Agents Which Affect the Immune Response

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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

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
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 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 intestinal health
 This led to marketing of fermented milk
drinks, a.k.a. Probiotics
Neutrophil Chase
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/images/uesc_0
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
http://www.taconichills.k12.ny.us/webquests/no
ncomdisease/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/588/548/5885
48-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/753/753Calcineuri
nInhibitors.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


Used to 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_illust
rations/FACET_MoA_ELOTUZUMAB.jpg
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. 1005030. 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): 398417. 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.

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