Imunski mehanizmi rezistencije imunokompetentnih jedinki Dark Agouti i Albino Oxford pacova na pulmonarnu infekciju izazvanu gljivom Aspergillus fumigatus Fresen
Immune mechanisms in resistance of immunocompetent Dark Agouti and Albino Oxford rats to pulmonary infection with fungi Aspergillus fumigatus Fresen
Doktorand
Mhfuod El-Muzghi, Amal AtiaMentor
Mirkov, IvanaČlanovi komisije
Kataranovski, MilenaGlamočlija, Jasmina
Mirkov, Ivana
Kataranovski, Milena
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Although rat models of pulmonary aspergillosis are used to same extent as
mouse models in exploring antifungal therapeutics, the understanding of immunology of
Aspergillus infection in rats is deficient. In this study pulmonary immune responses to
sublethal A. fumigatus infection were investigated in two rat strains, Albino Oxford
(AO) and Dark Agouti (DA), differently susceptible to some inflammatory diseases.
Slower elimination of fungus following intratracheal (i.t.) application of 107
conidia was noted in AO rats (by the day 21 post infection, compared to day 14 in DA
rats). In both rat strains elimination of fungi occurs in similar environment: enriched in
proinflammatory cytokines interferon-γ (IFN-γ) (level of IFN- γ was slightly higher in
infected DA rats at day 3 p.i.) and interleukin-17 (IL-17) and unchanged Th2/antiinflammatory
cytokines (IL-4 and IL-10). Although proinflammatory cytokines were
present at similar amount in lung tissue homogenates, in AO rats elimination of f...ungi
from lungs was associated with lower degree of lung leukocyte infiltration and their
basic effector activities (i.e. CD11b expression, adhesion, production of reactive oxygen
species, intracellular myeloperoxidase content). Generally, similar levels of effector
cell-stimulating proinflammatory cytokines IFN-γ and IL -17 production by lung
leukocytes during the entire post-infection period (except late in infection) were noted
in both strains. In contrast, production of IL-10 was found to be significantly higher in
AO rats. In draining lymph nodes (as sites of generation of cytokine-producing cells)
cells differentiate toward IFN-γ-producing cells (higher amount of this cytokine
detected in infected AO compared to DA rats), IL-17-producing cells (levels of cytokine
produced lower in AO compared to DA rats) and IL-10 producing cells (similar levels
in both strains). Unchanged (and even decreased antigen specific) IL-4 production was
noted as well. CD4+ cells differentiated in draining lymph nodes are the main source of
IFN-γ, IL-17 and IL-10. These cells following differentiation migrate to the lung tissue,
judging by increased number of CD4+ cells in lung tissue digest and BAL cells.The knowledge of mechanisms of defense against A. fumigatus in rats might be
helpful in the future use of rat models of pulmonary aspergillosis in developing and
testing immunotherapeutic interventions of fungal diseases.
Iako se pacovski model pulmonarne aspergiloze koristi podjednako kao i mišiji
modeli u ispitivanju antigljivičnih terapija, slabije su ispitane karakteristike imunskog
odgovora na infekciju izazvanu gljivom roda Aspergillus kod pacova. U ovom radu
ispitan je imunski odgovor u plućima na subletalnu infekciju izazvanu gljivom A.
fumigatus kod dva soja pacova, Albino Oxford (AO) i Dark Agouti (DA), za koje je
poznato da razvijaju kvalitativno različit odgovor u nekim inflamatornim oboljenjima.
Sporije uklanjanje gljive nakon intratrahealnog (i.t.) ubrizgavanja 107 konidija
zapaženo je kod jedinki AO soja (do 21. dana nakon infekcije u poređunju sa 14 dana
kod DA pacova). Kod oba soja uklanjanje gljive iz pluća se odigrava u sličnoj sredini:
povišeni nivoi proinflamatornih citokina interferona -γ (IFN-γ) (nivo IFN-γ je blago viši
kod inficiranih jedinki DA soja trećeg dana nakon infekcije) i interleukina-17 (IL-17)
dok je nivo Th2/antiinflamatornih citokina (IL-4 i IL-10) bio nepromenjen. ...Iako je
sadržaj proinflamatornih citokina u homogenatu pluća sličan kod oba soja, kod jedinki
AO soja uklanjanje gljive iz pluća je povezano sa manjim stepenom infiltracije
leukocita u tkivo i nižim osnovnim efektorskim aktivnostima ćelija (ekspresija CD11b
molekula, adhezija, produkcija reaktivnih vrsta kiseonika i aktivnost unutarćelijske
mijeloperoksidaze). Leukociti izolovani iz pluća jedinki oba soja produkovali su slične
količine citokina koji stimulišu efektorske aktivnosti ćelija, IFN-γ i IL-17, u toku
infekcije (izuzev u kasnijim terminima nakon infekcije). Nasuprot tome, količina
produkovanog IL-10 je bila značajno viša u kulturi leukocita pluća izolovanih iz jedinki
AO soja. U regionalnim limfnim čvorovima (mestima gde se nastaju ćelije koje
produkuju citokine) zapaža se diferencijacija ćelija u smeru produkcije IFN-γ (veće
količine u kulturi ćelija jedinki AO soja), IL-17 (niže količine kod jedinki AO soja) i IL-
10. Nepromenjena (smanjena antigen specifična) produkcija IL-4 je takođe zapažena.
CD4+ ćelije u regionalnom čvoru su glavni producenti IFN-γ, IL-17 i IL-10. Ove ćelije
nakon diferentovanja migriraju u pluća sudeći po povećanju broja CD4+ ćelija u digestu
pluća i bronholaveolarnom ispirku.
Poznavanje mehanizama odbrane u infekciji izazvanoj gljivom A. fumigatus kod pacova
može da doprinese upotrebi pacovskog modela pulmonarne aspergiloze u razvijanju i
testiranju novih terapeutskih modaliteta u tretmanu infekcija izazvanih gljivama.
Fakultet:
Универзитет у Београду, Биолошки факултетDatum odbrane:
21-07-2014Projekti:
- Imunomodulatorni efekti ksenobiotika i biotičkih faktora životne sredine na populacije mišolikih glodara (RS-173039)