1. Agents Which Affect the
Immune Response

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
 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

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
 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

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_0
1_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/no
ncomdisease/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.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
Sirolimus Everolimus

23. Immunosuppression –
Anti-proliferative and Anti-Metabolic Drugs
◦ Azathioprine
 Purine anti-metabolite
Tioguanine
Azathioprine Mercaptopurine
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
Usedto 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_E

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.