Immunotherapy

Definition The approach to balance or intervene the immunologic function in order to fight against the disease by the principle of immunology. Most immunotherapeutic strategies remain experimental.

Classification of immunotherapy NameScope or uses ImmunoenhancementInfection, tumor, immunodeficiency disease ImmunosuppressionHVGR, GVHR, Autoimmune diseases, Anaphylaxis, inflammation Non-specific (active)BCG, levamisole, cytokines Specific (active)Therapeutic vaccines of tumor cells, cell extracts purified or recombinant antigen, peptides, heat shock proteins, or DNA antigen pulsed DC Non-specific (passive)LAK cells, CIK cells Specific (passive)Antibodies alone or coupled to drugs, pro-drugs, toxins or radioisotype, bi-specific antibodies, antigen-specific T cells CombinedLAK cells and bi-specific antibodies

 Molecular Immunotherapy 1. Molecular vaccines 2. Antibody 3. Cytokine

Molecular vaccine and whole organism vaccine DNA vaccine Synthetic peptide vaccine Recombinant molecules

Therapy with antibodies Polyclonal antibody Monoclonal antibody Genetic engineering antibody

Use of tumor associated antigens monoclonal antibodies tumor prodrug drug toxin radioisotope Enzyme

Cytokine therapy Cytokine supplement and addition Cytokine blockage and suppression Cytokine inhibitors Cytokine gene therapy

Cytokine addition IL-2 malignant tumor IFN-α Viral hepatitis, chronic myelogenous leukemia, multiple myeloma, non-Hodgkin’s lymphoma, cutaneous T cell lymphoma, malignant melanoma, renal cell carcinoma, bladder cancer, ovarian cancer IFN-β gliomas, multiple sclerosis IFN-γ kaposi’s sarcoma, idiopathic pulmonary fibrosis

Cytokine Blockage and suppression  Use of Th1 cell– derived cytokines to antagonize the Th2 cell activity  Some virus encode proteins-virokines or viroreceptors that resemble specific cytokines or cytokine receptors

Cytokine inhibitors Inhibitors of tumor necrosis factor (two strategies) A humanized mouse Ab (infiximab), binds to human TNF-α and prevents the binding of TNF-α to its receptors. A fusion protein (etanercept) that consists of the extracellular domain of the human TNF p75 receptor linked to the constant region of a human IgG.

Cytokine gene therapy

 Cellular Immunotherapy 1. Adoptive immunotherapy 2. Stem cell transplantation

Adoptive therapy LAK lymphokine activated killers TIL Tumor infiltration lymphocyte CIK Cytokine induced killers

Stem cell transplantation Blood stem cell (CD34+) Bone marrow transplantation (GVHD) Syngeneic Allogeneic

 Biological response modifiers Non-specific agents to stimulate the immune response Bacterial products BCG Synthetic molecules Polynucleotides Cytokines IFN-α, IFN-β, IFN-γ, IL-2, TNF Hormones Thymosin, thymulin, thymopoietin

 Immunosuppressive agents 1.Toxic agents 2.Folate antagonists (methotrexate) 3.Purine Analogs (6-mercaptopurine, 6-MP) 4.Alkylating agents (cyclophosphamide) 5.Mycophenolate mofetil 6.Leflunomide (inhibit pyrimidines) 7.Cyclosporine, tacrolimus and sirolimus

T cell Receptor Signaling Pathway

T cell Signaling: Calcineurin Calcineurin

Effect of CsA on graft survival