D D vitaminis zegavlena vitaminis zegavlena tuberkulozis mikobaqteriis tuberkulozis mikobaqteriis

mimarT maspinZlis mimarT maspinZlis imunitetsa da mkurnalobis imunitetsa da mkurnalobis

Sedegebze: translaciuri Sedegebze: translaciuri kvlevebisTvis infrastruqturis kvlevebisTvis infrastruqturis ganviTareba dietologiasa da ganviTareba dietologiasa da

infeqciur daavadebebSi infeqciur daavadebebSi saqarTveloSi.saqarTveloSi.

mTavari mkvlevari: mTavari mkvlevari: Tomas r. zigleriTomas r. zigleri M.D. M.D.

Tana-mkvlevarebi:Tana-mkvlevarebi: henri m. blumbergihenri m. blumbergi M.D. M.D. vin TangpriCavin TangpriCa M.D., PhD. M.D., PhD. reinaldo martorelireinaldo martoreli PhD. PhD. uSa ramakriSnanuSa ramakriSnan PhD PhD karlos del riokarlos del rio M.D. M.D. aleqsandra iamSikovialeqsandra iamSikovi M.D M.D ekaterina kurbatovaekaterina kurbatova M.D., MPH, M.D., MPH,

PhDPhD naSa talantinaSa talanti, M.D., M.D. arCil salayaiaarCil salayaia M.D., MPH M.D., MPH nestan tukvaZenestan tukvaZe M. D. M. D. veriko mircxulavaveriko mircxulava M.D., MPH M.D., MPH nino lomTaZenino lomTaZe M. D., M.Sc. M. D., M.Sc.

sponsoris saxelisponsoris saxeli: : emoris jandacvis globaluri emoris jandacvis globaluri institutiinstituti

D D vitaminiT Terapia da tuberkulozivitaminiT Terapia da tuberkuloziistoriuli rakursiistoriuli rakursi

nobelis lauriatma ils-finzenma 1900 wlebSi nobelis lauriatma ils-finzenma 1900 wlebSi popularizacia gauwia solariumebis gamoyenebas popularizacia gauwia solariumebis gamoyenebas kanis tuberkulozis samkurnalod.kanis tuberkulozis samkurnalod. 1947-1998 wlebSi dagrovili masalebi sxvadasxva 1947-1998 wlebSi dagrovili masalebi sxvadasxva

SedegebsSedegebs aCvenebs mziT insolaciisa da aCvenebs mziT insolaciisa da D D vitaminiT TerapiisvitaminiT Terapiis efeqturobasTan dakavSirebiTefeqturobasTan dakavSirebiT

D D vitaminis deficiti zrdis tuberkulozis mimarT vitaminis deficiti zrdis tuberkulozis mimarT winaswarganwyobaswinaswarganwyobas

pacientebs aqtiuri tuberkuloziT aqvT Sratis pacientebs aqtiuri tuberkuloziT aqvT Sratis 25(OH)D25(OH)D done ufro dabali vidre maT janmrTel kontrolebs.done ufro dabali vidre maT janmrTel kontrolebs.

DD vitaminis deficiti korelaciaSia radiografiuli vitaminis deficiti korelaciaSia radiografiuli monacemebiT dadasturebul tuberkulozis rTul formebTan.monacemebiT dadasturebul tuberkulozis rTul formebTan.

kani

TLR aqtivaciam adamianis

makrofagebSi moaxdina D vitaminis receptorebis aqtivacia da vitamin D-1-hidroqsilazas genebis eqspresia, ramac gamoiwvia antimikrobuli cila katelicidinis

(LL-37)-is gaaqtiureba da ujredSida Mycobacterium Tuberculosis ganadgureba.

TOLL-LIKETOLL-LIKE receptorebis mier receptorebis mier D D vitaminis vitaminis gaaqtiurebiT ganpirobebuli antimikrobuli gaaqtiurebiT ganpirobebuli antimikrobuli

pasuxis CarTva pasuxis CarTva 24, march, 200624, march, 2006

DOI: 10.1126/science.1123933Science 311, 1770 (2006);

LLLL-37-is regulacia -37-is regulacia D D vitaminiT, vitaminiT, antimikobaqteriuli meqanizmebiantimikobaqteriuli meqanizmebi

kvlevis dizainikvlevis dizaini ormagad-brma, randomizirebuli, kontrolirebadi 3 ormagad-brma, randomizirebuli, kontrolirebadi 3

wliani klinikuri kvleva vitaminwliani klinikuri kvleva vitamin D D –s efeqturobasa da –s efeqturobasa da antimikrobul meqanizmebze.antimikrobul meqanizmebze.

filtvis tuberkuloziT daavadebul axlad registrirebul filtvis tuberkuloziT daavadebul axlad registrirebul

pacientebs (pacientebs (n=110n=110) CautardebaT) CautardebaT D D vitaminiT Terapia vitaminiT Terapia oTxi Tvis manZilze, placebo kontrolis jgufis (oTxi Tvis manZilze, placebo kontrolis jgufis (n=110n=110) ) paralelurad. paralelurad.

kvlevis monawileebs CautardebaT antituberkulozuri kvlevis monawileebs CautardebaT antituberkulozuri

mkurnaloba programul farglebSi mkurnaloba programul farglebSi DOTDOT meTvalyureobis meTvalyureobis qveS.qveS.

radganac tubinfeqcia arsebul kvlevebze dayrdnobiT radganac tubinfeqcia arsebul kvlevebze dayrdnobiT

dakavSirebuliadakavSirebulia D D vitaminis naklebobasTan Seawavlil vitaminis naklebobasTan Seawavlil iqneba 80 arainficirebuli ojaxuri kontaqti piloturi iqneba 80 arainficirebuli ojaxuri kontaqti piloturi monacemebis Sesagroveblad. monacemebis Sesagroveblad.

hipoTezebi:hipoTezebi: 1. D 1. D vitaminiT Terapia gamoiwvevs filtvis tuberkuloziT vitaminiT Terapia gamoiwvevs filtvis tuberkuloziT

daavadebul pacientebSi antituberkulozuri mkurnalobis daavadebul pacientebSi antituberkulozuri mkurnalobis gaumjobesebul Sedegebs, aseve gaumjobesdeba am gaumjobesebul Sedegebs, aseve gaumjobesdeba am pacinetebis nutriciologiuri statusi placebo kontrolis pacinetebis nutriciologiuri statusi placebo kontrolis jgufTan SedarebiT. jgufTan SedarebiT.

2. D 2. D vitaminiT Terapia sagrZnoblad gazrdis vitaminiT Terapia sagrZnoblad gazrdis LLLL-37-is -37-is koncentracias naxvelSi, nerwyvsa da plazmaSi da koncentracias naxvelSi, nerwyvsa da plazmaSi da katelicidin/katelicidin/LLLL-37-is -37-is mRNAmRNA da proteinis eqspresias kanSi, da proteinis eqspresias kanSi, D placebos preparatiT mkurnalobasTan SedarebiT.D placebos preparatiT mkurnalobasTan SedarebiT.

3. 3. naxvelSi, nerwyvsa da plazmaSi naxvelSi, nerwyvsa da plazmaSi LLLL-37-is done da -37-is done da kanSi katelicidin/kanSi katelicidin/LLLL-37-is, -37-is, mRNA-mRNA-is da proteinis eqspresia is da proteinis eqspresia filtvis tuberkuloziT daavadebul pacientebSi dadebiT filtvis tuberkuloziT daavadebul pacientebSi dadebiT korelaciaSi iqnebakorelaciaSi iqneba organizmSiorganizmSi D D vitaminis nutriciologiur vitaminis nutriciologiur statustan, rac Sefasdeba plazmaSi 25-hidroqsivitaminstatustan, rac Sefasdeba plazmaSi 25-hidroqsivitamin D- D-s koncentraciiT.s koncentraciiT.

4. 4. saqarTveloSi filtvis tuberkuloziT daavadebul saqarTveloSi filtvis tuberkuloziT daavadebul pacientebs aqvTpacientebs aqvT D D vitaminis naklebobis/deficitis maRali vitaminis naklebobis/deficitis maRali prevalentoba da es problema ufro gamoxatulia maTSi, prevalentoba da es problema ufro gamoxatulia maTSi, vidre maT ojaxur kontaqtebSi, romelTac ar daudgindaT vidre maT ojaxur kontaqtebSi, romelTac ar daudgindaT aqtiuri tuberkulozi.aqtiuri tuberkulozi.

kvlevis miznebi da amocanebikvlevis miznebi da amocanebi

amocana 1 :amocana 1 :

pacientebSi, romelTac daudasturdebaT pacientebSi, romelTac daudasturdebaT fitvis tuberkulozis axali SemTxveva, fitvis tuberkulozis axali SemTxveva, Catardes randomizirebuli ormagad-brma Catardes randomizirebuli ormagad-brma kontrolirebadi kvleva, peroraluri kontrolirebadi kvleva, peroraluri DD vitaminis vitaminis antituberkulozur mkurnalobaSi CarTvis antituberkulozur mkurnalobaSi CarTvis fonze klinikuri da nutriciologiuri statusis fonze klinikuri da nutriciologiuri statusis SesaZlo gaumjobesebis Sesafaseblad. SesaZlo gaumjobesebis Sesafaseblad. Mantituberkulozur mkurnalobaSi Mantituberkulozur mkurnalobaSi D D vitaminis vitaminis CarTvis dizaini iTvaliswinebs plazmaSi CarTvis dizaini iTvaliswinebs plazmaSi D D vitaminis koncentraciis optimizacias vitaminis koncentraciis optimizacias 32ng/ml.-mde32ng/ml.-mde

amocana 2 :amocana 2 :

Sedardes vitaminiT Terapiasa daSedardes vitaminiT Terapiasa da

placebo kontrolze myof pacientebSi placebo kontrolze myof pacientebSi

sabaziso gamokvlevebSi sabaziso gamokvlevebSi LLLL-37-is-37-is

koncentraciebi naxvelSi, nerwyvsa dakoncentraciebi naxvelSi, nerwyvsa da

plazmaSi da katelicidin /plazmaSi da katelicidin /LLLL-37-is -37-is mRNA mRNA dada

proteinis eqspresia kanSiproteinis eqspresia kanSi

amocana 3 :amocana 3 :

LL-37-LL-37-isis koncentraciebi naxvelSi, nerwyvsa dakoncentraciebi naxvelSi, nerwyvsa da

plazmaSi da katelicidin /plazmaSi da katelicidin /LLLL-37-is -37-is mRNA mRNA da proteinisda proteinis

eqspresia kanSieqspresia kanSi seriulad Sedardes plazmis 25 seriulad Sedardes plazmis 25 (OH(OH)) DD

vitaminis koncentraciasTan amocana pirvelSivitaminis koncentraciasTan amocana pirvelSi

xsenebul monawileebSixsenebul monawileebSi

amocana 4 :amocana 4 : pacinetebSi filtvis tuberkuloziT ganisazRvrospacinetebSi filtvis tuberkuloziT ganisazRvros

sabaziso vitaminsabaziso vitamin D D statusi da Sedardes maTi statusi da Sedardes maTi

janmrTeli ojaxuri kontaqtebis kohortas janmrTeli ojaxuri kontaqtebis kohortas

skriningis formaskriningis forma

CarTvis kriteriumebi:CarTvis kriteriumebi:

1. skriningis momentisaTvis pacienti sul mcire 18 wlisaa 1. skriningis momentisaTvis pacienti sul mcire 18 wlisaa 2. pacients aqvs mgb(+) filtvis tuberkulozi 2. pacients aqvs mgb(+) filtvis tuberkulozi

3. pacients utardeba tubsaw. mkurnaloba araumetes erTi 3. pacients utardeba tubsaw. mkurnaloba araumetes erTi kvirisakvirisa

4. pacienti tubsawinaaRmdego mkurnalobas Caitarebs TbilisSi 4. pacienti tubsawinaaRmdego mkurnalobas Caitarebs TbilisSi

Tu pirvel nawilSi yvela kiTxvaze aRiniSneba uaryofiTi Tu pirvel nawilSi yvela kiTxvaze aRiniSneba uaryofiTi pasuxi, individi ar SeiZleba CaerTos kvlevaSi. pasuxi, individi ar SeiZleba CaerTos kvlevaSi.

gamoricxvis kriteriumebi:gamoricxvis kriteriumebi:1. 1. pacienti warsulSi namkurnalebia tubsawinaaRmdego medikamentebiT pacienti warsulSi namkurnalebia tubsawinaaRmdego medikamentebiT

30 dReze meti xnis manZilze30 dReze meti xnis manZilze2. pacienti mimdinare momentSi orsuladaa an meZuZuria 2. pacienti mimdinare momentSi orsuladaa an meZuZuria 3. pacients warsulSi Catarebuli aqvs organos transplantacia 3. pacients warsulSi Catarebuli aqvs organos transplantacia 4. pacients ukanaskneli 5 wlis ganmavlobaSi aReniSneba kibos diagnozi 4. pacients ukanaskneli 5 wlis ganmavlobaSi aReniSneba kibos diagnozi

(dasaSvebia kanis kibo - aramelanoma) (dasaSvebia kanis kibo - aramelanoma) 5. pacients anamnezSi aReniSneba gulyra 5. pacients anamnezSi aReniSneba gulyra 6. pacients aqvs hiperkalcemiis istoria 6. pacients aqvs hiperkalcemiis istoria 7. pacients aqvs hiperparaTireoidizmis istoria7. pacients aqvs hiperparaTireoidizmis istoria8. pacients aqvs sarkoidozis istoria 8. pacients aqvs sarkoidozis istoria 9. pacients aqvs nefroliTiazis istoria9. pacients aqvs nefroliTiazis istoria10. pacienti ukanaskneli 30 dRis ganmavlobaSi iRebda kortikosteroidebs10. pacienti ukanaskneli 30 dRis ganmavlobaSi iRebda kortikosteroidebs11. pacienti mimdinare momentSi iRebs citotoqsiur an imunosupresiul 11. pacienti mimdinare momentSi iRebs citotoqsiur an imunosupresiul

wamlebswamlebs12. pacienti saWiroebs dializur Terapias 12. pacienti saWiroebs dializur Terapias 13. pacients aqvs cirozis istoria 13. pacients aqvs cirozis istoria 14. pacienti mimdinare momentSi aris patimrobaSi 14. pacienti mimdinare momentSi aris patimrobaSi

15. pacients ar surs an ar SeuZlia Seasrulos yvela viziti 15. pacients ar surs an ar SeuZlia Seasrulos yvela viziti TbilisSiTbilisSiTu meore nawilSi romelime kiTxvaze aRiniSneba dadebiTi pasuxi, Tu meore nawilSi romelime kiTxvaze aRiniSneba dadebiTi pasuxi,

individi ar SeiZleba CaerTos kvlevaSiindividi ar SeiZleba CaerTos kvlevaSi

kvlevis algoriTmikvlevis algoriTmi

sabaziso informacia :sabaziso informacia :

_ kalciumi, _ kalciumi, D D vitamini ( 25(vitamini ( 25(OH)D OH)D vitamini vitamini ELIZA-sELIZA-s testiT) da testiT) da PTHPTH

_ naxvelSi nerwyvsa da sisxlSi _ naxvelSi nerwyvsa da sisxlSi LLLL-37 is donis gansazRvra -37 is donis gansazRvra ((ELIZAELIZA-s testiT)-s testiT) _ kanis biofsia _ kanis biofsia LLLL-37-is -37-is mRNAmRNA da proteinis eqspresiis da proteinis eqspresiis

gansazRvra ( emoris universitetSi gansazRvra ( emoris universitetSi RT- PCR - RT- PCR - is is gamoyenebiT)gamoyenebiT)

_ mikroskopia da kultura. _ mikroskopia da kultura.

monacemebi nutriciologiur statusze:monacemebi nutriciologiur statusze:

- sxeulis masis indeqsi (- sxeulis masis indeqsi (BMIBMI) ) - sxeulis Semadgenloba bioeleqtrul winaRobaze dayrdnobiT - sxeulis Semadgenloba bioeleqtrul winaRobaze dayrdnobiT

(raTa ganisazRvros sxeulis mWle da cximovani masa da (raTa ganisazRvros sxeulis mWle da cximovani masa da sxeulis siTxis Semcveloba) sxeulis siTxis Semcveloba)

- samdRiani kvebis kiTxvari, raTa Sefasdes pacientis mier - samdRiani kvebis kiTxvari, raTa Sefasdes pacientis mier moxmarebuli dRiuri energia, proteinebi, glutamini, vitamini moxmarebuli dRiuri energia, proteinebi, glutamini, vitamini D,D, vitamini vitamini A A, seleniumi da cinki., seleniumi da cinki.

infrastruqturis ganviTarebainfrastruqturis ganviTareba

Molecular Devices Microplate reader (96-well platereader)

Beckman Refrigerated Benchtop Centrifuge

Ultracold (-80C) freezer DSL bioelectrical impedance analyzers

(BIA machines; n=2) Tanita Digital scales (n=2) Dell labtop computer for web-based data

entry of CRFs into database ELISA kits and supplies for LL-37 and 25

OH vitamin D assays in Tbilisi Food models to facilitate food intake

record determinations