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Ab formation

Ab formation. Hallmarks of the Immune Response. Self/Non-self Discrimination Memory Specificity. Equilibrium Phase. 100. 75. Catabolic Decay Phase. Amount of Circulating Ag (%). 50. Immune Elimination Phase. 25. 8. 4. 2. 6. 10. 12. Days after Injection. Fate of the Immunogen.

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Ab formation

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  1. Ab formation

  2. Hallmarks of the Immune Response • Self/Non-self Discrimination • Memory • Specificity

  3. Equilibrium Phase 100 75 Catabolic Decay Phase Amount of Circulating Ag (%) 50 Immune Elimination Phase 25 8 4 2 6 10 12 Days after Injection Fate of the Immunogen • Clearance after 1o exposure • Equilibrium phase • Catabolic decay phase • Immune elimination phase • Clearance after 2o exposure • More rapid onset of immune elimination phase

  4. LOG PLATEAU DECLINE LAG A b T i t e r Ag D a y s A f t e r I m m u n i z a t i o n Kinetics of the Ab ResponseT-dependent Ag; 1o Response • Lag phase • Log phase • Plateau phase • Decline phase

  5. 2o Ag 1o Ag A b T i t e r D a y s A f t e r I m m u n i z a t i o n Kinetics of the Ab ResponseT-dependent Ag; 2o Response • Lag phase • Log phase • Plateau phase • Decline phase * Specificity

  6. Total Ab IgG Ab IgM Ab 2o Ag 1o Ag A b T i t e r D a y s A f t e r I m m u n i z a t i o n Qualitative Ab Changes during 1o and 2o Responses • Class variation • 1o - IgM • 2o - IgG, IgA or IgE

  7. IgM Ab IgG Ab 2o Ag 1o Ag Low Dose A f f I n I t y High Dose D a y s A f t e r I m m u n i z a t i o n Qualitative Ab Changes during 1o and 2o Responses • Class variation • Affinity • Affinity Maturation

  8. High Ag Concentration 1010 109 108 107 106 105 Moderate Affinity Ab Low Ag Concentration 1010 109 108 High Affinity Ab 107 106 105 Qualitative Ab Changes during 1o and 2o Responses • Class variation • Affinity • Clonal selection • Somatic mutation

  9. Qualitative Ab Changes during 1o and 2o Responses • Class variation • Affinity • Avidity • Cross reactivity

  10. 1o Ag IgM IgG Memory Cells Cellular Events in 1o Response to T-dependent Ags • Lag • Clonal selection • Log • IgM • Class switching • Stationary • Decline • Memory Cell Pool

  11. IgM Virgin B cell IgG Memory Cells Memory Pool IgG Memory Cells Cellular Events in 2o Response to T-dependent Ags • Lag phase • Virgin cells • Memory cells • Log phase • Pool size • IgG, IgA or IgE • Stationary • Decline • Sustained production

  12. Virgin cell Th Th Memory Cells Memory Pool Th Memory Cells Memory T cells • T Cells • Virgin cells • Memory cells • Th cells • Cytokines • Long Term Memory

  13. IgM Ab 2o Ag 1o Ag A b T i t e r D a y s A f t e r I m m u n i z a t i o n Kinetics of Ab Response toT-independent Ags • 4 Phases • IgM antibody • No secondary response

  14. 1 J J J J D D D D  3 4 1 2 V V V V  2  L DNA P DNA Rearrangement  1 2 L DNA S S P  L S S S S S S S S S  L  RNA Primary Transcript IgM or IgD Primary Transcript IgE Class Switching • DNA rearrangement • Antigen dependent • Switch site • Same VDJ • TH cytokines

  15. Polyadenylation Sites H3 H4 M M DNA H3 H4 H3 H4 M M Primary Transcript AAAA AAAA H3 H4 M M H4 H3 AAAA AAAA mRNA Secreted Membrane Bound Membrane vs Secreted Ig • Differential pre-mRNA processing • Membrane exons • Alternate polyA sites • Same VDJ region used

  16. Immunization

  17. Milestones in immunization • 3000BC • Evidence of sniffing powdered small pox crust in Egypt • 1500BC • Turks introduce variolation • 1700AD • Introduction of variolation in England and later in the US • 2000BC • Sniffing of small pox crust in China

  18. Introduction of variolation The wife of the British Ambassador in Turkey, in March 1717 wrote, following the variolation of her son, to a friend in England: “The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting….I am patriot enough to bring this invention into fashion in England.

  19. Milestones in immunization • 1780AD • Edward Jenner discovers small pox vaccine

  20. Edward Jenner Discovery of small pox vaccine

  21. Edward JennerAmong patients awaiting small pox vaccination

  22. Modern era of the vaccine • 1885 • Rabies vaccine (Pasteur) • 1934 • Pertussis • 1955 • Salk polio • 1920s • Diphtheria and Tetanus

  23. Modern era of the vaccine • 1960s • Mumps measles and rubella virus • Sabin polio • 1985 • Haemophilus • 1990s • Hepatitis and varicella • 2000 • Human Papillomavirus • (HPV)

  24. Pre- & post-vaccine incidence of common preventable diseases

  25. Acquired Natural resistance Passive Active Artificial Artificial Natural Natural Different modes of acquiring immunity Immunity

  26. Natural Artificial Passive Immunity Placental transfer of IgG Antibodies or immunoglobulins Colostral transfer of IgA Immune cells

  27.  disease diphtheria, tetanus human, horse antibody source  indication human vericella zoster horse gas gangrene, botulism, snake bite, scorpion sting prophylaxis, therapy immunodeficiencies post-exposure post-exposure human human rabies, prophylaxis hypogamma-globulinemia Passive Immunization

  28. Disadvantages Advantages Advantages and Disadvantages of Passive Immunization no long term protection serum sickness immediate protection risk of hepatitis and Aids graft vs. host disease (cell graft only)

  29. Artificial Natural Active Immunization Attenuated organisms killed organisms exposure to sub-clinical infections sub-cellular fragments toxins others

  30. Live Attenuated Vaccines • polio* • not used in std. schedule • hepatitis A • standard 2006 measles, mumps & rubella • yellow fever • Military and travelers • Varicella zoster • children with no history of chicken pox • Influenza • selected age group (5-49) • tuberculosis • not used in this country

  31. Killed Whole-Organism Vaccines polio • Q fever • population at risk • influenza • elderly and at risk • typhoid, cholera, plague • epidemics and travelers • pertussis • replaced by the acellular vaccine • rabies • post exposure

  32. Microbial Fragment Vaccines • Bordetella. Pertussis • virulence factor protein • Haemophilus influenzae B • protein conjugated polysaccharide • Streptococcus pneumoniae • Polysaccharide mixture • Neisseria meningitidis • polysaccharide

  33. Microbial Fragment Vaccines • Clostridium tetani (tetanus) • inactivated toxin (toxoid) • Corynebacterium diphtheriae • inactivated toxin (toxoid) • Vibrio cholerae • toxin subunits • Hepatitis B virus • cloned in yeast

  34. Toxoid chemical modification toxin moiety antigenic determinants Modification of Toxin to Toxoid Toxin

  35. Future Vaccines • anti-Idiotype Vaccine DNA Immuno-dominant peptide

  36. anti-Idiotype Vaccine

  37. Antiidiotype antibody in tolerance Antiidiotype antibody production Antiidiotype mediated tolerance

  38. Adjuvants Adjuvant type Human use Mode of action • Salts: • Al(OH)3; AlPO4; CaPO4 • Be(OH)2 • Yes • Yes • No Slow release of antigen; TLR interaction and cytokine induction • Mineral oils without bacteria • No Slow release of antigen • Bacteria in Mineral oils (Mycobacteria, Nocardia) Slow release of antigen TLR interaction and cytokine induction • Yes • No

  39. Adjuvants Adjuvant type Human use Mode of action • Bacteria: • Bordetella pertussis • Mycobacterium bovis • (BCG and others) • Yes TLR interaction and cytokine induction • No • Bacterial products: • Myramyl peptides TLR interaction and cytokine induction • No • Synthetic polymers: • Liposomes • ISCOM • Poly-lactate • No Slow release of antigen

  40. Adjuvants Adjuvant type Human use Mode of action • Poly-nucleotides: • CpG TLR interaction and cytokine induction • No* • Cytokines: • IL-1, IL-2, IL-12, IFN-γ, etc. Activation of T and B cells and APC • No* • *Used in experimental immunotherapy of human malignancies

  41. Recommended Childhood Immunization Schedule Recommended age range Catch-up immunization Certainigh risk groups MMWR, 55: Jan 5, 2007

  42. Recommended Immunization Schedule for Ages 7-18 Recommended age range Catch-up immunization Certain high risk groups MMWR, 55: Jan 5, 2007

  43.  Event Frequency • local • redness, swelling, pain 1 in 2-3 doses • systemic: Mild/moderate • fever, drowsiness, fretfulness vomiting • anorexia 1 in 2-3 doses 1 in 5-15 doses • systemic: more serious • persistent crying, fever • collapse, convulsions • acute encephalopathy • permanent neurological deficit 1 in 100-300 doses 1 in 1750 doses 1 in 100,000 doses 1 in 300,000 doses Adverse Events OccurringWithin 48 Hours DTP of Vaccination

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