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88 Cards in this Set
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Biologics |
Substances made from living organisms •vaccines are preps or components derived from or related to a pathogen •protective effect usually achieved through 1-3 small doses and can last from a year-lifetime
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Disease causing organisms have what 2 effects on the body? |
1. Effects manifested as symptoms 2. Effects underlying immune response to the infection *vaccines designed to imitate the second effect without the symptoms! |
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Preventative vaccine protection (4 steps) |
1. Vaccine introduces a small component or a non-harmful form of the pathogen into the body (foreign antigen/immunogen) 2. Immune system produces a response: •humoral response: B-cells produce antibody that help to neutralize and eliminate pathogens •cell-mediated response: cytotoxic T-cells attack the body cells that are infected 3. Small group of memory cells (B+T) remain and can quickly initiate a strong immune response if same pathogen is encountered 4. Larger, quicker immune response: •can stop replication of the pathogen •can produce antibodies (humoral) •by producing immune cells that attack |
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What is a vaccine |
A substance introduced into the body to prevent infection or to control disease due to a certain pathogen •vaccine "teaches" the body how to defend itself by creating an immune response •protection includes the prevention of disease and/or related sequelae |
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Specific immunity |
Refers to a response that is initiated by an antigen, and in which the immune system remembers each antigen that it has previously encountered •can result from active or passive immunization naturally or artificially |
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Active immunity |
•immunity produced by the body following exposure to antigens Natural: infection (primary immune response triggered with clinical and sub clinical symptoms) Artificial: vaccine (primary immune response without causing symptoms of disease) |
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Passive immunity |
•acquired without the immune system being challenged with an antigen - by the transfer of antibodies from an immune donor •immune cells from immunized individual can transfer immunity •natural: pregnancy! And first milk to baby •artificial: IVIG. |
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IVIG used when: |
1. There is no time to wait for development of active immunity 2. No effective active vaccine exists 3. When individual is non-reactive and can't produce own antibodies |
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Effectiveness of active immunization naturally depends on:
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the ability of the host to mount a normal immune response
Also: route, dose, and schedule of vaccine can influence vaccine effectiveness |
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Vaccines are generally administered via:
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1. injection: muscle, blood stream, under skin
2. orally: often boosters required to maintain memory 3. Topical 4. Inhalation |
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Adjuvants
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Aluminum salts, oil and water emulsions
-used to increase vaccine effectiveness -by enhancing IS or eliciting a specific type of IS |
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Physical nature of vaccine antigen:
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Depends on how vaccine is made!
Impacts vaccine effectiveness -live-attenuated (weakened) vaccines provide more potent immune response but may also pose greater safety risk. |
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Vaccination protecting communities
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when a critical number of people in a community are vaccinated against an infectious disease, even those that are not vaccinated may acquire protection due to 'herd immunity'.
-lower risk of exposure for these individuals |
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First step in making vaccine
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isolate or create an organism (or component thereof) that is unable to cause full-blown disease but that still retains antigens responsible for inducing the host's immune response
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1. Killed, inactivated vaccine
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Pathogen killed through chemical process (formalin usually). Evokes robust immune response that mimics most of the responses seen during infection.
-typhoid, hepatitis A |
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2. Live, attenuated vaccine
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Pathogen weakened by genetic manipulations such that growth in host is limited and does not cause disease OR live vaccine using a related organism to a pathogen that naturally grows poorly in humans. Evokes a broad immune response similar to that seen by host infected with natural pathogen.
-varicella, rotavirus |
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3. Subunit, acellular (fragment) vaccine
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well-defined part of organism is purified and used as an antigen (proteins, peptides, polysaccharides, inactivated toxins) to create an immune response.
-pertussis |
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4. Conjugate vaccine
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Poorer antigens are chemically linked to carrier proteins. Creates a stronger immunogen, effective approach for younger children.
-haemophilis influenza B, pneumococcal strep pneumonia |
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5. DNA/RNA vaccine
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Genetic material from pathogen entered into human cells and use human cell 'equipment' to produce proteins of the pathogen encoded by those genes. Immune system detects protein as foreign antigen and produces an immune response.
-AIDS vaccine - still in development |
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6. Recombinant vaccine
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Defined genes incorporated into plasmid vehicle to allow for production of large quantities of well-defined proteins - used as vaccines. Immune response can be modified and targeted by insertion of specific genetic sequences
-Hepatitis B, HPV, looking to develop AIDS vaccine |
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Major vaccine classes
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-Target populations, ie. child or adult
-Manufacturing method (1-6) -international travel (NACI makes recommendations) -preventative vs. therapeutic vaccines |
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preventative vaccines
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traditional vaccine - prophylactic
-prepare immune system to respond to future exposure to a specific pathogen -intended for people who have not yet been infected with the organism -polio, measles, hep B and tetanus etc. |
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therapeutic vaccines
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can be administered after infection or disease onset with the goal of enhancing natural immunity against a specific pathogen - reducing the burden of disease and/or enhancing quality of life.
- often specifically formulated for individual patients, relying on clinical specimens from patient such as WBC to create the vaccine. -currently being evaluated to treat a wide range of human disorders such as AIDS and non-infectious diseases such as cancers, metabolic diseases, neurodegenerative disease, and autoimmune disease. |
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Measles
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virus - highly contagious
-symptoms appear 7-14 days after infection. Spread through coughing and sneezing - virus can live for up to 2h on a surface or in an airspace. Human disease only. |
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Pertussis
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Bordatella pertussis- whooping cough. Very contagious respiratory illness. Bacteria attach to cilia and release toxins which damage and cause inflammation.
-can cause serious illness in infants, children and adults. Cough appears after 1-2 weeks. -only found in humans, spread by contact with droplets. |
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Edward Jenner
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1796. Used cowpox scabs to create immunity to smallpox. First vaccine. First cholera vaccine produced 200 years later by louis pasteur.
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Diphtheria
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Corynebacterium - produces a toxin in respiratory system creating a grey pseudomembrane made from dead tissue that makes it difficult to breathe and swallow. Toxin can be absorbed into blood stream and damage heart kidneys and nerves. Spreads person to person through droplets, or contact with infected object or discharges from a skin lesion.
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Tetanus
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infection caused by clostridium tetani in environment, soil, dust, manure - lockjaw.
Enters body through broken skin |
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What is autoimmunity
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a breakdown of the immune system.
-immune system unable to discriminate between self and nonself. The body's immune system becomes misdirected and attacks the organs it was designed to protect |
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Frequent individual autoimmune disorders:
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thyroid disease, diabetes, rheumatoid arthritis, systemic lupus erythematosus
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Autoimmune disorder
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when demonstrable immunoglobulins (autoantibodies) or cytotoxic T cells display specificity for self antigens (autoantigens), and contribute to the pathogenesis of the disorder.
- characterized by persistent activation of immunologic effector mechanisms that alter integrity and function of individuals cells and organs. |
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Spectrum of autoimmune disorders
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The spectrum of tissue reactivity.
organ specific (such as Hashimoto's) to organ nonspecific (systemic) diseases such as RA. |
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Factors influencing the development of autoimmunity
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1. Genetic factors
2. patient age 3. exogenous factors |
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Genetic factors influencing development of autoimmunity
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1. currently no direct genetic cause for autoimmune diseases but it tends to run in families
2. tendency if an individual has autoimmune disease, they'll have more than one. 3. tend to see autoimmune disease more in women. |
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How autoimmunity begins:
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abnormal interaction of T and B lymphocytes with autoantigens. **no single theory or mechanism has been identified as a cause.
-potential for autoimmunity if given the appropriate circumstances is constantly present in every immunocompetent individual because lymphocytes that are potentially reactive with self antigens exist in the body. |
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Patient age as an influence for the development of autoimmunity:
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infrequently see autoimmunity in general population, BUT there is a steady increase with age. Peaks in individuals 60-70 years old.
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Exogenous factors influencing the development of autoimmunity:
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1. UV radiation
2. drugs 3. viruses 4. chronic bacterial infections |
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What prevents autoimmune disorders?
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The normal functioning of immunologic regulatory mechanisms.
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What happens when immunologic regulatory mechanisms dysfunction?
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Humoral: 1. antibodies to self antigens may be produced and bind to antigen in the circulation to form immune complexes, or bind to antigens deposited in specific tissue sites.2. Wherever these complexes accumulate, compliment is activated along with release of inflammation mediators (vascular permeability, chemoattractant, local tissue damage). Cell-mediated: 3. Alternatively, cytotoxic T cells can directly attack body cells bearing the corresponding target antigen which releases mediators that amplify inflammatory reaction. 4. Autoantibody and complement fragment coat cells bearing target antigen which leads to destruction by phagocytes |
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Different immunologic stimuli that may trigger an autoimmune response:
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1. antigens that don't normally circulate in blood
2. altered antigens that arise because of chemical, physical or biological processes. 3. inability to respond to a particular antigen 4. mutation of immunocompetent cells to acquire a response to self antigens 5. loss of the immunoregulatory function by T lymphocytes |
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1. Antigens not normally present in blood:
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hidden "sequestered" antigens. ie: lens of the eye, thyroglobulin, lymphocytes in fetus might not 'see' all antigens.
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2. altered antigens that arise because of chemical, physical, or biological processes:
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1. x-rays, viruses and bacteria can alter body components to the point where it is unrecognizable as "self". New antigen = new epitopes. Autoantibody is produces.
2. autocoupling > haptens can bind together and stimulate production of antibody. |
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3. inability to respond to a particular antigen:
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immunological hyporeactivity. related to disease, not a cause.
-microorganism that immune system doesn't eliminate causes damage and damaged tissue proteins can look foreign, antibody is produced. |
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4. mutation of immunocompetent cells to acquire a response to self antigens:
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mutations among lymphocytes - immune system fails to destroy them and they form clones. These can attack tissues, the tissue damage can induce antibody production.
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5. loss the immunoregulatory function by T lymphocytes:
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-impaired or defective supressor T-cells. T cells that go against body can damage the tissue - autoantibody produced.
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Self-tolerance
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The immunological tolerance against self-antigen. All individuals inherit essentially the same antigen receptor genes - these recombine and are expressed on lymphocytes as it matures from a stem cell.
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Central tolerance
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1. bone marrow and thymus
2. Induced in generative lymphoid organs as a sequence of immature self-reactive lymphocytes recognizing self-antigens. -all lymphocytes pass through a stage in which they encounter self-antigens (in high concentration) - this leads to tolerance rather than activation. -The clones of lymphocytes with HIGH AFFINITY receptors that recognize these self-antigens are killed = negative selection -This eliminates self-reactive lymphocytes (MOSTLY T). |
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Peripheral tolerance
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occurs in peripheral sites as a result of mature self-reactive lymphocytes encountering self-antigens under particular conditions
-induced when mature lymphocytes recognize antigens without adequate levels of co-stimulators (cytokines) that are required for activation. OR as a result of persistent or repeated stimulation by self antigens in peripheral tissues. -most important for maintaining unresponsiveness to self-antigens that aren't in generative lymphoid organs. MOSTLY B. |
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Self tolerance maintained by:
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-several mechanisms that prevent the maturation and activation of potentially harmful self-reactive lymphocytes (due to self-nonself discrimination)
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Failure of self-tolerance results in:
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immune reactions against self-antigens
=Autoimmune disease ** it is possible for self-antigens to be ignored by immune system so that lymphocytes that encounter the self antigen but fail to respond in any negative way (remain viable and functional). There are autoantibodies present but they don't react. |
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principal mechanisms of lymphocyte tolerance:
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1. apoptotic cell death: clonal deletion
2. functional inactivation without death: clonal anergy 3. suppression of lymphocyte activation and effector function by regulatory lymphocytes **central tolerance = deletion (T), peripheral tolerance = all 3. (B). |
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organ specific disorders
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Thyroid: Hashimoto's, Graves
Pancreatic: Insulin-dependent Diabetes Mellitus GI: Crohn's, celiac Hematological: Autoimmune hemolytic anemia, pernicious anemia Neuromuscular: MS |
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Autoimmune hematologic disorders
(4 groups of autoimmune hemolytic anemia) |
Caused by alloantibodies and autoantibodies.
1. Warm autoimmune hemolytic anemia 2.cold autoimmune hemolytic anemia 3. paroxysmal cold hemoglobinuria 4. drug induced hemolysis |
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Warm autoimmune hemolytic anemia
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-caused by warm reacting autoantibody
-occurs secondary to other autoimmune diseases, ie. lupus -IgG -need constant transfusions -extravascular hemolysis - nonhaemorrhagic, destroys RBC in tissues |
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Cold autoimmune hemolytic anemia
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-cold-reacting autoantibody ~32C
-IgM -extremities can drop to this temperature - activates the antibody which binds to RBC and activates complement - intravascular. |
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Paroxysmal cold hemglobinuria
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-transient
-seen more in young children -antibody: Doneth Landsteiner. Cold reacting antibody but it's IgG. -binds to antigen on RBC when it circulates back to body temp. > this activates complement. -Antibody gets off cell before it lyses. |
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Drug induced hemolysis
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1. Drug complex: drug binds non-specifically to red cell and look foreign and antibodies specific to drug attach and activate complement.
2. Immune complex: antibody that has good fit with drug - this binds to RBC non-specifically and activates complement. |
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First solid organ transplant
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A kidney! in 1954.
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Tissues and organs transplanted in humans:
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bone marrow, stem cells, skin, kidney, liver, cardiac valves, heart, pancreas, corneas, lungs
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What is used to enhance the probability of success in organ and tissue transplantation?
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tissue (histocompatibility) matching - of tissue antigens.
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Two basic problems of transplantation?
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1. Genetic variation between donor and recipient
2. recognition of genetic differences by a transplant recipient's immune system that causes rejection of a transplanted organ. |
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MHC
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a cluster of genes on the short arm of chromosome 6 - code for proteins that have a role in immune response.
- encodes HLA's which are the molecular basis for T cell discrimination of self and non-self. * hundred of genes, some code for leukocyte antigens, others have no role in immunity at all. |
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Rejection
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destructive mechanism triggered by transplanted tissue - if recipient's cells recognize the MHC protein on the surface of the transplanted tissue as foreign, or if immunocompetent cells transplanted on the donor tissue target the foreign cells of the recipient for elimination (reverse rejection).
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Most important HLA antigens
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Proteins located on the surface of WBCs and other tissues.
HLA-A, HLA-B, HLA-DR. |
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Inheritance of HLA
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inherited as a set of 3, A, B, DR. HAPLOTYPE
Inherit one haplotype from each parent, therefore 4 different haplotype combinations from 2 parents. |
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Basic rule in HLA inheritance
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-25% chance of inheriting all of the same HLA as one of your siblings (2 haplotypes) 6/6
-25% chance of inheriting none of the same HLA -50% chance of sharing one haplotype with your siblings. THEREFORE you have a 1 in 4 chance of being an identical match with your siblings. |
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HLA matching
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completed first (after ABO) when an patient requires an organ transplant
-family searched first, if unsuccessful then the patient goes on a waiting list. When an organ becomes available, the donor is HLA-typed and matched with a suitable recipient. |
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Percent Reactive Antibody (PRA) testing
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immune reactivity between the recipient and potential donors must be established.
-HLA antibody level present in serum must be determined. -blood test which measures the degree of response or strength of preformed antibody against 60 different types of HLA (this is a titre). -PRA is a measure of a potential recipient's sensitivity against most possible donor's HLAs -if patient has high PRA - they have formed antibodies to many different HLAs and are more likely to reject a donor organ. |
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Histocompatibility crossmatch
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Completed if patient has HLA antibodies to evaluate whether the patient has specific HLA antibodies to the particular donor.
-mix small amount of recipient serum with a very small amount of potential donor B & T cells. If HLA antibody present to donor HLA - cells will be injured = positive cross match (BAD). |
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How patient's have HLA antibodies:
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1. transfusion of blood products > WBC because theyre nucleated body may form antibody to the HLA on the WBC.
2. previous transplant 3. pregnancy |
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Organ transplant
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preferred treatment for end-stage organ failure - because of the quality of life that the treatment offers patients and long term cost benefits.
demand for transplant increases 15% every year |
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Wait list factors for organ transplant
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1. blood type, ABO and others, Lewis etc. (29+)
2. tissue type + cadaver or living? 3. height and weight of transplant candidate 4. actual size of donated organ (**lungs) 5. medical urgency 6. time on the waiting list 7. distance between recipient hospital and potential donor 8. number of donors in local area over time 9. transplantation centre criteria for accepting organ offers. |
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Need for organ donors in canada:
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4500 are waiting
2124 have had transplants (2012) 256 have died before receiving transplant |
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Ontario's organ and tissue donation agency:
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Trillium Gift of Life network
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Autograft
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graft transferred from one position to another in the same individual - bone, skin, hair * burn victims
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Syngraft
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Graft transplanted between different but identical individuals
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Allograft
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graft between genetically different individuals of the same species. contains antigens that aren't in the recipient.
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Xenograft
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graft between individuals of different species.
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Graft vs. Host Disease (GVHD)
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unintentional consequence of blood transfusion or transplantation in severely immunocompromised or immunosuppressed patients.
-degree of immunodeficiency in the host determines whether GVHD will occur. |
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GVHD etiology
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Immunocompetent T cells transfused into immunodeficient/immunosuppressed recipient. The transfused or grafted lymphocytes recognize host antigens are foreign and react. Reverse rejection!
-engraftment and multiplication of donor lymphocytes in an immunosuppressed recipient are a real possibility because lymphocytes capable of mitosis can be found in stored blood products - if recipient can't reject transfused lymphocytes they may cause uncontrolled destruction of the host's tissues and death (even in identical twins). |
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Requirements for potential GVHD
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-Source of immunocompetent lymphocytes: blood products, bone marrow, solid organ transplants
-HLA differences between donor and recipient: the stronger the antigen difference, the greater the reaction -Inability to reject donor cells: patients are severely immunocompromised/immunosuppressed. |
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GVHD in a normal patient
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not usually serious - recipient is capable of destroying foreign lymphocytes.
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prevention of GVHD
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-depletion of mature lymphocytes from marrow by using monoclonal antibodies (MAbs)
-irradiation of blood product or bone marrow. (cobalt or cesium (#) destroys nucleus of cells) |
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Immunosuppression
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immunosuppressant drug therapy and monitoring of the concentration of immunosuppressants play a critical role in success of the transplant.
used for: -induction (intense, right after transplant) -maintenance -reversal of established rejection |
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forms of immunosuppression:
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1. chemical
2. biological 3. irradiation of lymphoid system Directly interfere with the allograft rejection response Problem: more susceptible to infection - must stop therapy when this occurs and allogenic reaction can occur. |
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heart transplants
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Cardiac transplant donor must have sustained irreversible brain death but near-normal cardiac function must be maintained.
Urgent! most grafts performed despite multiple HLA incompatibilities -maintained on immunosuppressive therapy, anticoagulants, antithrombotic agents. |
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Kidney transplants
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-Donations not accepted from: over 65y/o, chronic renal disease, sepsis.
-Generally not accepted from individuals with generalized or systemic diseases like hypertension or diabetes. -severe shortage - accepting from donors > 55 with a history of hypertension or diabetes. - newer methods of harvesting kidneys have reduced the sensitizing effect related to passenger leukocytes against transplant antigens borne on these cells. |
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Lung transplants
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Difficult to achieve because of technical, logistical, immunological problems.-donor and recipient must have identical bronchial circumferences for good match. Technical problem: lungs extremely sensitive to ischemic damage and can't be successfully preserved. Lung-heart transplant often less difficult than a single transplant procedure.
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