Transcript Alzheimer`sDisease_Nguyen

AUTOIMMUNE
DISEASES
Misty Mauldin
Medicinal Chemistry
Spring 2009
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Immune System
Autoimmune
Disease
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Pathogenesis
Diagnosis
Treatments
Ankylosing
Spondylitits
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Signs & Symptoms
Diagnosis
Treatments
Anti-inflammatory
Drugs
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NSAIDs
Steroidal
Opioid
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Immunosuppressant Drugs
 DMARDs
 Ciclosporin
 Methotrexate
 Sulfasalazine
 TNF-α Blockers
 Enbrel
 Humira
 Remicade
Future
Resources
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Body’s means of protection against
microorganisms and other “foreign” substances
Composed of two major parts
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B lymphocytes- Humoral Immune System
 produces antibodies and proteins attack “foreign”
substances and cause them to be removed from the
body
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T lymphocytes – Cellular Immune System
 attacks “foreign” substances directly
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Normally, the immune system can distinguish
between “self” and “not self” and only attack
those tissues that it recognizes as “not self”
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Caused by the body producing an inappropriate
immune response against its own tissues
When immune system ceases to recognize one
or more of the body’s normal constituents as
“self” and will create autoantibodies (antibodies
that attack its own cells, tissues, and/or organs)
This leads to inflammation and damage which
leads to autoimmune disorders.
Currently, there is no cure whatsoever for
autoimmune diseases, just treatments
1. Systematic Autoimmune Disease
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Damages many organs
2. Localized Autoimmune Disease
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Damages only a single organ or tissue directly
Systematic Autoimmune
Disease
Localized Autoimmune
Disease
Rheumatoid Arthritis (RA) and
Juvenile RA (JRA) – joints, lung,
skin
Type 1 Diabetes Mellitus –
pancreas islets
Lupus – skin, joints, kidneys,
heart, brain, red blood cells
Hashimoto’s thyroiditis
Graves’ disease – thyroid
Scleroderma – skin, intestine,
lung
Crohn’s disease – GI tract
Sjogren’s syndrome – salivary
glands, tear glands, joints
Addison’s disease – adrenal
Ankylosin Spondyltis – joints,
Another one..
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The exact cause for autoimmune diseases is unknown, but
there appears to be inherited predisposition to developing an
autoimmune disease
 Associated with multiple genes plus other risk factors
 3 sets of genes
 1. Immunoglobulins
 2. T-cell receptors
 3. MHC – major histocompatibility complexes
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Immunoglobulins and T cell receptors are involved in
recognition of antigens and are inherently variable and
susceptible to recombination
These variations enable immune response to respond to a
wide variety of invaders, but also these variations might give
rise to lymphocytes capable of self-reactivity
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MHC Class II – strongly
correlated with specific
autoimmune diseases
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HLA-DR2: systemic
Lupus Erythematosus
HLA-DR3: Sjogren’s
syndrome
HLA-DR4: Rheumatoid
Arthritis
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MHC Class I – fewer
correlations with
specific autoimmune
diseases
Most notable is:
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HLA-B27: ankylosin
spondyltis
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3 hypothesis that have gained widespread
attention:
1. Clonal Deletion Theory
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Self-reactive lymphoid cells are destroyed during the development of
the immune system in an individual
2. Clonal Anergy Theory
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Self-reactive T- or B- cells become inactivated in the normal individual
and cannot amplify the immune response
3. Idiotype Network Theory
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A network of antibodies capable of neutralizing self-reactive antibodies
exists naturally within the body
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Sex:
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most known autoimmune diseases show a female
preponderance except the disease ankylosing
spondylitis which has a male preponderance, and
Crohn's disease which is roughly equal
Environmental:
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Inverse relationship seen between infections
diseases and autoimmune diseases
Areas where multiple infectious diseases are
endemic, autoimmune diseases are rare, and vise
versa
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T-Cell Bypass
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Molecular Mimicry
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A cross reaction between the Idiotype (molecule recognized by antigen)
on an antiviral antibody and a host cell receptor for the virus in question
Cytokine Dysregulation
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An exogenous antigen shares structural similarities with host antigen
and when an antibody is produced, it can bind to host antigen
Idiotype Cross Reaction
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The requirement of T cells to activate B cells in order to produce large
amounts of antibodies is bypassed
Certain cytokines have a role in the prevention of the exaggeration of
pro-inflammatory immune response
Dendritic Cell Apoptosis
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Defective dendritic cells can lead to inappropriate systemic lymphocyte
activation and a decline in self tolerance
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Autoantibody blood tests
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Levels of autoantibodies are measured to determine
the progress of the disease
Blood tests to measure inflammation and organ
function
Clinical presentation
Non-laboratory examinations (X-rays)
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Immunosuppressive
Anti-inflammatory
Palliative (reducing symptoms)
Dietary Manipulation
Non-immunological therapies
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A chronic, inflammatory arthritis
Affects joints in the spine and the sacroilium in
the pelvis, causing eventual fusion of the spine
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The typical patient is
young, aged 18-30, with
chronic pain and stiffness
in the lower part of the
spine, often with pain
referred to one or other
buttock or back of thigh
from the sacroiliac joint
early on
Pain is often severe on rest,
and improves with physical
activity
Men are affected more than
women by a ratio about of
3:1
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In 40% of cases, ankylosing
spondylitis is associated
with an inflammation of the
white of the eye (iritis)
Another common symptom
is generalized fatigue
Psoriasis (skin disorder)
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AS is a systemic rheumatic
disease and is one of the
seronegative
spondyloarthropathies.
About 90% of the patients
express the HLA-B27 genotype
Tumor necrosis factor-alpha
(TNF α) and IL-1 are also
implicated in ankylosin
spondylitits
Autoantibodies specific for AS
have not been identified.
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There is no direct test to diagnose AS. A clinical examination and
X-ray studies of the spine, which show characteristic spinal
changes and sacroiliitis, are the major diagnostic tools.
Other options for diagnosis are tomography and MRIs of the sacroiliac
joints, but the reliability of these tests is still unclear
 The Schober's test is a useful clinical measure of flexion of the lumbar
spine performed during examination
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During acute inflammatory periods, AS patients will usually show
an increase in the blood concentration of C-reactive protein (CRP)
and an increase in the erythrocyte sedimentation rate (ESR)
Variations of the HLA-B gene increase the risk of developing
ankylosing spondylitis, although it is not a diagnostic test. Those
with the HLA-B27 variant are at a higher risk than the general
population of developing the disorder. HLA-B27, demonstrated in
a blood test, can occasionally help with diagnosis but in itself is
not diagnostic of AS in a person with back pain.
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Anti-inflammatory
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Steroid/NSAID drugs
Immunosuppressive
DMARDs
 TNFα blockers (antagonists)
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Surgery
Physical Therapy
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NSAIDs
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Aspirin
ibuprofen phenylbutazone
Indomethacin
Naproxen
COX-2 inhibitors
Steroidal
Opioid analgesics
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Morphine
Oxycodone
Hydrocodone
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DMARDs
 Cyclosporin
 Methotrexate
 Sulfasalazine
 corticosteroids
TNFα blockers (antagonists)
 Etanercept (Enbrel)
 Infliximab (Remicade)
 Adalimumab (Humira)
DMARDs
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Immunosuppressant drug
Mostly used for the prevention
of organ transplant rejection
Discovered in Switzerland
on January 31, 1972
 Approved for use in US in 1983
 Also used for treatment of psoriasis, dermatitis, RA, and
related diseases
SIDE EFFECTS
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Adverse effects with lots of different drugs, including grapefruit juice
Convulsions, pancreatitis, fever, vomiting, diarrhea, breathing problems,
nephrotoxicity, and Hepatotoxicity
Mode of action:
It is thought to bind to the cytosolic protein cyclophilin
of immunocompetent lymphocytes, especially Tlymphocytes
This complex of cyclosporin and cyclophilin inhibits
calcineurin, which is responsible for activating the
transcription of interleukin 2. It also inhibits
lymphokine production and interleukin release, and
therefore leads to a reduced function of effector T-cells
Marketed under various names:
Restasis (topical version)
Neoral (orally administered)
Cicloral & Gengraf (generics)
Uses:
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Cancer chemotherapy
Medical termination of pregnancy
Treatment of autoimmune diseases
(a parallel use with TNA-a blockers
has been shown to markedly
improve symptoms
An antimetabolite and antifolate drug used in
treatment of cancer and autoimmune diseases
Acts by inhibiting the metabolism of folic acid
Originated in the 1940’s
Mode of Action
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competitively and reversibly
inhibits dihydrofolate
reductase (DHFR), and
enzyme that participates in
the Tetrahydrofolate
synthesis. DHFR catalyses
the conversion of
dihydrofolate to the active
Tetrahydrofolate.
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Folic acid is needed for the
de nova synthesis of the
nucleoside thymidine,
required for DNA synthesis
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Folate is needed for purine
base synthesis, so all purine
synthesis will be inhibited
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Therefore, MTX inhibits the
synthesis of DNA, RNA,
thymidylates, and proteins
MTX acts specifically during
DNA and RNA synthesis
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It has a greater toxic effect
on rapidly dividing cells
(such as malignant cells),
which replicated their DNA
more frequently, and thus
inhibits the growth and
proliferation of these noncancerous cells as well as
causing side effects
SIDE EFFECTS:
anemia, increased risk of bruising
Hepatitis
Serious adverse effects with
penicillin
fever, chills, dizziness
Lowered risk to infection
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Brand name: Azulfidine (in US)
Sulfa drug; used primarily as an antiinflammatory agent for inflammatory
bowel disease as well as RA
NOT an immunosuppressant!
Main mode of action is believed to be inside the
intestine
It can do this by a number of mechanisms, one of
which is by reducing the synthesis of inflammatory
mediators.
SIDE EFFECTS:
Can result in serious Hepatotoxicity
Mouth ulcers, sore mouth
Loose bowels
Headache/ dizziness
Rash that can be itchy
Type of hepatitis (liver inflammation)
Orange discoloration of urine as well as
perspiration and content lenses can be stained
Severe depression in young males
Decrease sperm count in men
Temporary infertility in women, but usually safe
during pregnancy
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First synthesized in the early 1990’s at
UTSW in Dallas!
Treats autoimmune diseases by interfering
with the TNF receptor, a part of the immune
system
A recombinant-DNA drug made by
combining two proteins (fusion protein).
It links human soluble TNF receptor to the
Fc component of human immunoglobulin GI
(IgGI) and acts as TNF inhibitor
Binds to TNF-a and decreases its role in
disorders involving excess inflammation in
humans, including autoimmune diseases,
such as ankylosing spondylitis, juvenile RA,
psoriasis, psoriatic arthritis, and RA.
Etanercept mimics the inhibitory effects of naturally
occurring soluble TNF receptor, the difference being
that since it is a fusion protein rather than simple TNF
receptor, it has a greatly extended half-life in the
bloodstream, and therefore a more profound and longlasting biologic effect than a naturally occurring soluble
TNF receptor.
Safety:
 Immunosuppressant
Administration:
 In May 2, 2008, the FDA
 Injected subcutaneously,
placed a black box
typically by patient at
warning on Enbrel due to
home
a number of serious
 Come in pre-filled
infections associated with
50mg/ml syringes in 2004
the drug
and a single-use 50mg
auto-injector pen in 2006
Cost:
 $10,000-$40,000 per
year (depending on
number of treatments
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TNF inhibitor, binds to
TNFα, preventing it from
activation TNF receptors
immunosuppressant
Constructed from a fully
human monoclonal
antibody
Approved by FDA in
2008 for treatment of:
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Rheumatoid arthritis
Psoriatic arthritis
Ankylosin spondylitits
Crohn’s disease
Administration:
 Injected subcutaneously by patient at home
 Preloaded 0.8 ml syringes, or Preloaded pen
devices (Humira pen)
Safety:
 Serious or fatal blood disorders
 Serious infections (including TB)
 Given black box warning by FDA
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Remicade video
Used to treat:
-Skin diseases (psoriasis)
-Ankylosing spondylitits
-Crohn’s disease
-RA, PsA
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Developed at New York
University School of
Medicine
Manufactured by Johnson
& Johnson
Prevents the binding of
TNFα to its receptor cell
Artificial antibody,
originally developed in
mice, as a mouse antibody,
and later humized into a
human antibody
Because it’s a combination
of a mouse and human
antibody, its called a
chimeric monoclonal
antibody
Administration:
 IV fusion, typically 6-8 week intervals at clinic
or hospital
 Can NOT be done orally because digestive
system would destroy the drug
Cost:$19,000-$22,000 per year
- approx. $1650 per 100mg
Safety:
 Fatal blood disorders
 Infections
 Rare reports of lymphoma and cancer (less likely when
used with Methotrexate)
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Possible Association between TNF Blockers and
Cancer | Pharmainfo.net
Enbrel is being studied for treatment of
Alzheimer’s disease
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Wikipedia.org
Pub Med
Remicade.com
Pharmainfo.net
Simonportfolio.com