Immunomodulation
What is immunomodulation?
Down regulate vs up regulate
Mechanism for altering or regulating the immune response--Often used as part of immunotherapy in which the immune responses are induced, amplified, attenuated or prevented based on therapeutic goals
Used in a variety of diseases
Autoimmune diseases (down regulate)
Cancers-(up regulate)
Transplantation-(down regulate)
Infectious disease-(up regulate)
Down regulate: Autoimmune diseases--Limit action of cytokines(too many cytokine storm), Destroy self-reactive T or B cells, Prevent T-cell activation, Up-regulated or create regulatory T cells
Transplantation: Increase action of regulatory T cells
Cytokines:goldie locks rule--dont want too much or too little-want just right
Upregulation: Cancers-- Up-regulate the immune response--Increase action of cytokines, Increase antibodies, Increase action of antigen-presenting cells, Increase action of cytotoxic T cells
Infectious disease--Increase action of immune response--Vaccines
Inactive vs active
Inactivated/Killed Inactivation of pathogen, usually by chemical means, which--generates preparation which induces an immune--response but does not replicate in the host--Relatively safe
•Examples: Salk polio vaccine, inactivated (conventional) influenza, hepatitis A, cholera vaccine
•Typically handled as exogenous antigens so usually only induces antibodies--so MHCII, CD4+, and antibody production and stimulation
Active/Live/Attenuated: “Weakened” preparation--Attenuated by environmental conditions or genetic engineering--Generally not as safe as killed/inactivated preparation because of potential for reversion of attenuation.
•Examples: Varicella zoster virus(chicken pox), measles, mumps, rubella, oral Sabin polio vaccine
Typically handled as endogenous and exogenous antigens so can induce both antibodies and cellular (i.e. CTL responses)--will create both T cell and antibody production
Antibody to prevent T cell activation
Abatacept: drug used to block T cell activation
T cells need a CD28(always on T cells) and B7 interaction (on APCs) in order to be fully activated.
This drug acts in place of B7 in binding CD28 thus inhibiting the co-stimulation and T cell activation
B7 =CD80/CD86
Natural Killer Cell response to tumors
Kills tumor or virus infected cells in a nonspecific fashion (NK-activity). If MHCI is downregulated on tumor or other infected cells this triggers NK cells through the ADCC mechanism---Inactivates the killer inhibitory receptors
NK cells see an inhibitory molecule[KIR (killer cell immunoglobulin like receptor)] on the MHCI causing down regulation. NK cell binds the receptor activation ligand causing a release of cytokines and toxic granules killing the cell
Body's Microbiome
Normal Flora: Population of microorganism that inhabit the body naturally--Skin and mucous membranes --Bacteria, yeasts, viruses, bacteriophages--lead to a healthy homeostasis--If disturbed (relocated or subjected to antibiotics) can lead to disease state
Microbiome-bacteria in gut--thought to have about 10 bacteria cells for each one of our own cells.
What is a vaccine overall?
How do you give them?
Deliberate attempt to provide, induce, or boost protective immune responses
Goal in any one individual is the prevention of disease (Prep for HIV-antiviral retrotherapy)
Goal of a population is the eradication of disease(eradicate small pox)
A major effect has been control of infectious diseases
Parenteral Route : elicits IgG--next to the GI route
Subcutaneous, Intramuscular, Intradermal--require a needle
Oral Route :elicits IgA-just as affective maybe more
Types of Vaccines:
Toxoid
Subunit
Conjugate Polysaccharide
Toxoid:1.toxins treated with or absorbed with aluminum salts to generate toxoids which are immunogenic but not toxic.; 2.example: tetanus and diphtheria toxoid vaccines. Only applicable to bacterial toxins. 3.Typically handled as exogenous antigens thus only induces antibodies (Al to make immunogenic but not toxic, tetanus, bacterial, exogenous, antibody creation)
Subunit:
1.isolate subunit from organism to be used as a vaccine; generally has good safety profile; purified from the organism or generated by recombinant DNA technology. 2.Example: acellular pertussis (whooping cough) antigens. 3.Typically handled as exogenous antigen so only antibodies produced (purified/recombinant attenuation, whooping cough, exogenous, antibodies)
Conjugate Polysaccharide:1.For some bacteria virulence is imparted by polysaccharide capsule (PC); therefore, vaccines directed against these PCs is desirable. PCs do not activate T helper cells; therefore protein conjugation with the PCs is needed to generate T helper cell responses to PCs. 2.Examples : Hib (Haemophilus influenzae b), pneumococcal vaccine, meningococcal vaccine. 3.Typically handled as exogenous antigens so usually only antibodies produced (dealing with encapsulated bacteria-specifically targeting capsule/protein conjugation to activate Th/menigococcal/exogenous/antibody)
Tumor Immunology and Immunosurveillance
Immunology:
Immune responses to new antigenic structures on tumors or their detection by immune methods can be used for 3 purposes:(1) Diagnosis or prognosis of cancer (2) prophylaxis against cancer (3) anti-cancer therapy
Surveillance: 1. Prevention of tumors by early destruction of abnormal cells.2. Evidence for immunosurveillance-- Many tumors contain lymphoid infiltrates and may indicate a favorable clinical course--phenomenon of spontaneous regression of tumors, which typically is not well understood--tumors are frequent in the neonatal period or in old age when immune function is underdeveloped or suppressed--tumors arise frequently in immature/immunosuppressed individuals.
Cell-Mediated response to Tumors
Tumor evading techniques
Cell Mediated Immune Response :
1. Macrophages activated by T cell derived IFN gamma kill tumor cells by the same mechanisms they use to kill microbes (i.e via TNF alpha, lysozyme, oxygen radicals, etc).
2. NK cells kill tumors by the same mechanisms they use to kill virus infected cells
3. Cytotoxic T cells kill tumors in an Ag specific and MHC restricted manner
Evasion:
Main two: Lack or down-regulation of co-stimulatory molecules or MHC on tumor cells-- 1.lack co-stimulatory B7 and other adhesion molecules.(production of immunosurpressive proteins or expression of inhibitory cell surface protiens) 2. Downregulation of MHC class I(mutation in MHC genes or genes needed to process antigen)
3. Loss of tumor antigen expression (Failure to produce tumor antigen)
Pathogen traits, entry/exposure, and colonization
Traits:Invade the host (enter)-Resist host protective responses (innate immunity and adaptive immunity)-Remain in a niche[where they live/colonize] (attach)-Gain access to nutrients and multiply-Transfer to another host (exit)-Ability to cause disease (virulence factors)
Entry:Skin, eyes, ears--Respiratory tract (nasopharynx)--Gastrointestinal Tract (mouth)--Urogenital tract--Trauma (anywhere)
Exposure:Ingestion,Inhalation(arasols),Trauma, Needle stick(IV drug or hospital), Arthropod Bite, Sexual transmission
Colonization:Overcolonization by one bacterial species of a normally non-sterile area: GI tract, external mucosa of GU tract, upper respiratory tract--caused by normal flora or introduction of an external pathogen
Colonization of normally sterile organs and tissues: blood, lymph, CNS, lower respiratory system, internal organs and tissues--new portal of entry (bite, trauma) or a change in natural barriers, defenses--Blood, lymph, phagocytes carry bacteria to sterile body sites
Each has a preferred site
Modified when one microbe takes over(antibiotics)
movement from one body system to another(e. coli in gut is normal but in urinary tract-UTI
What are adjuvants?
Non-specific immune enhancers; functions partially through stimulation of innate immune system
Depot effect (concentrated for slow release)=Particle increase/Production of cytokines/Inflammatory response(good as an acute response)/Typically required with non-live vaccines
Adjuvant Types-redirect the immune response Inorganic salts and Aluminum OH
Types of Vaccines:
Recombinant Vector
Recombinant Protein
Recombinant Vector:1. vaccinia virus which is a large pox virus can deliver proteins (i.e. vaccines) which are generated by specific genes which have been cloned into the vector 2. safety issues are a concern with these kinds of preparations; other vectors are based on adenoviruses and retroviruses (mouse); these vaccines can be considered to mimic live attenuated vaccines in inducing both antibody and CTL responses. 3. None currently clinically approved. 4. Typically handled as endogenous and exogenous antigens (Administer the entire vector that makes up the pathogen including what is needed to translate the gene-all exposed to different types of adenovirus-issue can have different responses)
Recombinant Protein: 1.generate protein from organism through recombinant DNA technology and use as vaccine; can be considered a type of subunit vaccine. 2.Example: hepatitis B surface antigen vaccine which is made in yeast, recombinant influenza vaccine. 3.Typically handled as exogenous antigen and therefore only generates antibody responses (purify the protien from the vector system--inject just the protien
Tumor Specific Antigens (TSA) vs. Tumor Associated Antigens (TAA)
1.TSAs are unique to cancerous cells and are not found on normal counterparts 2.TSAs unique to a given neoplasm arise through point mutations in DNA damaged by carcinogenic chemicals, UV, or X-irradiation or through expression of unique proteins from oncogenic viruses (HPV and Hep B are viruses that can cause cancer)
1.TAAs are found on both normal and neoplastic cells, but their expression is greatly increased on tumors. 2.oncofetal antigens :CEA (carcinoembryonic antigen): elevated in colon,pancreas 3.CA AFP (alpha-feto protein): elevated in liver and testicular
Anti-cancer vaccines:
1. Immunization against oncogenic viruses constitute the only true prophylactic cancer vaccine examples hepatitis B(liver cancer) and human papillomavirus vaccines(cervical carcinoma)
2. More difficult to develop a targeted vaccine against a tumor of non-viral origin because of the lack of a true non-viral tumor specific antigen.
3. Immune Stimulators/Strategies for Anti-Cancer Vaccines--
Immunostimulant: Sipuleucel-T--FDA approved in 2008 for metastatic hormone refractory prostate cancer. Consists of patients’ dendritic cells fused to PAP (prostatic acid phosphatase) and a cytokine growth factor.--Extends life about 3-4 months
Cell-based approaches: In vitro activated LAK and TIL cells--2. Stimulate leukocytes (CTL and NK cells) in vitro with IL-2 and infuse into patients--3. TIL – tumor infiltrating lymphocytes – remove lymphocytes that infiltrate tumor cell mass, stimulate with growth factors and re-introduce into patients to reduce tumor burden
Modes of transmission
respiratory
fecal-oral
sexual
arthropod born
zoonotic
zoonotic with arthropod
1. Respiratory/aerosols--what happens when you sneeze-aerosol particles stay suspended in air for a time-transmission from one respiratory tract to another-common cold, influenza, Tb
2. Fecal-oral: could be in food and water, big problem on cruises with something getting into water supply- norovirus, e. coli
3. Sexual: gonorrhea, herpes, chlamydia-most common bacterial infection around 2 million confirmed cases each year probably closer to 5 million because its a lot of times asymptomatic
4. Arthropod-born-flees, ticks, lice--zika, malaria-only female transmits--takes blood from infected person and ends up transferring to next person it bites
5. Zoonotic with animal reserve:in animals but can be transferred to humans--rabies(bats, cats, racoons)
6. Zoonotic with animal reservoir and arthropod vector--goes from animal to arthropod to human--lyme disease, plague
Passive vs active Immunization
Passive:Temporary/Prevent disease after a known exposure/Protect immunosuppressed patient(cant give live to these patients)/Block action of bacterial toxins
Examples: Snake bite anti-venom(extremely toxic-patient would die before they developed an adaptive immune response)--passive transfer of Ig from mother to child through placenta, breast milk
Active: Delayed immunity but more permanent than passive--Prevent disease before a known exposure
Examples: Natural exposure to antigens from pathogens and vaccines--Vaccines
Immunotherapy overview
1.Treatment of disease by inducing, enhancing, suppressing immune response:
2. Activation immunotherapies - elicit or amplify an immune response
3. Suppression immunotherapies - reduce or suppress an immune response
4. Use of monoclonal antibodies
A.Blocking action of molecular targets: Can work antagonistically by binding a receptor to prevent activation--Can also bind the antigen and prevent activation
B.“Magic Bullet”: Compound with target specificity is coupled with various effector groups--Toxins, radionuclei, enzymes, DNA
Types of Tumor Antigens Recognized by Immune Cells
1. Normal self protien=no response
Tumor antigens
2. Mutated self protein= immune response
3. Product of oncogene or mutated tumor supressor gene=Tc cell response
4. Overexpressed or aberrently expressed self protien=Tc cell response
5. Oncogenic Virus=Virus-antigen specific Tc cells
Targeting Immune Checkpoints for Potential Therapy
CD28, CTLA-4 and B7 Expression on Immune Cells
CD28 is on resting and activated T cells--CTLA-4 is undetectable on resting T cells and is expressed on activated T cells--B7 molecules on dendritic cells, activated macrophages and activated B cells
We target CTLA-4 as a point for cancer therapy--want to up regulate immune response so we want to inhibit the inhibitor so that CTLA-4 does not turn off immune response
Virulence Factors
Can be direct toxin or indirect-must use factor to establish/colonize
Mechanisms and products used by bacteria to invade and colonize; bacterial by-products of living cause damage to the host, examples: enzymes, acids, gases
Many bacteria cause disease by directly destroying host tissue
Many bacteria release enzymes or toxins that inhibit host functions or destroy host tissue (bacteria may or may not be present in host)
Many different kinds and types of virulence factors
Vaccine creation and characteristics
Giving live, virulent organisms--would be unsafe--may induce disease so must make a weakened form that still retains antigens to induce host immune responses(trick body into thinking its seeing the real thing
Live vaccine-weakened form of pathogen-more effective because it creates both antibody and T cell response
Characteristics: Effectiveness:Must evoke protective levels of immunity: at appropriate site, of relevant nature, of adequate duration, Induce immune memory,
Availability: Readily cultured in bulk or accessible source of subunits
Stability: Stable under extreme climatic conditions, Preferably not requiring refrigeration
Biological effects of antibodies:
Reduced damage to host due to inflammatory response
Direct antimicrobial activity
Antibody dependent cell cytotoxicity
virus and toxin neutralization
activation of classical complement
opsonization
immunomodulation: antibodies used--Anti-venom (Snake bite) and Monoclonal antibodies [Monoclonal anti-RSV (respiratory syncytial virus)]
Antibodies targeting inflammatory cytokines such as tumor necrosis factor alpha(TNF-a) – against inflammatory bowel disease, RA, psoriasis
TNF-a-inhibitors: Block interaction of TNF-a with TNF receptors on cell surface
Immune response to Tumors
Both humoral and cell-mediated immune (CMI) mechanisms contribute to suppressing tumor growth and metastasis
CMI is the most important component.
Humoral Immunity :
1. IgG and IgM antibodies that fix complement can destroy soft tumors.
2. Antibodies directed against tumor cell surfaces may interfere with the adhesive properties that some tumor cells need to survive.
3. IgG antibodies may mediate the destruction of tumors via ADCC (antibody dependent cellular cytotoxicity)
Flagella
Organelles of motility--provide advantage to microbes--E.Coli in urinary tract must swim against the urine flow
Long filamentous protein structures projecting in various patterns--Responsible for motility--Enables motile bacteria to migrate as opposed to being moved by melieu
Immune response- proteins antigens, induce humoral immune response