Anti-inflammatory response in severe sepsis and septic shock
Immune related illnesses/diseases and treatmentsdb.phm.utoronto.ca/Dojo Soeandy lecture 3.pdf ·...
Transcript of Immune related illnesses/diseases and treatmentsdb.phm.utoronto.ca/Dojo Soeandy lecture 3.pdf ·...
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Immune related illnesses/diseases and
treatmentsLecture 3- Dojo Soeandy’s section
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity • Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Complications of immune response• Extensive tissue damage
• hemorrhage (redness)• frustrated phagocytosis
• If a stimulus is overwhelming or if a target is too large, the cell will spread as if trying to engulf it, but cannot close to form phagosomes.
• Instead cells will release materials normally released into phagosomes (e.g. ROS and degradative enzymes)
• release of cytotoxic molecules (e.g. cytotoxic T cells)
• Abscess formation• contains fibrin, viable and necrotic neutrophils/macrophages,
tissue debris, and dead & live pathogen; surrounded by fibrous capsule
• Progression to chronic inflammation• Can lead to various diseases like cardiovascular diseases,
cancer, diabetes, etc.4
Slide adapted from Latif 2018
saintlukeskc.org
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Complications of immune response• Systemic involvement
• Fever - cause: pyrogens (e.g. bacterial components, interleukin-1 released from activated macrophages) that affect the hypothalamus; functions: increase host metabolic activity + inhibit pathogens
• In some instances, this immune response can be too strong, causing tissue and organ damage and, in severe cases, even death
5Slide adapted from Latif 2018courses.lumenlearning.com
prostaglandin E2 (PGE2)
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Complications of immune response
• Sepsis• Sepsis is the body’s overwhelming and life-threatening
response to infection that can lead to tissue damage, organ failure (e.g. kidneys, heart and lungs), and death- i.e. it’s your body’s overactive/extreme and toxic response to an infection.
• The immune system stops fighting the “invaders,” and begins to turn on itself.
• Septic shock is the most severe level and is diagnosed when your blood pressure drops to dangerous levels.
• On average, approximately 30% of patients diagnosed with severe sepsis do not survive. It’s the #1 leading cause of death in hospitals.
• Early detection and treatment is essential for survival and limiting disability for survivors.
• At risk populations: 65+ yrs old, <1yr old, weakened immune system, chronic medical conditions
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Complications of immune response• Signs and symptoms of sepsis
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Complications of immune response
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Complications of immune response
• Treatments• Antibiotics
• IV fluids- usually crystalloid like saline (sometimes colloids like albumin or dextran); help keep the blood pressure from dropping dangerously low
• Cortocosteroid- reduce inflammation in the body and depress the immune system
• Vasopressors- increase blood pressure
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity (arthritis, type 1 diabetes)
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Hypersensitivity
• Hypersensitivity reactions (HR) are immune responses that are exaggerated or inappropriate against an antigen or allergen (usually a secondary response).
• 4 types: based on mechanism of action; type I, II, and III reactions are the result of antibody reactions, while type IV reactions involve T cell lymphocytes and cell-mediated immune responses.
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Hypersensitivity- ACID• Type I: Allergic
• IgE mediated • Fast response from mast cells and basophils after re-exposure
• Type II: Cytotoxic/ antibody-mediated• IgG/IgM mediated against antigens on cell surfaces (e.g. red blood cells) • Activate either the complement system or antibody-dependent cell-
mediated cytotoxicity (ADCC) - i.e. activate cytotoxic T cells (CTLs), natural killer cells, neutrophils, etc.
• E.g. ABO blood group incompatibility
• Type III: Immune complex/ IgG/IgM-mediated• IgG/IgM form antigen-antibody complexes that settle on tissues and organs
(contain greater antibody concentrations than antigen concentrations)• Activate complement system and recruit neutrophils and phagocytes
• Type IV: Delayed or cell-mediated• T-cell mediated (TH1 usually)• Delayed type (takes a few days to develop)• Activates natural killer cells, macrophages, CTLs, etc.
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Hypersensitivity- Type I
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courses.lumenlearning.com
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Hypersensitivity- Type II
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courses.lumenlearning.comCould also induce antibody-dependent cell-mediated cytotoxicity (ADCC) in other examples
Example of alloimmune hemolytic anemia
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Hypersensitivity- Type III
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courses.lumenlearning.com
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Hypersensitivity- Type IV
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courses.lumenlearning.com
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Hypersensitivity- summary
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Ag = antigenAb = antibodyADCC = antibody-dependent cell-mediated cytotoxicity
Mast cell
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Hypersensitivity- summary
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courses.lumenlearning.com
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Hypersensitivity- summary
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Adverse drug reactions
• Adverse drug reaction (ADR) is an unwanted, undesirable effect of a medication that occurs during typical clinical use.
• Type A (intrinsic)• reactions are predictable from known pharmacology of a drug
• high morbidity and low mortality
• dose-dependent
• Type B (idiosyncratic)• reactions are idiosyncratic and cannot be predicted from the
known pharmacology or therapeutic effect of a drug
• low morbidity and high mortality.
• not easily explained by dose
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Idiosyncratic drug reactions (IDR)
• Thought to be immune-mediated and caused by chemically-reactive species
• Major targets: skin, liver, bone marrow (blood cells)
• Each drug has spectrum of IDRs• eg halothane IDRs limited to the liver vs carbamazepine
IDRs include liver injury, skin rash, agranulocytosis, aplastic anemia, autoimmunity
• Delayed onset; more rapid onset upon second exposure
• Genetic component - MHC genes, slightly higher risk in women
22Slide adapted from Latif 2018
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Idiosyncratic drug reactions- skin
1. Maculopapular Rash
• most common type of IDR skin rash
• onset: 1-2 weeks of treatment
• resolves even with continuation of drug
• mediated by cytotoxic CD4 cells that bind MHC Class II
23Slide adapted from Latif 2018
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Idiosyncratic drug reactions- skin
24Slide adapted from Latif 2018
2. Urticaria (Hives)
• second most common type of IDR skin rash
• IgE-mediated allergic reaction
• usually responsive to cyclosporine
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Idiosyncratic drug reactions- skin
25Slide adapted from Latif 2018
3. Fixed Drug Eruption
• rash occurs at the same site (hyperpigmentation)
• onset is approx. 2 hours upon rechallenge
• mediated by CD8+ T cells
4. Drug-Induced Hypersensitivity Syndrome
• acute onset of rash, fever and hepatitis/nephritis/ pneumonitis/etc.
• onset is 2-6 weeks; mortality rate up to 10%
• treatment: corticosteroids
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Idiosyncratic drug reactions- skin
26Slide adapted from Latif 2018
5. Acute Generalized Exanthematous Pustulosis• pustules on the face, neck and groin; fever; neutrophilia• onset as short as one day• largely associated with antibiotics
6. Toxic Epidermal Necrolysis• sudden onset of fever and malaise followed by painful
rash and blisters – gentle pressure results in sloughing off of the epidermis due to keratinocyte apoptosis
• mortality rate ~30% - the most severe type of skin rash• involves mucus membranes of the mouth, genitals,
intestine, and eyes (sometimes blindness)• onset is 7-21 days
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Idiosyncratic drug reactions- liver
27Slide adapted from Latif 2018
1. Hepatocellular Liver Injury• most common idiosyncratic liver injury• involves death of hepatocytes• onset usually 1-3 months; can be days to one year• damage is often greater in the regions of the liver
containing high levels of cytochrome p450
2. Cholestatic Liver Injury• characterized by a greater increase in alkaline
phosphatase (ALP) and bilirubin compared to alanine transaminase (ALT)
• associated with phenothiazines, amoxicillin/ clavulanic acid, and flucloxacillin
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Idiosyncratic drug reactions- blood
28Slide adapted from Latif 2018
1. Agranulocytosis
• Low granulocyte WBC count (usually involves severe neutropenia-peripheral neutrophil count <500 cells/microliter, normal= ~3,000-7,000/µL)
• onset is 1-3 months
2. Thrombocytopenia
• Low platelet count
• classically associated with heparin – antibodies directed to complexes containing heparin and an endogenous platelet protein, platelet factor 4 (PF4); no memory
3. Anemia
• due to hemolysis or decreased production of RBCs
• aplastic anemia: lack of hematopoietic cells in the bone marrow
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IDR mechanism
• The Hapten Hypothesis: chemically reactive drug/ metabolite binds protein →drug-modified protein adduct recognized as “foreign” →results in immune response or tolerance
• Hapten (definition): a low molecular weight chemical that binds irreversibly to protein through formation of a covalent bond
29Cho & Uetrecht, Chem. Res. Toxicol. 2017
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IDR mechanism• The Danger Hypothesis : 2
signals• Signal 1- recognition of
MHC-complexed antigen (hapten) on an APC by TCR
• Signal 2- stressed or damaged cells produce danger signals (DAMPs) that lead to the activation of APCs and upregulation of costimulatory interactions such as B7 on APCs that bind to CD28 on T cells
30Cho & Uetrecht, Chem. Res. Toxicol. 2017
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Transplantation and immune consideration
• Definition: replacement of a patient’s non-functional tissue or cells from a donor.
• Types of transplantations:• Autologous graft/autograft–Transplantation
of cells, tissues or organs between sites within the same individual e.g. skin graft.
• Isograft – Transplantation of tissue between genetically identical individuals (e.g. identical twins).
• Allograft – Transplantation of organs or tissues from a donor to a non-genetically identical individual of the same species. The most common type of transplant.
• Xenograft – Transplantation of an organ or tissue between two different species. ‘Pig valves’, for example, are commonly used to repair or replace a defective heart valve in humans.
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Roitt, Brostoff, Male, et al: Immunology, ed 7, Philadelphia, 2006
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Transplantation and immune consideration• Graft/transplant rejection is caused by recognition
of allelic differences in major histocompatibility complex (MHC) loci between donor and recipient. For humans, we refer specifically to HLA (human leukocyte antigen complex = human MHC)
• Allorecognition= recipient immune response mounted against donor MHC
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Leukocyte infiltration
heartpathology.com
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Transplantation and immune consideration• Allorecognition includes:
• Alloantibody production by B cells against the allo-MHC/HLA
• Direct allorecognition by T cells: donor antigen-presenting cells (APCs) interact and activated recipient T cells directly
• Indirect allorecognition by T cells: recipient APCs present processed donor allogeneic peptides to recipient T cells, similar to more typical immune responses
• Semidirect allorecognition by T cells: recipient APCs acquire donor HLA molecules that present peptides directly to recipient T cells
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Transplantation and immune consideration
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DeWolf and Sykes, 2017
“cross-dressing”= transfer of preformed peptide–MHC/HLA complexes from donor cells to recipient cells
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Transplantation and immune consideration
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• Types of graft rejection
This includes ABO blood group
(i.e. direct allorecognition)
Sometimes called acute humoral rejection (AHR)
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Transplantation and immune consideration• Minimizing graft rejection:
• HLA typing- to ensure the closest possible match between MHC alleles of recipient and donor
• Alloantibody analysis- to make sure there aren’t already existing antibodies against donor (e.g. ABO blood groups)
• Immunosuppressive drugs- to reduce immune function generally
• Induction of graft tolerance- still currently researched; include things like inhibiting only recipient T cells that will attack graft
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity • Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Autoimmunity
• Occur when immune system does not appropriately differentiate self from non-self
• Healthy individuals exhibit limited autoimmunity (low-levels of anti-self antibodies)
• Autoimmune disease: • Arise when autoimmunity cause clinical damage to
tissue or disrupt its normal function
• Generally considered to be disorder of adaptive immune system
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Autoimmunity
• Examples of autoimmune diseases:• Multiple sclerosis- autoimmune attack against myelin
sheath of nerve axons
• Rheumatoid arthritis- autoimmune attack on antigens expressed in the synovial tissue and cartilage of the joints
• Systemic lupus erythematosus- autoimmune disease that affects the skin, joints, kidney, lung, heart and brain
• Type 1 diabetes mellitus- autoimmune attack against pancreas (β-islet cells)
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Autoimmunity
• Autoimmune disease determinants:• Genetic
• External triggers • Chemicals (hair dyes, smoking,
silica dust, etc.)
• Pathogens (inflammation, molecular mimicry)
• Drugs, toxins
• Hormone (e.g. lupus is more common in women, whereas graves’ disease is more common in men)
41
Mak, Saunders & Jett, 2008
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Autoimmunity
• Autoimmune disease general treatments:• Conventional therapies include
• Anti-inflammatory drugs
• Immunosuppressive drugs
• Plasmapheresis (mechanical removal of all antibodies from blood)
• Immunotherapies include• Targeting of leukocyte extravasation
• Targeting of T-lymphocyte receptors
• Cytokine blockade/administration
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity • Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
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Immunodeficiency
• Immunodeficiency results from a failure or absence of elements of the immune system. • Primary immunodeficiency (PIDs): individual is
born with a genetic mutation that results in an immune defect
• Secondary immunodeficiency: individual is born with normal immune responses, but later experience an event that damages the immune system• E.g. acquired immunodeficiency syndrome (AIDS)
caused by human immunodeficiency virus (HIV)
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Primary immunodeficiencyDefects in innate immunity:
1. Leukocyte adhesion deficiency• Leukocytes cannot extravasate into areas of injury • Patients suffer from severe infections and compromised
wound healing • Clinical sign e.g. absence of pus at sites of infection• Autosomal recessive mutations in integrin components (e.g.
CD18, CD15 or kindlin-3)
2. Congenital neutropenia• mild (ANC 1000-15000 cells/μL); moderate (ANC 500-1000
cells/μL); severe (ANC<500 cells/μL)• Causes recurrent bacterial and fungal infections• Many autosomal dominant and autosomal recessive causes
• E.g. autosomal dominant mutation of CXCR4 chemokine receptor-mature neutrophils can’t leave bone marrow and enter circulation
45
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Primary immunodeficiency
3. Chronic granulomatous disease• Characterized by failure in phagosomal killing
• Patients suffer from recurrent and sometimes life-threatening bacterial and fungal infections; persistent infections result in excessive granuloma formation
• Caused by mutation in any of the subunits that make up the NADPH oxidase that generates ROS in phagosomes• X-linked mutation in gp91 (most common and severe)
• Autosomal recessive mutations in p22
46
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Primary immunodeficiencyDefects in adaptive immunity:
1. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID)• Account for 20% of primary
immunodeficiency, with a prevalence of ~1 in 50,000 live births
• Multiple different types, but in all cases, T cell development is impeded, and may also affect B cells and natural killer (NK) cell development
• “Boy in the bubble” David Vetter suffered from X-linked SCID, which accounts for ~40% of all SCID cases 47
Gaspar, Gilmore & Jones, 2001
Immunology.org
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Primary immunodeficiency2. Common variable immunodeficiency
(CVID)• Most frequently diagnosed primary
immunodeficiency (~50%)
• Family of diverse diseases characterized by general impairment of humoral response
• Present in patients who are in their 20s or 30s
• All patients demonstrate significantly decreased IgA and IgG, and about 50% lack IgM.
• Circulating B cells are present, but differentiation into plasma cells are inhibited, and memory B cells may be absent.
48
Mak, Saunders & Jett, 2008
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Primary immunodeficiency
• Treatments:• Immunoglobulin/enzyme replacement
• Hematopoietic stem cell transplantation
• Gene therapy
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity • Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
50
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Secondary immunodeficiency- HIV• UNAIDS: approximately 37.9 million people living with
HIV, ~1.7 million people became newly infected globally in 2018; as many as 43.8 million people have died from AIDS-related illnesses since the beginning of the epidemic.
• HIV (human immunodeficiency virus): an enveloped single-strand RNA virus• mechanisms of transmission: sexual transmission,
transmission via injection drug use, exposure of blood and blood products during transfusion, and exposure of fetus/infant to HIV from an infected mother
• AIDS (Acquired Immunodeficiency Syndrome): disease caused by HIV mediated destruction of CD4+ T lymphocytes• diagnosis: CD4+ T cell count below 200 cells per microlitre
(normal range is 500-1500); antibodies against virus51
Slide adapted from Latif 2018
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Secondary immunodeficiency- HIV
• Evasion from host immune system (esp. humoral immunity) via:
1. Glycoproteins- carbohydrate “cloak” conserved protein regions underneath
2. Variable loops
3. Error-prone reverse transcription • HIV genome: 10 thousand nucleotides
• on avg.: 1-10 nucleotides mutated/replication
• 10 billion virions/day
52Slide adapted from Latif 2018
Wilen, Tilton, Doms, 2011
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Secondary immunodeficiency- HIV• Molecular mechanisms of HIV entry: three steps for
infecting CD4+ T cells1. Attachment and CD4 Binding
2. Coreceptor binding
3. Membrane Fusion
53
Slide adapted from Latif 2018
Wilen, Tilton, Doms, 2011
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Secondary immunodeficiency- HIV
54
aidsinfo.nih.gov
For more info, please watch: https://www.youtube.com/watch?v=PlSvywlLuNw
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Secondary immunodeficiency- HIV
• Treatments:• Antiretroviral Therapy
• To date there are 24 FDA-approved drugs available for HIV treatment
• Works by suppressing HIV replication and so reduce viral load to undetectable levels → increase in circulating T lymphocytes
• Can’t cure HIV per se, but can help people with HIV live longer, healthier lives and help reduce HIV transmission
55Slide adapted from Latif 2018
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
56
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Vaccines• Vaccines:
• Modified form of a natural immunogen; can be either the whole pathogen, one of its components, or a toxin
• Does not induce disease per se, but does activate host primary response to generate large numbers of memory B and T cells
• Usually a form of active immunization: because host lymphocytes are being actively induced to form antibodies.
• Passive immunization: protective antibodies are directly transferred from immune individual to unimmunized.
• Helps promote herd immunity: the probability of infection in the population decreases if a sufficiently high proportion of individuals are immuned to the disease 57
Mak, Saunders & Jett, 2008
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VaccinesRequirements of vaccine design:• Efficacy
• The immune response that the vaccine induce must be appropriate forthe elimination of the pathogen of interest.
• Refers specifically to an ideal situation, such as a tightly controlled clinical trial where it is compared to a placebo or other intervention
• Usually expressed as coverage- i.e. percentage of individuals that do not experience disease after exposure to the pathogen.
• No vaccine is 100% effective because of human genetic variations, but generally 80-95% effective.
• Safety• Have very few detrimental side effects or adverse events
• Effectiveness• Describes how the drug works in a real-world situation• Includes interactions with other medications or health conditions of the
patient• Protection must be long-lasting and help induce herd immunity• Low cost (<$1, WHO); genetic stability; storage considerations; delivery
(oral vs. needle)58
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Vaccines
59
Types of vaccines
toxoid
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VaccinesType Description Advantages Disadvantages Examples
Live, attenuated
Weakened strain of whole pathogen
- Low number of doses, usually very effective
- Minimal need for adjuvant
- Cellular and humoral immunity
- ”Cold chain” required for storage and transport
- Chance of reversion of attenuating mutation
Chickenpox, measles, mumps, tuberculosis, typhoid fever
Killed or inactivated
Whole pathogen killed or inactivated with heat, chemicals, or radiation
- No possibility of reversion
- No cold chain required
- Require boosters and adjuvants
- Limited longevity- Weaker immunity
(primarily humoral)
Cholera, hepatitis A, influenza, plague, rabies
ToxoidChemically inactivated toxin of pathogen
- Avoids use of whole organism
- Effective only if disease caused solely by toxin (not prevent infection)
Botulism, diphtheria, pertussis, tetanus
Subunit, recombinant, polysaccharide, and conjugate
Pathogen protein and/or polysaccharide (antigen) purified directly from natural sources or synthesized using recombinant DNA methods
- Avoids use of whole organism
- Can be manipulated to increase immunogenicity
- Lower risk of side effects
- Can be costly to produce
- May not be as immunogenic as natural pathogen
- Identifying specific antigen takes time
Anthrax, hepatitis B, influenza,meningitis, pneumococcal pneumonia
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VaccinesType Description Advantages Disadvantages Examples
Recombinant DNA vector
Virus-based vector containing recombinant DNA of pathogen antigen. Vacinee is infected with the viral vector and the pathogen DNA is transcribed and translated within the vacinee’s cells like a viral protein
- Avoids use of natural pathogen
- Replicates like a pathogen to produce large amounts of immunogen
- Minimal need for boosters and adjuvant
- Possible side effects due to vector components
- Anti-vector antibodies raised during priming may necessitate boosting with a different vector
- Experimental
HIV, rabies, measles
Naked DNA
Small plasmid-containing recombinant pathogen DNA. Plasmid is injected into a vacinee, and the pathogen DNA is taken up by the vacinee’s cells and transcribed and translated
- Easy and inexpensive to manipulate
- Cellular and humoral immunity activation
- Plasmid sequences may act as adjuvant
- Not as immunogenic as protein vaccines in humans
- Integration of plasmid into host cell genome may induce tumorigenesis
Influenza, Herpes, HIV
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Topics to be covered:• Exaggerated immune responses:
• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:
• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations
• Autoimmunity
• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV
• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs
62
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Immunosuppressants /anti-inflammatory drugs:
• Numerous immunosuppressive/anti-inflammatory agents available:• Calcineurin inhibitors
• mTOR inhibitors
• Corticosteroids
• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
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Calcineurin inhibitors Calcineurin
• Activated upon TCR binding of MHC-antigen complex, resulting in Ca2+ increase
• A subunit: Phosphotase activity, dephosphorylation of NF-AT
• B subunit: Calcium binding• Results in: Upreg. of cytokines & costimulatory
molecules important in T cell activation (eg IL-2,4,6; Interferon; CD40)
Calcineurin inhibitors:ligand/receptor complex bind to and inhibit calcineurin
1. Cyclosporine (immunophilin: cyclophilin A)• Side effects: High blood pressure, swollen or
inflamed gums, numbness or tingling of the hands or feet, nephrotoxicity, etc.
2. FK506 (immunophilin: FKBP12)• Also known as Tacrolimus• Side effects: hypertension, tremor, neurologic
toxicity, anemia, etc. 64Slide adapted from Latif 2018
Snyder, Sabatini, etc. 1998
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mTOR InhibitorsmTOR (mammalian target of rapamycin)
• Ser/Thr kinase involved in PI3K/Akt signaling pathway• transcriptional regulation of T cell glycolytic enzymes• regulates the cell cycle of proliferating cells (including
lymphocytes)
mTOR inhibitors
1. Rapamycin• used alone or in combination with calcineurin inhibitors• similar structure to FK506 - also binds FKBP12 immunophilin• rapamycin-FKBP12 complex binds and inhibits mTOR• immunosuppressant and antiproliferative properties (blocks T
cell proliferation and others)• side effects: nephrotoxicity, myelotoxicity, etc.
65Slide adapted from Latif 2018
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CorticosteroidsPrednisone + Methylprednisolone
• Mechanism: 1. Passive diffusion into the cell2. Bind glucocorticoid receptors in the
cytoplasm3. Translocates to nucleus4. Reduces transcription of inflammatory
cytokines and increase anti-inflammatory cytokines
• Glucocorticoid also inhibit Phospholipase A2 in the prostaglandin pathway
• Effects: stabilize lysosomal membranes, suppress prostaglandin synthesis, reduce histamine release, reduce capillary permeability, impair macrophage function, reduce number of CD4+ T cells.
• Side effects: diabetogenesis, protein loss from skeletal muscle, fluid retention + hypertension, adrenal suppression + atrophy, psychosis, etc. 66
Slide adapted from Latif 2018
Kino, 2017
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NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
• Group of drugs that reduce inflammation and relieve pain and fever
• Work by inhibiting cyclo-oxygenase enzymes (COX-1 and/or COX-2), which are responsible for the production of prostaglandins.
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NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
68Slide adapted from Girnita, 2014
Phospholipase A2Membrane phospholipid
corticosteroids
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NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
69Slide adapted from Dutta, 2017
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NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
• Side effects of COX-1 inhibitors: stomach bleeding and risk GI ulcer formation• inhibits cox-1 activity thereby increasing tissue
unsaturated fatty acid levels and causing acidosis
• decreases PGE2 levels that protect stomach membrane
• inhibits thromboxane formation and platelet aggregation
• Side effects of COX-2 inhibitors: increased risk of cardiovascular disease
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NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
Drug examples:• Aspirin (e.g. Bayer)- irreversibly
acetylate Ser530 of COX-1 and COX-2 (slight selectivity for COX-1)
• Ibuprofen (e.g. Advil & Motrin), Naproxen (e.g. Aleve)- reversibly bind to COX-1 and COX-2
• Celecoxib (Celebrex)- COX-2 inhibitor
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Midterm
Wednesday, October 9 from 3:30 to 6:30 p.m. in EX 200
•Make sure to bring your T-card•Write with pen if potentially want a
regrade
GOOD LUCK!72