Transcript Immunopharmacology

Immunopharmacology
Fen-Fei Gao
Elements of the Immune System
 Normal
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Immune Responses
The innate immune system:
• The first line of defense
• Including physical (eg, skin), biochemical (eg,
complement(补体), lysozyme(溶菌酶)), and cellular
(macrophages, neutrophils) components
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The adaptive immune system:
• Humoral immunity – B lymphocytes: antibodies
• Cell-mediated immunity – T lymphocytes
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Abnormal Immune Responses
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Hypersensitivity:
• Immediate hypersensitivity: usually antibody-mediated.
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Type Ⅰ: cross-linking of membrane-bound IgE on blood basophils(嗜碱
细胞) or tissue mast cells(肥大细胞) by antigen.
Type Ⅱ: the formation of antigen-antibody complexes between foreign
antigen and IgM or IgG immunoglobulins(免疫球蛋白). eg, blood
transfusion reactions and hemolytic disease of the newborn.
Type Ⅲ: the presence of elevated levels of antigen-antibody complexes
that cause tissue damage.
• Delayed hypersensitivity: cell-mediated. Induces a local
inflammatory response and causes extensive tissue damage
characterized by the influx of antigen-nonspecific inflammatory cells.
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Autoimmunity: an immune response against itself due to failure
to distinguish self tissues and cells from foreign (nonself)
antigens.
Immunodeficiency diseases:
Immunosuppressive Drugs
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Common characteristic:
①
②
③
④
Deficiency in specific or selectivity:
More effective in the first immume response
action than in that of the second.
Action related to the time of administration of
drugs, the interval of antigen stimulation and
subsequence.
Non-specific anti-inflammatory effect.
Cyclosporin
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Fat-soluble peptide antibiotic
Pharmacokinetics
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Slowly and incompletely absorbed after oral
administration.
Almost totally metabolized and excreted in the bile.
Pharmacological Effects:
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Act at an early stage in the antigen receptor-induced
differentiation of T cells and block their activation.
Inhibit the gene transcription of IL-2, IL-3, IFN-γ, and
other factors produced by antigen-stimulated T cells,
but it does not block the effect of such factors on
primed T cells nor does it block interaction with
antigen.
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Mechanisms
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Clinical Uses
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cyclosporin + cyclophilin → complex → calcineurin(钙调磷酸
酶)↓→ dephosphorylation of nuclear factors of activated T cells↓
→ gene transcription↓ → IL-2,3,4↓, TNF-α↓, IFN-γ↓
cyclosporin → TGF-β↑ → proliferation of T cells induced by IL-2
↓, cytotoxic T cells↓
Organ transplantation
Autoimmune disorders
Adverse Effects and Cautions
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Nephrotoxicity(中毒性肾损害),
Transient liver dysfunction
secondary infection: viral infection
Lymphoma and other cancers (Kaposi’s sarcoma, skin cancer)
Tacrolimus (FK506)
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Macrolide(大环内酯) antibiotic produced by streptomyces
tsukubaensis(链霉菌属).
 It is not chemically related to cyclosporine, but their
machanisms of action are similar, both bind to
cytoplasmic peptidyl(肽基)-prolyl(脯氨酰) isomerases(异
构酶).
 For liver, kidney, heart, pancreas, and bone marrow
transplant applications.
 Toxic effects: nephrotoxicity, neurotoxicity, hyperglycemia
(requiring insulin therapy), gastrointestinal dysfunction.
 Some studies suggested the higher efficacy and the
higher incidence of serious toxicities of tacrolimus than
cyclosporine in the management of of liver transplant
patients.
Adrenocortical Hormones
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Lympholytic(淋巴细胞溶解) properties
Interfere with the cell cycle of activated lymphoid
cells.
Their immunologic effects are due to their ability
to modify cellular functions rather than to direct
cytotoxicity.
Immunosuppressive and anti- inflammatory
properties.
Indications include organ transplantation and
autoimmune disorders.
Antimetabolite
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Including Aza, MTX, 6-MP, et al.
 Aza is an imidazolyl(咪唑) derivative of 6-MP.
 Aza is the purine analog that interferes with nucleic acid
metabolism at steps that are required for the wave of
lymphoid cell proliferation which follows antigenic
stimulation.
 T cells is more sensitive than B cells.
 Benefit in maintaining renal allograft(同种异基因移植物)
 Treatment of autoimmune disorders: rheumatoid
arthritis(类风湿关节炎), systemic lupus erythematosus(系
统性红斑狼疮), et al.
 Adverse reactions: bone marrow suppression,
gastrointestinal symptoms, hepatic dysfunction.
Alkylating(烷化) agent
 Cyclophosphamide
(CTX) destroys
proliferating lymphoid cells but also
appears to alkylate some resting cells.
 B cells is more sensitive than T cells.
 Organ transplants, autoimmune disorders.
 Adverse reactions: bone marrow
suppression, gastrointestinal symptoms,
hemorrhagic cystitis(出血性膀胱炎).
Antilymphocyte Globulin (ALG)
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Antiserum is usually obtained by immunization of
large animals with human lymphoid cells or by
the hybridoma(杂交瘤) technique for monoclonal
antibody generation.
Antithymocyte(抗胸腺细胞的) globulin (ATG).
Destruction or inactivation of the T cells.
primary immune response＞secondary immune
response
Adverse reactions are mostly those associated
with injection of a foreign protein obtained from
heterologous serum.
Mycophenolate Mofetil (RS-61443)
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A semisynthetic derivative of mycophenolic acid
(MPA), isolated from the mold Penicillium
glaucum.
MPA is the inhibitor of IMPDH. Inhibit the de
novo(重新) pathway of purine synthesis.
Inhibit a series of T and B lymphocyte responses.
Kidney and liver transplant, et al.
Adverse reactions are mainly gastrointestinal .
Leflunomide
 A prodrug
of an inhibitor of pyrimidine
synthesis rather than purine synthesis.
 Inhibit DHODH through A771726.
 It is orally active, and the active metabolite
has a long half-life of several weeks.–
should be started with a loading dose.
 Mainly for rheumatoid arthritis.
 Toxicities: liver damage, renal impairment,
teratogenic(致畸) effects.
Immunostimulants
 Increase
the immune responsiveness of
patients who have either selective or
generalized immunodeficiency.
 Use for immunodeficiency disorders,
chronic infectious diseases, and cancer.
Immune Adjuvant
 Bacillus
Calmette-Guerin-Vaccine (BCG)
is a viable(可培育的) strain of
Mycobacterium(分支杆菌) bovis(牛型) that
has been used for immunization against
tuberculosis.
 Also been employed as a nonspecific
adjuvant or immunostimulant in cancer
therapy.
Cytokines
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Interferon (INF): INF-α,β,γ
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Antiviral, anticancer, immunomodulating effects.
Antiviral effects : INF-α,β＞ INF-γ
immunomodulating effects: INF-γ
Adverse Effects: flu-like symptoms, fatigue(疲乏),
malaise(不适)
Interleukin-2 (IL-2)
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T cell proliferation, TH, NK, LAK cell activation
Treatment of malignant melanoma(恶性黑素瘤), renal
cell carcinoma, Hodgkin disease
Adverse Effects: fever, anorexia(食欲缺乏), et al.
Other Immunomodulators
 Entanercept
 Transfer
Factor (TF)
 Thymosin
 Levamisole (LSM)
 Isoprinosine