Manipulation of the Immune Response - Immunomodulation -
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1 Manipulation of the Immune Response - Immunomodulation - Janeway s Immunobiology, 9 th ed., Ivana Novak Nakir
2 Immune system Immune system make components, cells and organs that act together to defend the host from microbes.
3 Aim of immunomodulation Hyperimmune response Hypoimmune response E.g. - Autoimmune diseases - Allergies - Transplant rejection E.g. - Infections - carcinomas
4 Immunomodulation methods IMMUNOSUPPRESSION: Immunosupressive drugs Monoclonal antibodies Antitumor therapy Gene manipulation (CRISPR-Cas9, sirna) IMMUNOSTIMULATION: BCG Interferons Talidomide, levamisol IL-2 IMMUNISATION Vaccination Immunoglobulins
5 Immunosupression - Autoimmune diseases - Organ transplantation Problems: Lifetime usage of drugs Infections, tumors Nephrotoxicity Diabetogens
6 Immunosupressive drugs - Anti-inflammatory (NSAIDs, corticosteroids) - Cytotoxic (azathioprine, cyclophosphamide) - Noncytotoxic (cyclosporin A, tacrolimus, rapamycin)
7 Immunosuppressive drugs: Nonsteroidal anti-inflammatory drugs - NSAIDs phospholipids Arachidonic acid Phospholipase A 2 Cyclooxigenase (COX)-1 or -2 Prostaglandins thromboxans x NSAIDs Lipoxigenase leukotriens!inflammation
8 Immunosuppressive drugs: steroids Corticosteroids antiinflammatory drugs Prednisone (synthetic cortisol analog) Used in transplantations, autoimmune diseases, allergies Activated steroid receptors act as transcription factors
9 Immunosuppressive drugs: steroids
10 Corticosteroids physiology - Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (ACTH) + STRESS + cortisol
11 Corticosteroids physiology Possible multiple side effects Used in combination with other drugs to reduce toxicity from P. Stewart, Williams Textbook of Endocrinology, 2003
12 Immunosupressive cytostatics Azathioprine (AZA), cyclophosphamide Interfere with DNA synthesis (dividing cells) Primarily planned to be used for anti-tumor therapy Used in low dosage for autoimmune diseases (combination with corticosteroids) Used in high dosage only before bone marrow transplantation to eliminate all lymphocytes Cyclophosphamide (more toxic) developed as chemical weapon
13 Immunosupressive cytostatics Cyclosporin A, tacrolimus (FK506), rapamycin (sirolimus) Less toxic Bacterial/fungal origin Interfere with clonal expansion of activated lymphocytes Used in transplanted patients Block calcineurin (cyclosporin A & tacrolimus) Present in other cells in higher concentrations than in T cells T cells more susceptible to inhibitory effects - Rapamycin inhibits lymphocyte proliferation and increases the number of Treg
14 Cyclosporin A and tacrolimus
15 Cytotoxic immunosupressive drugs
16 DOI: /NEJMra Immunosupression
17 Antibodies in therapy Monoclonal antibody therapy: transplantations, autoimmune diseases, tumors Cytotoxic (antibody-mediated cytotoxicity) Neutralizing (block the function of target molecule) Usually produced in mice problems?!?!? Examples: - anti-cd3 - anti-tnf-α - anti-il-2 - anti-lfa1, 100% mouse 30% mouse 10% mouse 100% human
18
19
20 Anti-CD4 Ab & graft tolerance
21 Anti-TNFα Ab in autoimmune diseases Works well for: Rheumatoid arthritis, Crohn s disease, ankylosing spondylitis Does not work for: multiple sclerosis
22 Anti-integrin Ab im MS VLA-4
23 Immune responses and tumors
24 Immune responses and tumors
25 Malignant cells are monitored by immune system
26 Tumors can avoid immune recognition
27 Tumors can avoid immune recognition
28 mabs and tumors or chemotherapeutic drug Ricin A
29 Immunostimulants Levamisole: antihelmintic, leukocyte activator (colon cancer) Thalidomide: increases cytokine production, activates NK cells (multiple myeloma) BCG: live microbes (bladder cancer) Interferons: antiviral effects (hepatitis, melanoma, Kaposi sarcoma) IL-2: (kidney carcinoma, melanoma)
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