Capítulo 3: La respuesta educativa al alumnado con TEA en el sistema educativo español
3.1.3. Vinculación de la iniciativa en los centros educativos
!
The! vast! majority! of! asthma! models! are! of! allergic! asthma! as! this! is! the!
most! predominant! form! in! humans.! Sheep! are! thought! to! be! the! most!
representative! models! of! human! asthma! allowing! multiple! inhaled!
challenges! of! Ascaris! suum! antigen! to! which! they! can! become! naturally!
sensitised! [219].! The! acute! and! late! phase! reaction! have! been! well!
documented! with! increases! in! airway! hyperresponsiveness! (AHR)! to!
bronchoconstrictors!and!a!predominant!eosionophilia!on!bronchoalveolar!
lavage![220L222].!
!
There!are,!however,!a!multitude!of!rodent!models!of!asthma!with!the!most!
established! centring! around! mice,! rats! and! guinea! pigs! [219,! 223].! In! the!
context!of!this!thesis!allergic!asthma!with!an!increase!in!AHR!is!the!entity!
to!be!studied!so!this!will!be!the!focus!of!following!discussion.!
!
3.2.1.1. Ovalbumin(model(of(allergic(asthma(
!
The! ovalbumin! (OVA)! model! of! allergic! asthma! is! currently! the! best!
characterised! in! all! rodent! species! [219,! 223L225].! It! causes! an! immune!
mediated!allergic!airways!disease!that!replicates!many!features!of!human!
asthma!including!AHR!and!can!lead!to!subLepithelial!fibrosis!and!epithelial!
and!smooth!muscle!cell!changes!seen!in!airway!remodelling.!
!
There! are! a! multitude! of! dosing! regimes! available.! The! process! typically!
involves! sensitizing! the! animal! by! one! or! two! intraperitoneal! or!
subcutaneous!injections!of!OVA!mixed!with!an!adjuvant,!usually!Al(OH)3! (alum)!to!prime!the!desired!TLhelper!2!cell!response.!
!
After! sensitization! the! animals! are! challenged! repeatedly! with! OVA!
delivered! to! the! airways.! Aerosolized! delivery! through! a! nebulizer! or! by!
the!intraLnasal!or!intraLtracheal!routes!can!be!performed.!!Within!24!L!48!
hours!after!the!airway!challenge!the!maximal!allergic!response!is!found!in!
the!lungs.!
!
InterLspecies!differences!occur!and!are!summarized!in!table!3.1.!!Guinea!
pigs!develop!the!largest!AHR!as!they!have!the!most!muscular!airways!with!
high! levels! of! cholinergic! (constrictive)! and! nonLcholinergic! (relaxant)!
innervation![224].!
! !
!
Aspect' of' human'
asthma'modeled' Guinea'Pigs' Rats' Mice'
IgE!dependent! ✕!
Mainly!IgG1! ✓! Either!IgE!or!
IgG1!
d! Recorded! Recorded!
Pulmonary!
Airway!oedema! ✓! ✓! ✓!
!
Table'3.1.W'Summary'of'aspects'human'asthma'modelled'by'each'of'the'common' rodent'ovalbumin'models.!Adapted!from!ref.![224].!
!
Guinea! pigs! would! therefore! seem! to! be! the! ideal! model! with! the! most!
responsive! airways! and! an! early! phase! response! regulated! by! histamine!
and!leukotrienes!as!it!is!in!humans![226]!but!the!response!is!mainly!IgG1! mediated!and!guinea!pigs!have!been!shown!to!suffer!seasonal!eosinophilia!
confounding! results.! In! addition,! limited! transgenic! technology! has!
resulted!in!the!guinea!pig!model!falling!out!of!favour.!
!
Mice!and!rats!show!considerable!strain!variation!in!response!to!OVA![227L 231].! Inbred! rat! and! mice! strains! with! predictable! responses! to! the!
inflammatory! models! are! used! to! reduce! the! effects! of! genetic! variability!
and!hence!the!number!of!animals!required.!In!addition,!the!Brown!Norway!
rat!(BNR)!and!the!Balb/C!mouse!are!the!most!frequently!used!as!they!are!
known! to! be! high! IgE! responders.! C57/BL6! mice! have! also! been! used! as!
they! show! a! similar! IgE! response! and! there! are! many! knockout! variants!
available! but! they! have! been! shown! to! have! less! smooth! muscle!
hypertrophy!and!hyperplasia!with!less!AHR![228].!
!
Rats!are!often!preferable!to!mice!because!they!are!large!enough!to!allow!
handling! and! in! particular! with! hp! 129Xe! MR! imaging! will! facilitate!
development! of! imaging! techniques! in! contrast! to! mice! where! tidal!
volumes!are!very!low,!adding!increasing!technical!difficulties.!
!
The! hallmark! of! asthma! is! variable! airflow! obstruction! [232].! BNR! rats!
have!been!reported!to!develop,!acute!and!late!phase!allergic!responses!to!
common!antigens![224,!233].!
!
Although! BNR! show! the! development! of! tolerance! to! antigens,! the!
responses! are! more! predictable! and! initially! the! airways! become!
increasingly! sensitive! to! bronchoconstrictors! with! cumulative! doses! of!
OVA![230,!234]!although!it!should!be!noted!that!this!tends!to!plateau!after!
3! L! 6! challenges! in! mice! and! so! is! likely! to! be! similar! in! rats! due! to!
tolerance! [235,! 236].! Belvisi! and! coLworkers! however! noted! a! difficulty!
reproducing!this!AHR!to!methacholine!(MCh)!and!bradykinin!in!the!BNR,!
noting!that!the!response!that!had!been!found!by!other!groups!earlier!was!
rather! weak! [65].! They! postulated! that! weakening! of! the! BNR! response!
may! have! been! due! to! methodological! issues! with! the! study! in! terms! of!
animal! sensitization! protocols! or! different! measurements! of! AHR.! They!
also! suggested! that! it! is! possible! that! there! is! variation! between! BNRs!
obtained! from! different! suppliers.! Allakhverdi! et! al.! did! however! record!
considerable! bronchial! responsiveness! to! leukotrienes! of! OVA! sensitized!
BNRs![237].!
!
BNR! and! Balb/C! mice! have! been! noted! to! develop! airwayLremodelling!
changes! as! seen! in! humans! [238,! 239].! A! chronic! model! with! loss! of! the!
inflammation!after!cessation!of!OVA!challenges!and!loss!of!AHR!was!seen!
by!Hove!et!al.!in!2009![228].!
!
3.2.1.2. Alternative(models(of(allergic(asthma(in(the(rat(
!
Other! common! sensitizing! agents! used! in! rats! and! mice! are! human!
allergens!such!as!house!dust!mite!(HDM)!extract!or!the!fungus!Aspergillus!
fumigatus![224,!235,!240].!In!addition,!the!parasite!pig!roundworm!Ascaris!
suum!has!been!used![241].!
!
Of!these!models!most!interest!has!centred!around!the!use!of!HDM.!!It!like!
the! OVA! model! involves! sensitization! of! the! animal! by! subcutaneous!
injection!of!HDM!extract!followed!by!a!respiratory!challenge![224].!!It!has!
been! shown! that! continuous! intranasal! exposure! where! the! antigen! is!
instilled! 5! days! per! week! over! 5! L! 7! weeks! can! also! produce! the! same!
results! in! mice! and! that! this! might! be! a! more! comparable! model! as! it!
mimics!more!closely!the!situation!with!human!exposure!to!antigens![235].!