Agents Which Affect the Immune Response

1. Agents Which Affect the Immune Response Dan Fernandez

2. Overview • I. Immune System Overview • II. History of Immunology • III. Current Treatment Techniques • Immunosuppressants • Tolerogens • Immunostimulants • Immunization • IV. What the future holds • V. Conclusion

3. History of Immunology • 430 BC: Earliest known mention of immunity during the plague of Athens • Thucydides noted that recovered individuals could help nurse the sick without getting the illness a second time • University of Maryland conference concluded that typhus was the causative disease, though its still up for debate • 18th Century: Scientist de Maupertuis experimented with scorpion venom and found some mice and dogs were immune to effects. • Louis Pasteur later exploited these observations in developing vaccination and germ theory of diseases. • 1891: Robert Koch published proof that microorganisms caused infectious diseases

4. History of Immunology • Paul Erlich • Noted for curing syphilis and research into autoimmunity • Side-Chain Theory: explained effects of serum and enabled measurement of antigen • Coined term “chemotherapy” • Work showed the existence of a blood brain barrier • Popularized concept of “magic bullet” • Target specifically a bacterium without affecting other organisms • Salvarsan

5. History of Immunology • IlyaIlyichMechnikov • Received nobel prize in 1908 for his work on phagocytosis • Realized digestion was basically same mechanism done by white blood cells to engulf and destroy harmful bacteria • Current popular thought was that white blood cells actually helped spread the ingested pathogens around the body • Also believed that aging is caused by toxic bacteria in gut and that lactic acid could help prolong life • Drank sour milk everyday • Thought inspired Minoru Shirota to investigate relationship between bacteria and good intestinal health • This led to marketing of fermented milk drinks, a.k.a. Probiotics Neutrophil Chase

6. Immune System Overview • Two types of Immune Response • Non-specific (Basically just recognizes foreign vs native) • Barriers • Inflammation • Phagocytes • All types of White Blood Cells (Leukocytes) • Dendritic Cells • Macrophages • Neutrophils

7. Immune System Overview • Specific (Adaptive) Response • Lymphocytes (also types of white blood cells) • B Lymphocytes (B Cells) • Produced in bone marrow • Humoral Response • Before Infection/Infiltration • T Lymphocytes (T Cells) • Start in bone marrow, but mature in Thymus • Cell Mediated Response • Helper T Cells • Cytotoxic T Cells • Once activated, T Cells and B Cells differentiate and divide • Causes cytokine and lymphokine release

8. B-Cells • Have membrane-bound antibodies on cell surface • Variable and specific for each B-Cell • Make antibodies • Activation: • Antigen must bind to sites • Stimulation by Helper T-Cells

9. T-Cells • Helper T Cells • Respond to nearly all antigens, • Produce CD4, which helps bind to class II MHC complexes on antigen presenting cells • Cytolytic T Cells • Main response towards infected and cancerous cells • Produce CD8 protein, binds transplanted tissue, infected cells, cancer cells • Secrets proteins that cause cell death • T-Regulatory Cells (Tregs) • Suppress the activation of the immune system to help maintain homeostasis

10. Rheumatoid Arthritis • Disease that leads to inflammation of the joints and surrounding tissues • Can affect organs • The immune system confuses healthy tissue with foreign and begins to attack itself • Occurs at any age, usually affects women more than men • Affects joints on both sides equally • Wrists, fingers, knees, feet, ankles http://www.scienceclarified.com/images/uesc_01_img0050.jpg

11. Systemic Lupus Erythematosus • Autoimmune disease • Symptoms: • Chest pain, fatigue, fever, general discomfort, hair loss, mouth sores, sensitivity to sunlight, skin rash, swollen lymph nodes, arrhythmias, blood in urine, abdominal pain, coughing up blood, patchy skin colors • Other form: lupus nephrititis • Can cause kidney failure and lead to dialysis http://www.taconichills.k12.ny.us/webquests/noncomdisease/lupuspic.jpg

12. Other Immunological Diseases • Type I diabetes mellitus • Multiple sclerosis • Asthma • Allergies • SCID

13. Treatment Strategies • Immunosuppression – involves downregulating immune system activity • Tolerance – the idea that a body can be taught not to reject somthing • Immunostimulation – involves upregulating immune system activity • Immunization – active or passive

14. Immunosuppression – Glucocorticoids • Usually co-administered with other suppressive agents to treat auto-immune disorders or treatment of transplant rejection • Exact mechanism not elucidated • Very broad anti-inflammatory effects • Downregulate IL-1 and IL-6 • Cause apoptosis in activated cells

15. Immunosuppression – Glucocorticoids • Side Effects • Toxic • Causes increased infection risk • Poor wound healing • Hyperglycemia • Hypertension

16. http://img.medscape.com/article/588/548/588548-fig3.jpg

17. Immunosuppression – Glucocorticoids Prednisone Dexamethasone Cortisol

18. Immunosuppression – Calcineurin Inhibitors • Calcineurin – protein phosphatase that activates T Cells by dephosphorylating transcription factors, including NFAT (nuclear factor of activated T cells). • Blocks T Cell proliferation • Decreased immune response

19. Immunosuppression – Calcineurin Inhibitors Tacrolimus a.k.a. FK-506 Cyclosporin A

20. http://drtedwilliams.net/cop/753/753CalcineurinInhibitors.GIFhttp://drtedwilliams.net/cop/753/753CalcineurinInhibitors.GIF

21. Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs • Inhibit immune cell proliferation, reducing the immune response • mTOR inhibitors • Enzyme in lymphocyte cell that is key to transition from G1 to S phase

22. Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs Everolimus Sirolimus

23. Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs • Azathioprine • Purine anti-metabolite Tioguanine Mercaptopurine Azathioprine Guanine

24. Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs • Mycophenolate Mofentil (CellCept®) • Hydrolyzed to mycophenolic acid • IMPDH inhibitor (inosine monophosphate dehydrogenase enzyme • Important in biosynthesis of guanine • Good alternative to azathioprine when toxicity is an issue Mycophenolic acid

25. Immunosuppression – Monoclonal Antibodies • Anti-CD3 Antibodies • Binds to chain of CD3, which is involved in T-cell antigen recognition, signaling, and proliferation • Administration of mAb followed by depletion of T cells from bloodstream and lymphoid organs • Lack of IL-2 production • Reduction of multiple cytokines • Not IL-4 and IL-10 • Used to treat organ transplant rejection • Muromonab-CD3 (Orthoclone OKT3®)

26. Immunosuppression – Monoclonal Antibodies • Anti-IL-2 Receptor [Anti-CD25] Antibodies • Exact mechanism not understood • Binds to IL-2 receptor on surface of activated T cells • No effect on resting T cells • Stops current response • Daclizumab and Basiliximab

27. Immunosuppression – Monoclonal Antibodies http://www.facetbiotech.com/images/moa_illustrations/FACET_MoA_ELOTUZUMAB.jpg

28. Immunosuppression – Other Agents • Others include • Alemtuzumab (mAb) – targets CD52, causes lympholysis by inducing apoptosis of targeted cells • IL-1 Inhibition • Alefacept – protein, interferes with T-cell activation

29. Tolerance • Strategy is to induce and maintain tolerance • Useful strategy for organ transplantation • Very much the target of research today • Would represent a true cure for autoimmune conditions without side effects of immunosuppressive agents • “Holy Grail” of immunomodulation

30. Tolerance • Co-Stimulation • Requires two signals to activate • Donor Cell Chimerism • Co-existence of two genetic lineages in a single individual • First dampen or eliminate immune function with ionizing radiation, drugs, or antibodies • The provide new source of immune function by transfusion • Shows promise in development of long-term unresponsiveness

31. Immunostimulants • Immunostimulants are applicable during infections, immunodeficiency, and cancer • Levamisole • Restores depressed immune function of B and T Cells, monocytes, and macrophages • Causes agranulocytosis • Removed from market in 2005 Levamisole

32. Immunostimulants • Thalidomide • Teratogenetic • BUT is useful to treat erythema nodosum leprosum and multiple myeloma Thalidomide

33. Immunostimulants • Interferons • Bind to spefici cell-surface receptors that initiate series of intracellular events • Induction of enzymes • Inhibition of cell proliferation • Enhancement of immune activity • Intron A ® - peptide used for tumor treatment and infectious diseases; • Actimmune ® - peptide that activates phagocytes and induces generation of oxygen metabolites that are toxic to a number of microorganisms

34. Immunization • Active or passive • Active – stimulation with antigen to develop antigens for future prevention • Passive – administration of antibodies to individual already exposed or about to be exposed to antigens • Vaccines – active; administration whole, killed organism, live organism, or specific peptide from organism • Immune Globulin – used in passive immunization; used in individuals deficient in antibodies

35. Future • More research into Tolerance may yield less immunological diseases • Always looking for more specific targets • Less toxic compounds needed with less side effects

36. Conclusion • Most immunomodulatory drugs are suppressants • Cause problems as it makes patients more susceptible to infection • Most are somewhat toxic • Tolerance is a great concept but not yet fully realized • Stimulants are helpful to boost the immune system • Immunization has been a proven tool against fighting infectious diseases

37. References • Besedovsky, Hugo O., and Adriana Del Rey. "Regulating Inflammation by Glucocorticoids." Nature Immunology 7.6 (2006): 537. Print. • Campbell, Neil A., and Jane B. Reece. "43. The Immune System." Biology. 7th ed. San Francisco: Pearson, Benjamin Cummings, 2005. 898-921. Print. • Goodman, Louis Sanford, Laurence L. Brunton, Bruce Chabner, and Björn C. Knollmann. "35. Immunosuppressants, Tolerogens, and Immunostimulants." Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill Medical, 2011. 1005-030. Print. • Hamawy, MM. "Molecular Actions of Calcineurin Inhibitors." Drug News & Perspectives 16.5 (2003): 277-82. Print. • Marder, Wendy, and W. McCune. "Advances in Immunosuppressive Therapy." Seminars in Respiratory and Critical Care Medicine 28.4 (2007): 398-417. Print.  

38. Reading Assignment • Hamawy, MM. "Molecular Actions of Calcineurin Inhibitors." Drug News & Perspectives 16.5 (2003): 277-82. Print. • Marder, Wendy, and W. McCune. "Advances in Immunosuppressive Therapy." Seminars in Respiratory and Critical Care Medicine 28.4 (2007): 398-417. Print.  

39. Homework Questions • Who were the two main fathers of modern immunology and what were their major contributions? • What is the mechanism of action of Azathioprine? • What is the mechanism of action of Leflunomide? • Explain the Calcium-calcineurin cascade.