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

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

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

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

10. Cytotoxic immunosuppressive drugs

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

12. 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??? Murine 100% Mouse Protein Chimeric 33% Mouse Protein Humanized 10% Mouse Protein

13. Anti-CD4 Ab and graft tolerance

14. Anti-TNF  Ab in autoimmune disease

15. Anti-integrin Ab in multiple sclerosis

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

17. Cancer immunology

19. Escape from immune surveillance

22. mAbs and cancer

24. Fighting infectious disease: vaccines

26. 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

27. Making a vaccine

28. Making a vaccine using molecular biology

29. DNA vaccines

30. 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