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Agents Which Affect the Agents Which Affect the Immune ResponseImmune Response
Dan Fernandez
OverviewOverviewI. Immune System OverviewII. History of ImmunologyIII. Current Treatment Techniques
◦Immunosuppressants◦Tolerogens◦Immunostimulants◦Immunization
IV. What the future holdsV. Conclusion
History of ImmunologyHistory of Immunology430 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 ImmunologyHistory of ImmunologyPaul 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 ImmunologyHistory 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 OverviewImmune System OverviewTwo 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 OverviewImmune System OverviewSpecific (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-CellsB-CellsHave membrane-bound
antibodies on cell surface◦Variable and specific for each B-Cell
Make antibodiesActivation:
◦Antigen must bind to sites◦Stimulation by Helper T-Cells
T-CellsT-CellsHelper T Cells
◦ Respond to nearly all antigens,◦ Produce CD4, which helps bind to class II MHC
complexes on antigen presenting cellsCytolytic T Cells
◦ Main response towards infected and cancerous cells
◦ Produce CD8 protein, binds transplanted tissue, infected cells, cancer cells
◦ Secrets proteins that cause cell deathT-Regulatory Cells (Tregs)
◦ Suppress the activation of the immune system to help maintain homeostasis
Rheumatoid ArthritisRheumatoid 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
Systemic Lupus Systemic Lupus ErythematosusErythematosus
Autoimmune diseaseSymptoms:
◦ 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
Other Immunological Other Immunological DiseasesDiseasesType I diabetes mellitusMultiple sclerosisAsthmaAllergiesSCID
Treatment StrategiesTreatment StrategiesImmunosuppression – 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 – Immunosuppression – GlucocorticoidsGlucocorticoidsUsually co-administered with
other suppressive agents to treat auto-immune disorders or treatment of transplant rejection
Exact mechanism not elucidatedVery broad anti-inflammatory
effectsDownregulate IL-1 and IL-6Cause apoptosis in activated cells
Immunosuppression – Immunosuppression – GlucocorticoidsGlucocorticoidsSide Effects
◦Toxic◦Causes increased infection risk◦Poor wound healing◦Hyperglycemia◦Hypertension
http://img.medscape.com/article/588/548/588548-fig3.jpg
Immunosuppression – Immunosuppression – GlucocorticoidsGlucocorticoids
PrednisoneDexamethasone
Cortisol
Immunosuppression – Immunosuppression – Calcineurin InhibitorsCalcineurin 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 – Immunosuppression – Calcineurin InhibitorsCalcineurin Inhibitors
Tacrolimusa.k.a. FK-506
Cyclosporin A
http://drtedwilliams.net/cop/753/753CalcineurinInhibitors.GIF
Immunosuppression – Immunosuppression – Anti-proliferative and Anti-Anti-proliferative and Anti-Metabolic DrugsMetabolic 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 – Immunosuppression – Anti-proliferative and Anti-Anti-proliferative and Anti-Metabolic DrugsMetabolic Drugs
Sirolimus Everolimus
Immunosuppression – Immunosuppression – Anti-proliferative and Anti-Anti-proliferative and Anti-Metabolic DrugsMetabolic Drugs
◦Azathioprine Purine anti-metabolite
TioguanineAzathioprine Mercaptopurine
Guanine
Immunosuppression – Immunosuppression – Anti-proliferative and Anti-Anti-proliferative and Anti-Metabolic DrugsMetabolic 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 – Immunosuppression – Monoclonal AntibodiesMonoclonal AntibodiesAnti-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-10Used to treat organ transplant rejectionMuromonab-CD3 (Orthoclone OKT3®)
Immunosuppression – Immunosuppression – Monoclonal AntibodiesMonoclonal AntibodiesAnti-IL-2 Receptor [Anti-CD25]
AntibodiesExact mechanism not understoodBinds to IL-2 receptor on surface
of activated T cells◦No effect on resting T cells◦Stops current response
Daclizumab and Basiliximab
Immunosuppression – Immunosuppression – Monoclonal AntibodiesMonoclonal Antibodies
http://www.facetbiotech.com/images/moa_illustrations/FACET_MoA_ELOTUZUMAB.jpg
Immunosuppression – Immunosuppression – Other AgentsOther AgentsOthers include
◦Alemtuzumab (mAb) – targets CD52, causes lympholysis by inducing apoptosis of targeted cells
◦IL-1 Inhibition◦Alefacept – protein, interferes with T-
cell activation
ToleranceToleranceStrategy is to induce and maintain
toleranceUseful strategy for organ
transplantationVery much the target of research
todayWould represent a true cure for
autoimmune conditions without side effects of immunosuppressive agents
“Holy Grail” of immunomodulation
ToleranceToleranceCo-Stimulation
◦Requires two signals to activateDonor 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
ImmunostimulantsImmunostimulantsImmunostimulants 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
ImmunostimulantsImmunostimulantsThalidomide
◦Teratogenetic◦BUT is useful to treat erythema
nodosum leprosum and multiple myeloma
Thalidomide
ImmunostimulantsImmunostimulantsInterferons
◦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
ImmunizationImmunizationActive 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
FutureFutureMore research into Tolerance
may yield less immunological diseases
Always looking for more specific targets
Less toxic compounds needed with less side effects
ConclusionConclusionMost 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
ReferencesReferences 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.
Reading AssignmentReading AssignmentHamawy, 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.
Homework QuestionsHomework QuestionsWho 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.
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