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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
1. Immunological defense (免疫防御)
2. Immunological homeostasis (免疫稳定)
3. Immunological surveillance (免疫监视)
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
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
Properties of Immunosuppressive agents
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 antiinflammatory effects
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
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
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.
2. calcineurin inhibitors
Cyclosporine (11 AA peptide)
环孢素
Tacrolimus (FK506)
他克莫司，属23元大环内酯类
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
Cyclosporine
1. Pharmacological effect
1) By blocking 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.
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.
Tacrolimus (FK506)
1. Pharmacological effect
By blocking 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,
3 Adverse effects
Nephrotoxicity, neurotoxicity, hyperglycemia,
hypertension, hyperkalemia, and gastrointestinal
complaints.
4. Drug interactions
Tacrolimus is metabolized primarily by P450
enzymes in the liver, and there is a potential for
drug interactions.
3. Cytotoxic agents
Azathioprine
巯唑嘌呤
Methotrexate
甲氨蝶呤
Azathioprine/methotrexate
1. Pharmacological effects
By inhibiting 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).
3. Adverse effects
1) 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
3. Anti-proliferation and anti-metabolism agents
Mycophenolate Mofetil
霉酚酸酯
Mycophenolate mofetil
mycophenolic acid，霉酚酸
Mycophenolate mofetil
鸟苷一磷酸
次黄(嘌呤核)苷酸
鸟苷酸
次黄嘌呤单核苷酸脱氢酶
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.
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
MPA  MPAG
MPAG

MPA
Kidney
enterohepatic circulation
霉酚酸-葡萄糖醛酸酐
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
1) Synergistic with CsA and FK506, inhibit rejection
after organ graft, esp. for long term usage.
3. Adverse effects
GI responses, peptic ulcer, interstitial pneumonia
4. Antibodies
• Antilymphocyte antibodies
• Antithymocyte antibodies
• Monoclonal antibodies directed against
specific antigens such as CD3, CD4,
CD20, IL-2 receptor
Immunological molecule in the cellular membrane
TCR:
T cell receptor
BCR:
B cell receptor
IgFcR:
CR:
complement receptor
CKR:
AM:
IgFc receptor
cytokine receptor
adhesive molecular
receptor
MHC
CD
Antilymphocyte antibodies
1. Pharmacological 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. Clinical uses
Renal transplant rejection
Antilymphocyte antibodies
3. Adverse effects
1) Local pain and erythema （红斑） often occur at
the injection site.
2) Anaphylactic reaction and serum sickness
3) lymphoma as well as other forms of cancer
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.
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
Monoclonal antibodies
Anti-CD20 drugs:
rituximab (利妥昔单抗)
Pharmacological effects and clinical uses:
Blocking the specific function of the surface of
CD20 molecule on pre-B and B cells
Used for non-Hodgkins lymphoma and
chemotherapy-resistant advanced follicular
lymphoma（滤泡性淋巴瘤）
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.
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.
Monoclonal antibodies
Infliximab(英夫利昔单抗，Remicade):
a chimeric human/murine anti-tumour
necrosis(TNF) monoclonal antibody
Pharmacological effects and clinical uses:
• 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
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）
Thanks!