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Th1 to Th2: Can worms, bacteria or allergens cause the switch?. Anna, Vinay, Soo-Kwan, and Megan April 7, 2003 BE.214. Hypothesis Th1 and Th2 responses are mutually antagonistic. Therefore, switching the response from Th1 to Th2 in the gut in Crohn’s disease can ameliorate the disease.

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th1 to th2 can worms bacteria or allergens cause the switch

Th1 to Th2: Can worms, bacteria or allergens cause the switch?

Anna, Vinay, Soo-Kwan, and Megan

April 7, 2003

BE.214

slide2

Hypothesis

    • Th1 and Th2 responses are mutually antagonistic.
    • Therefore, switching the response from Th1 to Th2 in the gut in Crohn’s disease can ameliorate the disease.
  • AIM:
  • Induce a Th2 response
    • localized to the gut or able to have an effect on gut
    • strong enough to tip the balance (from Th1 in gut)
    • in an acceptable manner
  • STEPS.
    • Identification and design of right
    • Immunogenic component
    • Delivery method
  • Characterization of immune response
  • cytokines
  • cell interactions
  • innate and adaptive interactions
slide3

Preliminary Evidence

Experimental evidence suggesting Th1 to Th2 switch has beneficial effect on Crohn’s disease

Steidler– IL10 secreting lactobacilli

Weinstock – studies with worms in humans

Studies with worms in animal models.

slide4

localised to the gut

  • Th1 to Th2 switch needed at the gut.
  • -- i.m. or s.c immunisation may not induce response in the gut.
  • Oral route required.

BUT

Oral route of antigen delivery typically induces tolerance.

-- no immune response to Food !

Why?

Absence of co-stimulation.

Oral antigens need an adjuvant for immune response.

NOTE: All oral vaccines (e.g. Polio, typhoid (Typhoral), rotavirus vaccine) are live attenuated organisms.

localized to gut or have an effect on gut
Localized to gut

Th1 to Th2 switch needed at the gut.

-- i.m. or s.c immunisation may not induce response in the gut.

Oral route required.

BUT

Oral route of antigen delivery typically induces tolerance.

-- no immune response to Food !

Why?

Absence of co-stimulation.

Oral antigens need an adjuvant for immune response.

NOTE: All oral vaccines (e.g. Polio, typhoid (Typhoral), rotavirus vaccine) are live attenuated organisms.

Or have effect on gut

Localized to gut or have an effect on gut

Elliot et al. showed intraperitoneal

Injection of S. Mansoti freeeze-killed

Eggs may limit the effects of TNBS

induced colitis in mice by forcing a Th1

to Th2 switch in the gut at the time of

TNBS treatment

slide6

2. strong enough to tip the balance

  • How?
  • Parasitic infection –
  • Strongly induce infiltration of eosinophils and Th2 cells.
  • Eosinophils produce large amounts of Th2 cytokines (IL4).
  • b) Exploit a memory response.
  • Immunize with an Th2 antigen - s.c./ i.m.
  • And Give the antigen orally during disease exacerbation
  • c) Adjuvants

3. in an acceptable manner

  • Worm components
  • Food Allergens
  • No human pathogens, no brain parasites!
slide7

Choice of worm

  • Criteria
    • non-humanparasite (cannot infect humans)
    • can beculturedin vitro
    • if possible incell freemedium
    • Or easily harvested from native host
  • Heligosomoides polygyrus
  • - An adjuvant to prime for an Ag-specific Th2 response
  • : IL-4, IL-10
  • - Protection against an Allergic response
  • : Down-regulation of PN Ag-specific IgE response
  • Trichinella spiralis
  • - Prior exposure cause reduction of the severity of DNBS
  • mediated colitis
  • : Increase of IL-4, IL-13 and decrease of IL-12, IFN
  • Acanthocheilonema viteae
  • - ES-62 (PC-containing glycoprotein) induce the maturation
  • of DC2 with the capacity to induce Th2 response
  • : Increased IL-4 and decreased IFN )
  • - ES-62 induces a Th2 response in vivo : Increased IgG1/IgG2a

Not easy to culture

through entire length

of life cycle

slide8

Choice of allergen

  • Criteria
  • Universal
    • Mild
    • Availablity of antidote (Ab ?)
  • Possibilities: Ragweed, seafood, peanut, dust mite

Problems:

Food allergens not well characterised as compared to respiratory allergens

Idiosyncratic response to allergens.

Allergic colitis is quite rare--> it may be hard to get a gut localized Th2 response from food allergens (?)

slide9

Worm Extracts!

Killed Worms? or Worm components?

Benefits

Killed “whole” organisms are better immunogens than

those made of single components

Some “Pathogen associated molecular patterns” retained in killed organism

Drawbacks

Both are worse than live organism

Among two, component antigens may need stronger adjuvants

PROBLEM: Body may treat both like exotic oriental food and do nothing apart from digesting them.

Although this may not provide a miracle treatment, it may allow for a characterization of the immune response associated with parasite induced Th1-->Th2 switch

ADVANTAGE: Anna can (WILL) capture the ‘natural product’ market!

slide10

Like Silk Worm, all are insect larvae

For mammals, nematodes are invariably parasites (?)

http://www.petros.com.my/eatworms.htm

http://www.mckandy.com/page/309

http://www.ent.iastate.edu/misc/insectsasfood.html

Know someone who eats worms or worm extracts for a snack?

Has he ever got Crohn’s disease?

TRY GOOGLE FOR THESE RECIPES !

Meal Worm

Army WormRoot Worm

Sago Worm

slide11

PLAN

Arrive at best

formulation.

screen

+

Advjuvant

OR

one of the

components

itself acts as

an adjuvant

Use mouse serum

to purify

immunodominant

Ag in extract

in vivo models
TNBS enema

C3H/HeJBir

C. rodentium

Acute Inflammation

Chronic Inflammation

In vivo Models

Naturally occuring, sponateous colitis

Th1 disease

Bacterial cause

Th1 mediated colitis

slide13

Delivery Possibilities

multi-component bio-engineered “immune response switching beads”

Extract equivalent to Food if given orally

Protective coat that

Keeps bead intact until it

Reaches the inflamed zone

IL-10

Surface studded with choicest

Ragweed, worm and fungus

Components.

IL10, IL4 slow release

slide14

Delivery Possibilities

Commensal Vectors

  • Make Super-Bugs that produce–
  • IL10
  • Parasite Ag (wormified bacteria)
  • Allergens
  • Ab to IFNg or other Th-1 cytokines
  • Eosinophil Chemotactic Agents
  • ON DEMAND – regulated promoters
  • Focus on bacteria that are non-pathogenic possibly consider chronic treatment with non-colonizing bacteria
  • Specifc commensal bacteria for drug targeting to different
  • zones of intestine (different zones have different microflora)
slide15

Use of Live Worms

  • Engineered strains with desirable properties
    • Increased susceptibility to antihelminthic
    • Low replication rate
  • Note: Genetic engineering of worms difficult if they
  • cannot be cultured in vitro.
  • Expose eggs to Irradiation? Mutagens?
  • Non-engineered worms that remain in the gut and cause no/limited systemic effects that can be eventually cleared (?)
  • Guarantee of strong Th2 response each time administered