Immunosuppressants df1
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  • Neutrophils hunt and kill white blood cells. Staph a have been added. Bacteria release chemoattractant sensed by the neutrophil, which becomes polarized and starts chasing the bacteria. Thermal energy moves the bacteria in a random path. When the neutrophil catches the bacteria, it engulfs the bacteria by phagocytosis
  • It depends on the disease which one you will use to treat. As such, it’s easy to sort of classify the drugs under a wide umbrella: -suppressants will be used when the immune system is overactive, like in auto-immune disorders, and used to help prevent transplant rejection -tolerance involves inducing and maintaining tolerance -stimulation will be used in diseases where there’s an immune deficiency, in order to stimulate the body to do what it was built to do
  • IL-1 and IL-6 are pro-inflammatory agents
  • Increased infection risk occurs with all immunosuppressants, as they decrease your body’s natural defenses. Must be careful!
  • Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. It is 20 to 30 times more potent than the naturally occurring hormone cortisol and 4 to 5 times more potent than prednisone.
  • When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which[2] activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.
  • Tacrolimus – Prograf®; macrolide antibiotic with greater efficacy than most Calcineurin inhibitors b/c it’s easy to monitor blood levels. It forms a complex with tacrolimus-FKBP-12, Ca+2, calmodulin, and calcineurin, which inhibits the phosphatase activity of calcineurin. Cyclosporine A has similar mechanism to Tacrolimus
  • Sirolimus administered with glucocorticoids, have a synergistic effect
  • Agranulocytosis – severe and dangerous lowered white blood cell count
  • Multiple Myeloma – cancer of plasma cells (B cells that make antibodies) Erythema nodosum leprosum – inflammation of fat cells under the skin characterized by red nodules or lumps

Immunosuppressants df1 Immunosuppressants df1 Presentation Transcript

  • Agents Which Affect the Immune Response
  • 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 18thCentury: 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 View slide
  • 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 View slide
  • 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 Neutrophil Chase drinks, a.k.a. Probiotics
  • 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 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
  • 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
  • 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
  • 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 TioguanineAzathioprine 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Usedto 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
  • 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 & Gilmans 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.  
  • 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.