibitors • Cyclosporin (cyclosporin A, CsA) • Pharmacological effects • Suppressing T-cell-dependent immune mechanisms. • Inhibiting antigen-triggered signal transduction in T-cells, blunting expression of many cytokines including IL-2, and the expression of antiapoptotic proteins. • Forming a complex with cyclophilin (环孢素受体) , which binds to calcineurin, inhibiting Ca2+-stimulated dephosphorylation of the cytosolic component of NFAT. This prevents NFAT dephosphorylation such that NFAT does not enter the nucleus, gene transcription is not activated, and the T lymphocyte fails to respond to specific antigenic stimulation. • Increasing TGF-β expression, so inhibiting IL-2-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes.

18. 2. Calcineurin inhibitors • Clinical uses • Organ transplantation(kidney, liver, heart, and other organs) • Autoimmune disorders(systemic lupus erythematosus, rheumatoid arthritis, psoriasis (银屑病), etc.)

19. 2. Calcineurin inhibitors • Adverse reactions • Renal dysfunction: especially combined with other renal toxic drugs • Hepatic toxicity • CNS toxicity: tremor, convulsion, coma, etc. • Increased risk of neoplasia • Increased susceptibility to infections • Others: hirsutism, hypertension, hyperlipidemia, and gum hyperplasia , etc.

20. 2. Calcineurin inhibitors • Tacrolimus (FK506) • Binding to FKBP (FK506-binding protein) • Used in organ transplantation • CNS, renal, reproductive toxicities

21. 3. Antiproliferative and antimetabolic drugs 霉酚酸酯 西罗莫司

22. 3. Antiproliferative and antimetabolic drugs • Rapamycin (Rapa, sirolimus) • Pharmacological effects • Inhibiting T-cell activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors • It binds to and inhibits a protein kinase, designated mammalian target of rapamycin (mTOR), which is a key enzyme in cell-cycle progression

24. 3. Antiproliferative and antimetabolic drugs • Clinical uses • prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoids

25. 3. Antiproliferative and antimetabolic drugs • Adverse reactions • Gastrointestinal effects • Other adverse effects:anemia, leukopenia, thrombocytopenia, hypokalemia or hyperkalemia, fever. Delayed wound healing may occur with sirolimus use.

26. 3. Antiproliferative and antimetabolic drugs • Mycophenolate mofetil (MMF) • A prodrug of mycophenolic acid (MPA) • Pharmacological effects • a selective, noncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH, 次黄嘌呤单核苷磷酸脱氢酶) , which is an important enzyme in the de novo pathway of guanine nucleotide (鸟嘌呤苷酸) synthesis and B and T lymphocytes are highly dependent on this pathway for cell proliferation

27. 3. Antiproliferative and antimetabolic drugs • Clinical uses • Prophylaxis of transplant rejection, and it typically is used in combination with glucocorticoids and a calcineurin inhibitor, but not with azathioprine • Systemic lupus erythematosus, rheumatoid arthritis, psoriasis (银屑病) , etc.

28. 3. Antiproliferative and antimetabolic drugs • Adverse reactions • Gastrointestinal and hematologic toxicitiesincluding diarrhea, vomiting and leukopenia

29. 3. Antiproliferative and antimetabolic drugs • Azathioprine (Aza)

30. 3. Antiproliferative and antimetabolic drugs Phamacological effects • Interfering purine nucleotide synthesis in lymphocytes. • Azathioprine appears to be a more potent immunosuppressive agent than 6-mercaptopurine, which may reflect differences in drug uptake or pharmacokinetic differences in the resulting metabolites.

31. 3. Antiproliferative and antimetabolic drugs • Clinical uses • Organ transplantation, systemic lupus erythematosus, rheumatoid arthritis, etc.

32. 3. Antiproliferative and antimetabolic drugs • Adverse reactions • Bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon) bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon) • Increased susceptibility to infections(especially varicella and herpes simplex viruses), • Hepatotoxicity, alopecia, GI toxicity, pancreatitis, and increased risk of neoplasia

33. 4. Antibodies • Antithymocyte globulin (抗胸腺细胞球蛋白) • Inducing immunosuppression:renal transplant patients with delayed graft function to avoid early treatment with the nephrotoxic calcineurin inhibitors and thereby aid in recovery from ischemic reperfusion injury. • Also used for acute rejection of other types of organ transplants and for prophylaxis of rejection. • Inducing allergic reactions, including fever and chills with the potential for hypotension. including fever and chills with the potential for hypotension.

34. 4. Antibodies • Muromonab-CD3 (OKT3, 莫罗单抗-CD3, • anti-CD3 monoclonal antibodies ) • Binding to the εchain of CD3, a monomorphic component of the T-cell receptor complex involved in antigen recognition, cell signaling, and proliferation • Acute organ transplant rejection • “Cytokine release syndrome":high fever, chills/rigor, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, myalgias, arthralgias, and generalized weakness.