Immunopharmacology

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Immunopharmacology

• Fen-Fei Gao

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Elements of the Immune System

• Normal Immune Responses
• The innate immune system
• The first line of defense
• Including physical (eg, skin), biochemical (eg,
  complement(??), lysozyme(???)), and cellular
  (macrophages, neutrophils) components
• The adaptive immune system
• Humoral immunity B lymphocytes antibodies
• Cell-mediated immunity T lymphocytes

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• Abnormal Immune Responses
• Hypersensitivity
• Immediate hypersensitivity usually
  antibody-mediated.
• Type ? cross-linking of membrane-bound IgE on
  blood basophils(????) or tissue mast cells(????)
  by antigen.
• Type ? the formation of antigen-antibody
  complexes between foreign antigen and IgM or IgG
  immunoglobulins(?????). eg, blood transfusion
  reactions and hemolytic disease of the newborn.
• Type ? 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.
• Autoimmunity an immune response against itself
  due to failure to distinguish self tissues and
  cells from foreign (nonself) antigens.
• Immunodeficiency diseases

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Immunosuppressive Drugs

• Common characteristic
• 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.

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Cyclosporin

• Fat-soluble peptide antibiotic
• Pharmacokinetics
• Slowly and incompletely absorbed after oral
  administration.
• Almost totally metabolized and excreted in the
  bile.
• Pharmacological Effects
• 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-?, 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
• cyclosporin cyclophilin ? complex ?
  calcineurin(?????)?? dephosphorylation of nuclear
  factors of activated T cells? ? gene
  transcription? ? IL-2,3,4?, TNF-a?, IFN-??
• cyclosporin ? TGF-ß? ? proliferation of T cells
  induced by IL-2 ?, cytotoxic T cells?
• Clinical Uses
• Organ transplantation
• Autoimmune disorders
• Adverse Effects and Cautions
• Nephrotoxicity(??????),
• Transient liver dysfunction
• secondary infection viral infection
• Lymphoma and other cancers (Kaposis sarcoma,
  skin cancer)

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Tacrolimus (FK506)

• Macrolide(????) antibiotic produced by
  streptomyces tsukubaensis(????).
• It is not chemically related to cyclosporine, but
  their machanisms of action are similar, both bind
  to cytoplasmic peptidyl(??)-prolyl(???)
  isomerases(???).
• 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.

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Adrenocortical Hormones

• Lympholytic(??????) 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.

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Antimetabolite

• Including Aza, MTX, 6-MP, et al.
• Aza is an imidazolyl(??) 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(????????)
• Treatment of autoimmune disorders rheumatoid
  arthritis(??????), systemic lupus
  erythematosus(???????), et al.
• Adverse reactions bone marrow suppression,
  gastrointestinal symptoms, hepatic dysfunction.

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Alkylating(??) 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(??????).

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Antilymphocyte Globulin (ALG)

• Antiserum is usually obtained by immunization of
  large animals with human lymphoid cells or by the
  hybridoma(???) technique for monoclonal antibody
  generation.
• Antithymocyte(??????) globulin (ATG).
• Destruction or inactivation of the T cells.
• primary immune responsegtsecondary immune response
• Adverse reactions are mostly those associated
  with injection of a foreign protein obtained from
  heterologous serum.

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Mycophenolate Mofetil (RS-61443)

• A semisynthetic derivative of mycophenolic acid
  (MPA), isolated from the mold Penicillium
  glaucum.
• MPA is the inhibitor of IMPDH. Inhibit the de
  novo(??) pathway of purine synthesis.
• Inhibit a series of T and B lymphocyte responses.
• Kidney and liver transplant, et al.
• Adverse reactions are mainly gastrointestinal .

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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(??) effects.

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Immunostimulants

• Increase the immune responsiveness of patients
  who have either selective or generalized
  immunodeficiency.
• Use for immunodeficiency disorders, chronic
  infectious diseases, and cancer.

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Immune Adjuvant

• Bacillus Calmette-Guerin-Vaccine (BCG) is a
  viable(????) strain of Mycobacterium(????)
  bovis(??) that has been used for immunization
  against tuberculosis.
• Also been employed as a nonspecific adjuvant or
  immunostimulant in cancer therapy.

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Cytokines

• Interferon (INF) INF-a,ß,?
• Antiviral, anticancer, immunomodulating effects.
• Antiviral effects INF-a,ßgt INF-?
• immunomodulating effects INF-?
• Adverse Effects flu-like symptoms, fatigue(??),
  malaise(??)
• Interleukin-2 (IL-2)
• T cell proliferation, TH, NK, LAK cell activation
• Treatment of malignant melanoma(?????), renal
  cell carcinoma, Hodgkin disease
• Adverse Effects fever, anorexia(????), et al.

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Other Immunomodulators

• Entanercept
• Transfer Factor (TF)
• Thymosin
• Levamisole (LSM)
• Isoprinosine