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Hillary Andrews and Heather Zwickey presenting
http://vaccineconsult.com/

class will help us
decide on vaccines based on timing, individual susceptibility, danger of infx
protocol for making vaccines more effective

AANP position in appendix 1
safer more effective vaccines should be developed
physicians should be attendtive to proper use
physicians should get signed consent
physicians should obey state laws

ACIP = advisory committee on immunization committee
most (all?) have conflict of interest requiring congressional waiver
goal: to eradicate certain diseases (polio, etc)
focus on herd immunity, no recognition of individual's immune status
36 vaccines by age 2 are given, 4 each of haemophilus and DTAP
linked to ped wellness visits
not determined by immune system development
hence revision is needed

alternative schedule based on
when system can mount most appropriate response
the individual's risk factors, health, and parent's habits
danger of infx

_________________

Zwickey Immunology review

Why vaccinate? strengthen immune response vs safer version of threatening microbe
vaccination -->100-1000 more immune cells specific for microbe
7-20 days to mount immune response 1st time, faster 2nd time (3 days)
specific cells increases every time you encounter the bug
flu has antigenic drift
flu is one of the few bugs that healthcare workers get in spite of multiple exposures
herd immunity: pop protected because disease is less prevalent
looks like smallpox has been eradicated worldwide

immune response review: 1st is innate response, skin, tears, then to protective proteins, acute phase proteins (complement, CRP), lysozyme in saliva,

CRP = complement regulatory prot marker for inflam, HS-CRP now tested, periodontitis is most common cause of chronic inflam, also high in obese

Macrophages and neutrophils, both phagocytic, neuts have granules that kill, are tethered to BV wall, live about 8 hours and become mucus or pus. secrete cytokines, IL1, IL6, TNFalpha, all proinflammatory. Goal: to keep things in check until specific response is mounted. Macrophages or dendritic cells pick up antigen and take it to lymph nodes to the T cells.

B cell response: make antibodies: IgM, D, G, E, A.
IgM is pentameric, triggered by IL2 from T cells.
IgD we don't know what it does, rhogam is IgD.
IgG-->Th1 response, highest level in blood, crosses the placenta, found in infx, T cells make IFNgamma which triggers prod.
IgE-->Th2 response, for parasites, causes allergies, triggered by IL4
IgA-->Th3 response, in secretions incl breast milk, tears, saliva, assoc w/ oral tolerance. triggered by TGF-beta and IL5. Can get IgA response in Th2.

B cells don't kill microbes, nor do AB's
AB's block toxins (neutralization)
AB's coat microbes for better phagocytosis
AB's help NK cells target microbe
AB's bind FC receptors and trigger cell fx, mast cells degranulate dt AB trigger
high titer doesn't mean 100% protection

How do we activate T cells
B cells process and present antigen
macrophage ingests microbe and presents antigen in MHC "hot dog bun"
T cell reads peptide in hot dog bun
two types of antigen presentation, MHC 1 & 2
2 good at presenting exogenous
1 good at presenting viral antigens, on all cells not just APC's
signal 1 is t cell reading antigen in MCH
signal 2 is CD28 on T cell touching CD86 on APC
(if vaccine doesn't have complete microbe you may not have signal 2)
if no signal 2 then no immune response
costimulateion = signal 2
then you get cytokine production by T cell

Th17 seems to be dt TGFb in gut meeting IL6, causes autoimmune incl Crohn's, RA, MS

Th1 is IFNg,
cell mediated immunity,
stims macrophages and CD8 T cells,
best for viral, bact & CA
IFNg and IL2-->IL12 activates NK's
stims CTL's aka killer T cells aka CD8's

Th2 response
IL4
humoral immunity
B cells make AB's
best for parasites & worms
allergies & asthma
IgE, A, G
AB's neutralize toxins, opsonize orgs and fix complement
this is the rxn we have in 1st year of life
mast cells degranulate, release histamine

Th3
TGFb
oral tolerance, can suppress Th1 & 2 so regulates the rest of immune response
cells called Treg when have CD25 and FoxP3 markers
foxp3 is transcription factor that leads to CD25
Treg control immune to contain autoimmunity
people with AI dz have reduced number of Tregs
mice with diabetes, increase Tregs and diabetes goes away
MS goes away in mice when increase Tregs
no drug to increase Tregs
retinoic acid increases Tregs, not yet researched in humans
works in every animal model so far
also increase Tregs with ashwagandha

Th17
newest
autoimmune response
role in tissue damage
IL17, IL21, IL22
response to fungal species in natural environment (??)
first described in 2005
humera to block Th17 treats psoriasis
drugs that block single cytokines are called biologicals
Th1 and 2 were implicated in AI, now seems to be Th1 and IL17, no Th2

Ideal response to vaccines is Th1 response
want IFNg for response to bugs bcs upregs MHC and switches B cell class to IgG
triggers CD8's to kill, T cells can live for years
Th2 response not ideal, AB's are not long lasting, B cells hang out longer
can't do Th1 in 1st year of life, infants have Th2 responses
National Jewish ctr for immunology and dz where Zwickey went, teacher says:
Th1 response in very young might destroy brain: encephalitis
probably don't want to drive any immune response in infants

Memory response: number of cells specific for microbe still in body
CD4, CD8 and B cells
CD8 T cells don't need costim (signal 2)
response time shorter than initial response
length of response depends on antigen, strength of immune response, and what cells are involved
CD4 & 8 last longer than B cells-->some vaccines requier boosters
4th DTAP gives memory, if give 1st DTAP shot after age one then don't need prior 3
better response from natural infection than from shot
tetanus memory cells have been shown to live as long as 23 years
average vaccine response? 10 years
adults don't keep up with boosters-->less herd immunity

Immune development of the baby
before conception, oocytes developing in mother
conception: have innate immune system
gestation 5 months B cells make IgM, no cytokines yet
class switching begins prebirth allowing other cytokines
birth, can make IL4 and Th2 response, also Th3 response
no IFNg at birth
breast feeding supplies IgA
week 6 thymic stroma develops
week 7-8 lymphocyte progenitors in fetal liver
week 8 gut assoc lymph begins
week 10-12 thymic cortex and T cell gene rearrangement
12 B cells appear in blood
14 T cells found in spleen
14-26 T cells increase
20 weeks T cells in cord blood
8 mo begins to make IFNg, by 12 mo most infants are making it and can mount Th1

implications: antigens introduced in 1st year induce IgE/Th2 response
Th2 shuts down Th1

MATERNAL RESPONSE
pre-preg normal healthy immune system
male orgasm causes cortisol burst gone in 2 min
woman orgasm cortisol burst takes 24 hours to decrease
50% of the time this response in females
high cortisol allows woman to get preg?
after orgasm prolactin increases, refractory period maintains one sperm type for fert

mom "eduates" fetus to induce tolerance with TGFb
non-inherited MHC crosses placenta and fetus could reject mother but doesn't
fetus makes more CD25, FoxP3, TGFb
makes Tregs
women with MS go into remission when preg dt TGFb
TGFb maintains trophoblast
probiotics really good during pregnancy
if decreased Th3 or TGFb then pre-eclampsia, vitamin A may help but is teratogenic/abortive
high vit C and E doses can increase TNFa, decrease TGFb, and increase risk of pre-eclampsia
progesterone to stabilize uterine lining increases TGFb

preg can trigger higher IL4-->more allergies while preg
preg can fight infx w/ AB's & T cells but shouldn't be vaccinated with live virus (killed OK)
preg may have some elevated Th1 cytokines locally in LN's

BIRTH
lactobacillus in vagina populates infant gut
bifidus is on nipple of breast
need microflora for normal immune development

BREAST MILK
IgA, G, M
G when mom has infx
lactoferrin
lysozyme survives freezing
lactoperoxidase etc for digesting milk
lactalbumin
leukocytes: macrophages, neuts, lymphs
cytokines, incl: proinflam, Th1, Th2, Th3 (can't freeze)
ab'S survive a single freeze & thaw
growth factors

BABES WITH NO BREAST FOOD
they get Th2 response only
child needs to have a "really decent" infx and Th1 to shut down Th2 response
study: lick the dog to stop asthma, it works

if mom stops breast feeding
cytokines last 24-48 hours
ab's last up to 6 days, G up to 40 days, etc

if tx with ABX early in infx
Th1 response doesn't develop fully
if Th2 was already established then it continues

pesticides and heavy metals, aluminum, toxins in breast milk
does it hurt immune sys?
nobody knows
Norway study comparing mom to goat milk
Foresight Institute in England and Australia
retrospective studies show ADHD, learning disabilites etc assoc w/ toxins in milk
lots of toxins in US breast milk
crit of retrospective studies: moms with toxic milk doing other toxic things
any toxic burden on child has an effect

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