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Manipulation of the Immune Response

Manipulation of the Immune Response. Chapter 14. http://www.nearingzero.net/screen_res/nz360.jpg. Objectives. Discuss modes of action of common immunosuppressive drugs Describe uses of monoclonal antibodies in immune disorders and cancer Explain how anti-tumor immune responses are generated

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Manipulation of the Immune Response

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  1. Manipulation of the Immune Response Chapter 14 http://www.nearingzero.net/screen_res/nz360.jpg

  2. Objectives • Discuss modes of action of common immunosuppressive drugs • Describe uses of monoclonal antibodies in immune disorders and cancer • Explain how anti-tumor immune responses are generated • Describe characteristics of an effective vaccine

  3. phospholipids phospholipase A2 arachidonic acid x cyclo-oxygenase (COX)-1 or -2 lipoxygenase NSAIDs leukotrienes prostaglandins thromboxane inflammation Anti-inflammatory drugs: NSAIDs

  4. Anti-inflammatory drugs: steroids • Corticosteroids are powerful anti-inflammatory drugs • Prednisone (cortisol analogue) • Used in transplantation, autoimmunity, allergy • Activated steroid receptors act as transcription factors

  5. Anti-inflammatory drugs: steroids

  6. + - STRESS - + Corticosteroid physiology Corticotropin releasing hormone (CRH) + Adrenocorticotropic hormone (ACTH) + cortisol

  7. Corticosteroid physiology • Many side effects are possible • Used in combination with other drugs to limit toxicity from P. Stewart, Williams Textbook of Endocrinology, 2003

  8. Cytotoxic immunosuppressive drugs • Azathioprine, cyclophospamide • Interfere with DNA synthesis • High doses used to eliminate all lymphocytes prior to bone marrow transplantation • Originally developed to treat cancer • Cyclosporin A, tacrolimus, rapamycin • Less toxic • Interfere with clonal expansion of activated lymphocytes • Used in transplant recipients

  9. Cytotoxic immunosuppressive drugs

  10. Immunosuppression Halloran P. New England Journal of Medicine 351:2715-2729, 2004.

  11. Antibodies as therapeutics • Monoclonal antibodies are used for transplantation, autoimmunity, cancer • Depleting (antibody-mediated cytotoxicity) • Nondepleting (block function of target molecules) • Monoclonal antibodies are traditionally made in mice… problems???

  12. Anti-CD4 Ab and graft tolerance

  13. Anti-TNFa Ab in autoimmune disease

  14. Anti-integrin Ab in multiple sclerosis

  15. Immunomodulation • Interfere with costimulation • Soluble CTLA-4 blocks CD28 : B7 interactions • Induce regulatory T cells or tolerance??

  16. Cancer immunology

  17. Escape from immune surveillance

  18. Escape from immune surveillance

  19. Escape from immune surveillance

  20. mAbs and cancer

  21. mAbs and cancer

  22. Fighting infectious disease: vaccines

  23. Fighting infectious disease: vaccines

  24. Vaccines • Antigen sources: • Small doses of the wild type virus or use of a “safe” counterpart (early smallpox vaccines) • Killed/inactivated pathogen • Toxoid • Viral subunits • Live attenuated virus

  25. Making a vaccine

  26. Making a vaccine using molecular biology

  27. DNA vaccines

  28. Other vaccine development strategies • Developing better adjuvants • ISCOMs (Immune Stimulatory Complexes) deliver peptides to MHC I processing pathway • Mucosal adjuvants (modified pertussis toxin) • Targeting APCs by coadministration of cytokines • Developing nasal or oral vaccines

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