Wei-Ping Zhang, Ph.D.

weiping601@zju.edu.cn

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!