wei-ping zhang, ph.d. weiping601@zju
DESCRIPTION
Immunomodulator. Wei-Ping Zhang, Ph.D. [email protected] Department of pharmacology, School of medicine, Zhejiang University. 2012.10.31. Immunomodulator ,免疫调节药 Immunosuppressive agents ,免疫抑制药 Immunopotentiating agents ,免疫增强药. Functions of the immune system. - PowerPoint PPT PresentationTRANSCRIPT
Wei-Ping Zhang, Ph.D.
Department of pharmacology, School of medicine,
Zhejiang University
Immunomodulator
2012.10.312012.10.31
Immunomodulator ,免疫调节药• Immunosuppressive agents ,免疫抑制药• Immunopotentiating agents ,免疫增强药
1. Immunological defense ( 免疫防御 )
2. Immunological homeostasis ( 免疫稳定 )
3. Immunological surveillance ( 免疫监视 )
Functions 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)
Disorders of the immune system
5. Graft rejection
6. Tumors
1. Glucocorticoids
2. Calcineurin inhibitors
3. Cytotoxic agents (anti-metabolism/anti-proliferation agents)4. Antibodies
Immunosuppressive agents
5. Cytokine inhibitors
6. TCM: Tripterygium glycosides 雷公藤总苷
1. Low specificity
2. More potent on primary immune response than the secondary immune response
3. The sensitivity of immune disorders to immunosuppressive agents is various
4. The therapeutic window are different according to the immunosuppressive agents
5. Most immunosuppressive agents posses anti-inflammatory effects
Properties of Immunosuppressive agents
1. Glucocorticoids
Commonly used drugsCommonly used drugs
Short-acting:Short-acting: hydrocortisone (cortisol) hydrocortisone (cortisol)
氢化可的松氢化可的松 cortisone cortisone 可的松可的松
Intermediate-acting:Intermediate-acting: prednisoneprednisone 泼尼松泼尼松 , , 强的强的松松
prednisolone prednisolone 泼尼松龙泼尼松龙 , , 强的松强的松龙龙
Long-acting:Long-acting: dexamethasone dexamethasone 地塞米松地塞米松
Topical:Topical: fluocinolone fluocinolone 氟轻松氟轻松
1. 1. Immunosupressive effectsImmunosupressive effects1)1) Inhibiting the functions of tissue macrophages and other antigen-presenting cells.2)2) Inhibiting lymphocyte cell proliferation and destroying lymphocyte cell3) Reducing production of antibody and release of cytokines.
2. 2. Clinical usesClinical uses 1) autoimmune diseases/allergic diseases:1) autoimmune diseases/allergic diseases: rheumatic rheumatic
fever, rheumatic carditis, rheumatic arthritis, rheumatoid artfever, rheumatic carditis, rheumatic arthritis, rheumatoid arthritis osteoarthritis, systemic lupus erythematosus (SLE), pohritis osteoarthritis, systemic lupus erythematosus (SLE), polyarthritis nodosa, nephritic syndrome, lyarthritis nodosa, nephritic syndrome, etc.etc. 2) rejection of organ transplantation2) rejection of organ transplantation
1. Glucocorticoids
3. 3. Adverse effectsAdverse effects
The toxicity of high-dose, long-term glucocorticoid therapy can be severe and will be discuss later.
4 Contraindications4 Contraindications
Psychiatric disorders; epilepsy; active peptic uPsychiatric disorders; epilepsy; active peptic u
lcers; fractures; hypercorticism; severe hypertlcers; fractures; hypercorticism; severe hypert
ension; diabetes mellitus; viral or fungal infectension; diabetes mellitus; viral or fungal infect
ions, ions, etc.etc.
Cyclosporine (11 AA peptide)环孢素
Tacrolimus (FK506)他克莫司,属 23 元大环内酯类
2. calcineurin inhibitors
Cyclosporine
CaN: calcineurin钙依赖磷酸酶
CsA: cyclosporin CpN: cyclophylin亲环蛋白
NF-ATc: nuclear factor of activated T cells
FKBP: FK506 binding protein
1. 1. Pharmacological effectPharmacological effect 1) 1) ByBy blocking the function of the enzyme calcineurin
(CaN), inhibit the expression of interleukin 2 2) Suppressing immune IFN- and other macrophage
growth factors
2. 2. Clinical usesClinical uses1) 1) Human organ transplantation, It has been used succe
ssfully as the sole immunosuppressant for cadaveric transplants of the kidney, pancreas, and liver, and heart.
2) 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.
Cyclosporine
3. 3. Adverse effectsAdverse effects1) Major side effects: nephrotoxicity, hepatic injury, neurotoxicity and hirsutism ( 多毛症 ).2) A increased incidence of lymphoma and other cancers, infection3) Very little bone marrow toxicity
4.4. Drug interactions Drug interactions
Cyclosporine is able to inhibit the hepatic cytochrome
P450 pathway, and there is a potential for many drug i
nteractions.
Cyclosporine
1. 1. Pharmacological effectPharmacological effectByBy blocking the function of the enzyme calcineurin (CaN), inhibit the expression of IL-2 and IL-3 and INF-IL-2 and IL-3 and INF- and and IL-2 receptor.IL-2 receptor. Inhibit T cell-dependent activation of B cell.
2. 2. Clinical usesClinical usesIt It is 10–100 times more potent than cyclosporine and utilized for the same indications as cyclosporine,
Tacrolimus (FK506)
3 3 Adverse effectsAdverse effects
Nephrotoxicity, neurotoxicity, hyperglycemia, hype
rtension, hyperkalemia, and gastrointestinal compl
aints.
4.4. Drug interactions Drug interactions
Tacrolimus is metabolized primarily by P450 enzy
mes in the liver, and there is a potential for drug int
eractions.
3. Cytotoxic agents
Azathioprine巯唑嘌呤
Methotrexate甲氨蝶呤
1.1. Pharmacological effectsPharmacological effects
ByBy inhibiting inhibiting the purine synthesisthe purine synthesis, , inhibit the proliferinhibit the prolifer
ation of ation of T cellsT cells and B cells. and B cells.
2. Clinical uses2. Clinical uses
1) 1) Benefit in maintaining renal all grafts and may be of
value in transplantation of other tissue
2) 2) Acute glomerulonephritis and in the renal componen
t of systemic lupus erythematosus (SLE).
Azathioprine/methotrexate
3. 3. Adverse effectsAdverse effects
1) Bone marrow suppression
2) Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur
3) Hepatic dysfunction,
4.4. Drug interactions 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
3. Anti-proliferation and anti-metabolism agents
Mycophenolate Mofetil霉酚酸酯
Mycophenolate mofetil
mycophenolic acid ,霉酚酸
Mycophenolate mofetil
次黄嘌呤单核苷酸脱氢酶
次黄 ( 嘌呤核 ) 苷酸 鸟苷一磷酸
鸟苷酸
1. 1. Pharmacological effectPharmacological effect
1) By 1) By inhibiting inhibiting the purine synthesis (guanine)the purine synthesis (guanine),, inhibit t inhibit the proliferative capability of T cells and B cells; he proliferative capability of T cells and B cells;
2) Inhibiting phagocytosis by macrophages, which enh2) Inhibiting phagocytosis by macrophages, which enhances their antigen-presenting capability.ances their antigen-presenting capability.
2. 2. Clinical usesClinical uses
1) 1) Solid organ transplant patients for refractory rejections
2) 2) Steroid-refractory graft-versus-host disease in hematopoietic stem cell transplant patients.
Mycophenolate mofetil
3. 3. Adverse effectsAdverse effects
Diarrhea, leukopenia, cytomegalovirus infection, bDiarrhea, leukopenia, cytomegalovirus infection, b
acterial infections and an increased incidence of lyacterial infections and an increased incidence of ly
mphomas and other malignacies.mphomas and other malignacies.
Low toxicity to liver and kidneyLow toxicity to liver and kidney
Mycophenolate mofetil
MPAG
MPA
MPA MPAG
Kidney
enterohepatic circulation
霉酚酸 - 葡萄糖醛酸酐
Rapamycin ,雷帕霉素
1. 1. Pharmacological effectPharmacological effect
1) By 1) By binding FKBP12,binding FKBP12, inhibit the activity of mTOR/P70 inhibit the activity of mTOR/P70 S60, thus inhibit the activation of T cells and B cells; S60, thus inhibit the activation of T cells and B cells;
2) Inhibiting the synthesis of IL-2 and IFN-2) Inhibiting the synthesis of IL-2 and IFN-. Inhibit IL-2 . Inhibit IL-2 and IL-4 induced proliferationand IL-4 induced proliferation
2. 2. Clinical usesClinical uses
1) Synergistic with CsA and FK506, inhibit rejection after organ graft, esp. for long term usage.
3. Adverse effects3. Adverse effects
GI responses, peptic ulcer, interstitial pneumonia
• Monoclonal antibodies directed against specific antigens such as CD3, CD4, CD20, IL-2 receptor
4. Antibodies
• Antilymphocyte antibodies
• Antithymocyte antibodies
TCR: T cell receptorTCR: T cell receptor
BCR: B cell receptorBCR: B cell receptor
IgFcR: IgFc receptorIgFcR: IgFc receptor
CR: complement receptorCR: complement receptor
CKR: cytokine receptorCKR: cytokine receptor
AM: adhesive molecular AM: adhesive molecular
receptorreceptor
MHCMHC
CDCD
Immunological molecule in the cellular membraneImmunological molecule in the cellular membrane
1. 1. Pharmacological effectPharmacological effect
1) Acting primarily on the small, long-lived peripheral
lymphocytes that circulate between the blood and
the lymph.
2) Inhibiting delayed hypersensitivity and cellular
immunity
2. 2. Clinical usesClinical uses
Renal transplant rejection
Antilymphocyte antibodies
3. 3. Adverse effectsAdverse effects
1) Local pain and erythema (红斑) often occur a
t the injection site.
2) Anaphylactic reaction and serum sickness
3) lymphoma as well as other forms of cancer
Antilymphocyte antibodies
1. 1. Pharmacological effectPharmacological 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. 2. Clinical usesClinical uses
• Primarily used in patients undergoing Primarily used in patients undergoing kidney transkidney transplants. plants.
3. Adverse effects3. Adverse effects
• Fever, chill, thrombocytopenia, arthralgia, serum dFever, chill, thrombocytopenia, arthralgia, serum disease, allergic shock etc.isease, allergic shock etc.
Antithymocyte antibodies
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 com
bination with cyclosporine, significantly inhibits th
e formation of cytotoxic T lymphocytes
• Effectively prevents acute rejection in renal transpl
ant recipient.
• Remove T cells from donor
Monoclonal antibodies
Anti-CD20 drugs:
rituximab ( 利妥昔单抗 )Pharmacological effects and clinical uses:
Blocking the specific function of the surface of CD
20 molecule on pre-B and B cells
Used for non-Hodgkins lymphoma and chemothera
py-resistant advanced follicular lymphoma (滤泡性淋巴瘤)
Adverse effects
Infusion-related side effects including fever, chills, nau
sea, vomiting, allergic reactions, flushing, and tumor p
ain.
Patients should be given an analgesic and an antihista
mine before each dose of rituximab to reduce these eff
ects.
Effectively blocking T-cell activation and in
hibiting colonel expansion of T cells.
In combination with immunosuppressants,
prolong the life of transplanted organs.
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:
Monoclonal antibodies
Infliximab( 英夫利昔单抗, Remicade):
a chimeric human/murine anti-tumour necrosis(TNF) monoclonal antibody
• Effectively blocking TNF binding to its receptor and thus down-regulate the inflammatory effects of TNF
• Used for rheumatoid arthritis and chronic inflammatory bowel disease
Pharmacological effects and clinical uses:
Immunopotentiating agents
• Used in immunodeficiency disorders, chronic infections and cancer.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)
Thanks!