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IMMUNOMODULATOR

Dr. Hj. Rika Yuliwulandari, PhD

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OVERVIEW

I. Immune System Overview


II. History of Immunology
III. Current Treatment Techniques
Immunosuppressants
Immunostimulants
Immunization

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IMMUNE RESPONSE

Non-specific (Basically just recognizes Antigen specific


foreign vs native)
MHC restricted antigen
First line of defense presentation
Activation (endotoxin, MAF) Humoral (antibody)
Phagocytosis (m, Cell-mediated (T cells)
neutrophils, All types of White Blood DTH: Lymphokines
Cells (Leukocytes), Dendritic Cells
produced by Ag-
Lysis (NK) stimulated T cells
Lysis (Complement cascade) recruit/activate m.

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CHARACTERISTICS OF
INNATE AND ADAPTIVE IMMUNITY

Innate Immunity Adaptive Immunity

Antigen independent Antigen dependent


A lag period
No time lag
Antigen specific
Not antigen specific Development
of memory
No Immunologic
CMI and Humoral
memory (Ab) immunity)
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EXAMPLE OF IMMUNOLOGIC CASES

Transplantation Rejection
Allografts from different individuals
Xenograft from different species
Tissue rejection may occur by T H cells recognizing
different MHC II, aid T C to destroy graft
(recognize MHC I)
TH cells also release cytokines, cue macrophages
Graft vs host disease (bone marrow transplants)

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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

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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
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OTHER IMMUNOLOGICAL
DISEASES

Type I diabetes mellitus


Multiple sclerosis
Asthma
Allergies

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TWO CATEGORIES

Drugs that suppress the immune system


Suppression overcomes rejection of organ/tissue transplantation and reduces effects of
autoimmune diseases

Drugs that stimulate the immune system


Stimulation enhances activity of immune system against infectious agents and neoplastic cells

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TREATMENT STRATEGIES

Immunosuppression involves downregulating immune


system activity
Tolerance the idea that a body can be taught not to reject
something
Immunostimulation involves upregulating immune system
activity
Immunization active or passive

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IMMUNOSUPPRESSIVE AGENTS

T-cell blockers/Calcineurin inh CYCLOSPORINE


TACROLIMUS
SIROLIMUS
Glucocorticoids CORTICOSTEROIDS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
Cytotoxic drugs MYCOPHENOLATE
MOFETIL
METHOTREXATE

Antibody reagents ANTIBODIES


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MAIN PURPOSES

Three main purposes

- Suppress rejection of transplant organ


- To suppress graft-versus-host disease in bone marrow
transplantation
- To treat incompletely understood conditions: ITP, haemolytic
anaemia, Glomerulonephritis, Myasthenia gravis, SLE,
Psoriasis, Ulcerative colitis
T-CELL BLOCKER

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T-CELL BLOCKERS/CALCINEURIN INH:
CYCLOSPORINE, TACROLIMUS, AND SIROLIMUS

Most effective / potent


immunosuppressive drugs
Target intracellular signalling
pathways
Blocks induction of cytokine genes
cyclosporine and tacrolimus act on
helper T-cells:
Inhibit T-cell proliferation by
inhibiting IL-2 release and
expression of IL2 rec
cyclosporine may also inhibit IgE-
stimulated mast cell degranulation and
stimulate TGF- expression Cyclospo
Tacrolimus: rin A
Very similar mechanism to cyclosporin
Much more potent
Tacrolimus
a.k.a. FK-506
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CsA and FK506 mechanism
of action
Complex with binding
protein (CpN, FKBP)
inhibits calcineurin (CaN)
CaN is required for de-
phosphorylation and
nuclear translocation of
NFAT (nuclear factor of
activated T cells)
CaN inhibition, blocks
NFAT resulting in
inhibition of IL-2 gene

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ABSORPTION AND METABOLISM OF
CYCLOSPORINE, TACROLIMUS

Can be given oral or iv


Oral bioavailability low and variable (20 -50% cyclosporine; 6 -
56% tacrolimus)
new cyclosporine microemulsion gives more consistent absorption
Almost all excreted in bile after liver metabolism by CYP3A
enzymes
bioavailability subject to drug interactions that can increase or decrease blood levels

Pharmacokinetics
variable, incomplete oral absorption
extensive hepatic metabolism, excreted in bile
used alone or in combination with prednisone and azathioprine (or other
antineoplastic drugs)
Adverse Effects
nephrotoxicity, hepatotoxicity, hirsutism, neurotoxicity, hypertension
Anorexia, lethargy, tremor, paraesthesia
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Drug interactions due to induction and inhibition of hepatic cy P450


USES OF CALCINEURIN INHIBITORS
(T-CELL BLOCKERS)

Cyclosporine commonly used with prednisone and other


immunosuppressants to prevent allograft rejections in renal,
hepatic and cardiac transplants, and in treatment of RA and
psoriasis
Tacrolimus is approved for prevention of solid-organ allograft
rejection, and eczema (topical)

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TOXIC EFFECTS OF CYCLOSPORINE AND
TACROLIMUS

Nephrotoxicity (C>T)
Neurotoxicity (T>C)
GI problems (T)
Hypertension (C>>T)
Hyperkalemia (T)
Hyperglycemia and onset of diabetes
especially with glucocorticoids (T>C)
Increased incidence of infections and secondary tumors
least of immunosuppressants

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SIROLIMUS AND EVEROLIMUS: NEW T-CELL
BLOCKERS WITH DIFFERENT ACTIVITY

Pre-drug sirolimus binds


FKBP, but the complex
inhibits mTOR kinase
mTOR activates p70S6K
mTOR inhibition prevents
activity of p34cdc2 which
complexes with cyclin E,
thus preventing elimination
of p27Kip which is a
negative regulator of cdks
and eIF-4F
Results in inhibition of cell
cycle proogression at G1 to
S phase

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SIROLIMUS AND EVEROLIMUS: NEW T-CELL BLOCKERS

similar poor bioavailability as cyclosporine and tacrolimus, much


longer half-life; 62 h vs. 18 and 12 h
same metabolism (CYP3A) and potential drug interactions
used for prophylaxis of organ transplant rejection in combination
with a calcineurin inhibitor and glucocorticoids
toxicities include:
hyperlipidemia, lymphocoele, anemia, leukopenia,
thrombocytopenia, fever, GI effects, hyper- or hypokalemia

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GLUCOCORTICOID

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IMMUNOSUPPRESSION
GLUCOCORTICOIDS

Dexamethasone Prednisone

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Cortisol
GLUCOCORTICOID USES IN IMMUNOSUPPRESSION

Used with other immunosuppressants to prevent transplant


rejection and GVHD (synergistic effect/lower toxicity).
natural glucocorticoids not used due to mineralocorticoid activity
prednisone and prednisolone are used orally at high -
moderate doses; Very high doses of methylprednisolone
used i.v. during acute organ rejection
Used before and after antithymocyte Abs to inhibit allergic
reactions

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GLUCOCORTICOID-SENSITIVE SITES OF IMMUNE
RESPONDING

proliferation &
differentiation
MHC Class I/peptides CD8 T-cell
X X
CD8 cytolytic T-cells
APCs
GC GC
MHC Class II/peptides proliferation
APCs X CD4 T-cell CD4 immune cell X
IL-1 (helper T-cells) (delayed hypersensitivity)

IL-1, -4,-5,-6

Protein antigen B-cell Plasma cell


proliferation &
differentiation antibody
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GLUCOCORTICOID EFFECTS AND TOXICITY

Reduced immune cell content in Major side effects are


lymph nodes, spleen and blood common due to high doses
necessary for suppression
lymphopenia, monocytopenia,
eosinopenia, but neutrophilia Cushings syndrome
glucose intolerance
Interference with antigen
infections
presentation, T-cell and
macrophage functions bone dissolution
muscle wasting

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CLINICAL CONCERNS WITH CORTICOSTEROIDS

Growth inhibition in pediatric transplants


Cataracts (10% incidence)
Bone disease (inhibition of osteoblastic activity,
decreased calcium absorption, increased urinary
calcium excretion)
Diabetes (insulin-resistance, gluconeogenesis)
Hyperlipidemia (40-60% posttransplant accelerated
atherogenesis, increased incidence if combined with
calcineurin inhibitors and sirolimus)
Hypertension (60-80% in transplant patients)
Increased cardiovascular risk factors
Predisposition to infection30 (decr. PMN, T cell activity)
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

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CYTOTOXIC DRUGS

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MECHANISM OF ACTION OF
MYCOPHENOLATE MOFETIL

Because the salvage


pathway of purine synthesis
is less active than the de
novo pathway, lymphocytes
depend on PRPP conversion
to IMP and in turn GMP for
DNA synthesis

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USES OF CYTOTOXIC AGENTS
Azathioprine; with cyclosporine and/or prednisone
for organ transplant rejection and severe RA

Mycophenolate mofetil; with cyclosporine and


prednisone for renal transplants

Cyclophosphamide; for BMT

Methotrexate; GVHD prophylaxis

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ANTIBODY REAGENTS

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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)

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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

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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

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IMMUNOSTIMULANTS

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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
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IMMUNOSTIMULANTS

Thalidomide
Teratogenetic
BUT is useful to treat erythema nodosum leprosum and multiple myeloma

Thalidomide

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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

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IMMUNIZATION

Active Stimulation with an Antigen


Passive Preformed antibody

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ACTIVE IMMUNIZATION

Vaccines
Administration of antigen as a whole, killed organism, or a specific protein or
peptide constituent of an organism
Booster doses
Anticancer vaccines immunizing patients with APCs expressing tumor
antigen.

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IMMUNE GLOBULIN

Indications
Individual is deficient in antibodies immunodeficiency
Individual is exposed to an agent, inadequate time for active immunization
Rabies
Hepatitis B

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Nonspecific immunoglobulins
Antibody-deficiency disorders
Specific immune globulins
High titers of desired antibody
Hepatitis B, Rabies, Tetanus

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RHO (D) IMMUNE GLOBULIN

Antibodies against Rh(D) antigen on


the surface of RBC
Rh-negative women may be sensitized
to Foreign Rh antigen on fetal RBC
Anti-RH Antibodies produced in
mother can damage subsequent
fetuses by lysing RBCs
Hemolytic disease of newborn

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IMMUNE TOLERANCE

Induction and maintenance of immunologic tolerance - active state of


antigenic specific nonresponsiveness
Still experimental

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SUMMARY

Immunosuppresion
Calcineurin inhibitors
Glucocorticoids
Antimetabolites
Newer immunosuppresive agents
Effective control of rejection
Glucocorticoid withdrawal

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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

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Jacomini et al, 2011