Agents Which Affect the Agents Which Affect the Immune ResponseImmune Response

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 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 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, ankleshttp://www.scienceclarified.com/images/uesc_01_img0050.jpg

Systemic Lupus Systemic Lupus ErythematosusErythematosus

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

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

Prednisone

Dexamethasone

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

Tioguanine

Azathioprine 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-10

Used to treat organ transplant rejection

Muromonab-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.