08 - March 5, 2013.docx

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Cell and Systems Biology
Gray- Owen

MIJ – March 6, 2013 Adjuvant – inject protein into animal, quite often will not be good immune response in animal; pure protein as vaccination strategy not effective – need to add something to that protein in order to enhance the immune response to it – a number of substances tried – these substances could enhance the immunity to the protein even though the adjuvant had nothing to do with the protein – unclear why Adjuvant perhaps makes the protein last longer in tissue – it was unclear what was happening – mouse experiment – ovalbulmin alone – ovalbulmin with adjuvant – antibody responses – higher with adjuvant Janeway – adjuvant seemed to be substances that induced inflammatory response in tissues – if gave the protein with the adjuvant and looked at the where the vaccination was given – see more inflammation , swelling, redness – if took tissue section, see more inflammatory cells adjuvants were causing inflammation can activate APC through receptors that seem to recognize common patterns found on pathogens to alert the organism that there is an invading pathogen – some rcognition receptors seem to also recognize when a cell is being destroyed – when a cell is dying – a lot of substances commonly found in nature that induce inflammatory response – alert that there is invasion by pathogen and danger or tissue-damage occurring ALUM – oldest adjuvant called Alum 1926- first animal experiments then in humans Form crystalling structures Change pH – allow protein to cyrstallize in association with aluminum salt – used as vaccination strategy – human study looking at diphtheria immunization in fluid form or precipitated with alum salt – done in children – immunized children with fluid or alum-and-diptheria-toxoid Looked at antibody responses to diphtheria toxoid Three injections of fluid – 63% of kids had high levels of antibodies; with alum, 94% of kids had antibodies so precipitating antigen with alum salt enhanced immunogenicity A lot of debate over how this works – one obvious thing was that because precipitation, stays in tissue longer – maybe the antigen stays around longer – some of these early researchers did experiment – right after vaccination, removed tissues around animal – no difference if removed the residual depo material from tissues – debate whether depo effect has any relevance – it seems that the aluminum and the antigen formed together – forms some sort of crystal – inflammatory cytokine interleukin beta found in injection sites – Induces IgE – skewed T cell response – Th2 response mainly – allergic type of response Alum mainly useful for strong Th2 response Alum – induce Th1 response also in humans; only Th2 in mice Inducing inflammation – one of the typical inflammatory cytokines Interleukin1 IL1 is part of inflammasome – typical inflammatory induction pathway – interleukin one and IL18 are both cleaved by caspase one for activation Aluminum forms crystals – first clue to alum Gout – disease where uric acid metabolism – uric acid build up in joints, form crystals, that induce inflammatory response MSU – induce good levels of IL1beta Block that by using caspase inhibitor so caspase mediated process Had a number of mice that were defective in one aspect of signalling pathway of inflamamsome and TLR pathway Caspase1 deficient mice deficient in inducing inflammasome; ADA deficient mice deficient in inducing TLR pathway Caspase knockout mice – no interleukin 1 in response to uric acid cyrstals; also same in ASC knockout mice ASC adaptor molecule Looked at a nod-like receptor 3 – found that if have one of these knockout mice- give injection of monosodium urate – no interleukin 1 beta production NLRP seems to be involved – member of the NLR family – activate IL1 Franchi and Nunez – if immunized mice could produce antibodies to antigen in presence of alum – showed that if immunize mice with human serum albumin – can induce immune response even in NLRP knockout mice – alum is not uric acid but the studies with uric acid suggests alum works the same way Alum could activate the inhibitor of NLRP A number of other papers since then showing that alum can do other things – can also activate another immune molecule, Prostaglandin E2 – even in IL1 knockout mice – the alum c
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