Agents Which Affect the Immune Response Dan Fernandez Overview I. Immune System Overview II. History of Immunology III. Current Treatment Techniques ◦ ◦ ◦ ◦ Immunosuppressants Tolerogens Immunostimulants Immunization IV. What the future holds V. Conclusion 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 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 History of Immunology Ilya Ilyich Mechnikov ◦ 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 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 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 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 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 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_0 1_img0050.jpg 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/no ncomdisease/lupuspic.jpg Other Immunological Diseases Type I diabetes mellitus Multiple sclerosis Asthma Allergies SCID 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 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 Immunosuppression – Glucocorticoids Side Effects ◦ ◦ ◦ ◦ ◦ Toxic Causes increased infection risk Poor wound healing Hyperglycemia Hypertension http://img.medscape.com/article/588/548/5885 48-fig3.jpg Immunosuppression – Glucocorticoids Prednisone Dexamethasone Cortisol 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 Immunosuppression – Calcineurin Inhibitors Tacrolimus a.k.a. FK-506 Cyclosporin A http://drtedwilliams.net/cop/753/753Calcineuri nInhibitors.GIF 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 Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs Sirolimus Everolimus Immunosuppression – Anti-proliferative and Anti-Metabolic Drugs ◦ Azathioprine Purine anti-metabolite Tioguanine Azathioprine Mercaptopurine Guanine 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 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®) 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 Immunosuppression – Monoclonal Antibodies http://www.facetbiotech.com/images/moa_illust rations/FACET_MoA_ELOTUZUMAB.jpg 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 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 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 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 Immunostimulants Thalidomide ◦ Teratogenetic ◦ BUT is useful to treat erythema nodosum leprosum and multiple myeloma Thalidomide 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 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 Future More research into Tolerance may yield less immunological diseases Always looking for more specific targets Less toxic compounds needed with less side effects 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 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. 1005030. 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. 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): 398417. Print. 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.