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
 430BC: 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
 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 Neutrophil Chase
intestinal health
 This led to marketing of fermented
milk 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

http://www.scienceclarified.com/imag
es/uesc_01_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
 Otherform: lupus
nephrititis
◦ Can cause kidney
failure and lead to
dialysis

http://www.taconichills.k12.ny.us/web
quests/noncomdisease/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/
548/588548-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/753/753Ca
lcineurinInhibitors.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
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

http://www.facetbiotech.com/images
/moa_illustrations/FACET_MoA_ELOTU
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. 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.  
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.