Uloga hormona jajnika u involuciji timusa pacova
Role of ovarian hormones in thymic involution in rats
Doktorand
Perišić, Milica M.Mentor
Leposavić, GordanaČlanovi komisije
Leposavić, GordanaBožić, Biljana
Božić, Biljana
Vučević, Dragana
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Timus je primarni limfoidni organ koji obezbeđuje mikrosredinu neophodnu za
diferencijaciju/sazrevanje T-limfocita. Tokom ontogeneze, ovaj organ trpi značajne
strukturne i funkcionalne promene koje se zbirno označavaju kao involucija timusa, i
manifestuju se kao smanjena efikasnosti timopoeze i posledično, smanjen izlazak
novoformiranih T-limfocita na periferiju. Involucija timusa je kod glodara najizraženija
u periodu sticanja polne zrelosti. Veliki broj literaturnih podataka ukazuje na to da
hormoni hipotalamo-hipofizo-gonadne (H-H-G) osovine, pre svega hormoni gonada,
utiču na razvoj i involuciju timusa. Međutim, uprkos brojnim istraživanjima u proteklim
decenijama, uloga hormona jajnika u inicijaciji i održavanju/progresiji involucije timusa
nije do kraja rasvetljena. Cilj ove doktorske disertacije je bio da se ispita uloga hormona jajnika u
inicijaciji i održavanju/progresiji involucije timusa. U tom cilju ispitivan je uticaj
jednokratnog davanja testosterona u kritičnom neonataln...om uzrastu, koji dovodi do
odlaganja sazrevanja H-H-G osovine i promena u obrascu sekrecije hormona jajnika
kod adultnih životinja (neonatalna androgenizacija) i uklanjanja jajnika ženkama pacova
u uzrastu od 10 meseci, kada su involutivne promene timusa jasno izražene, na građu
timusa i timopoezu u ranom adultnom uzrastu; odnosno u uzrastu od 11 meseci.
Posebno je ispitivan, mogući, indirektan uticaj promena u sekreciji hormona jajnika na
aktivnost timusnog kateholaminergičkog regulatornog sistema.
Neonatalna androgenizacija, delujući na različite stadijume
diferencijacije/sazrevanja T-ćelija, od ulaska/diferencijacije progenitorskih ćelija do
linijskog usmeravanja timocita, povećala je efikasnost timopoeze (na osnovu većeg
broja svežih timusnih emigranata u perifernoj krvi i slezini), uključujući, najverovatnije,
i povećano stvaranje ćelija regulatornog fenotipa (CD4+CD25+FoxP3+ i
CD161+TCRαβ+ ćelije). Pored toga, kod ovih životinja je uočeno favorizovano
stvaranje ćelija CD4-CD8+TCRαβ++ fenotipa (fenotipska
defeminizacija/maskulinizacija procesa timopoeze). Uprkos povećanoj efikasnosti
timopoeze, nepromenjena relativna zastupljenost timusnih epitelnih ćelija (TEC) kao i
nivo iRNK za IL-6, a smanjen nivo iRNK za IL-7 u tkivu timusa, ukazuju, da je kod neonatalno androgenizovanih životinja, u uzrastu od 3 meseca, najverovatnije, došlo do
pokretanja mehanizama negativne povratne sprege, koji ograničavaju ekspanziju TEC i
timopoezu.
Ovarijektomija u uzrastu od 10 meseci, nakon 30. dana, imala je za posledicu
povećanje relativne zastupljenosti TEC i efikasnosti timopoeze (uključujući i povećano
stvaranje ćelija regulatornog fenotipa), što se manifestovalo povećanim brojem svežih
timusnih emigranata CD4+ i CD8+ fenotipa u perifernoj krvi i slezini. Međutim, uprkos
regeneraciji epitelne komponente timusa i povećanoj efikasnosti timopoeze, smanjen
nivo iRNK za IL-6 i IL-7 u tkivu timusa ovarijektomisani životinja sugeriše da je kod
ovih životinja došlo do aktivacije intratimusnih mehanizama negativne povratne sprege
koji ograničava ekspanziju TEC koje sintetišu IL-6 i efikasnost timopoeze.
U zaključku, nalazi dobijeni u ovoj disertaciji ukazuju da neonatalna
androgenizacija menja kinetiku postnatalnog razvoja timusa i polno specifičan obrazac
diferencijacije/sazrevanja timocita i odlaže, ali vrlo verovatno ne sprečava involuciju
timusa, dok uklanjanje hormona jajnika u uzrastu kada su involutivne promene timusa
uznapredovale dovodi do delimične reverzije ovih promena i efikasnije timopoeze, koji
su, najverovatnije, vremenski ograničenog trajanja. Pored toga, pokazano je da se uticaj
hormona jajnika na ove procese odvija i indirektno, menjanjem efikasnosti
modulatornog delovanja noradrenalina na timopoezu.
The thymus is a primary lymphoid organ that provides the microenvironment
necessary for the differentiation/maturation of T-lymphocytes. During ontogeny,
thymus undergoes significant structural and functional changes leading to reduced
efficiency of thymopoiesis and, consequently, reduced output of newly generated Tlymphocytes.
These changes are collectively referred to as thymic involution. The most
profound thymic changes in rodents, occur around puberty. There is an accumulating
body of evidence indicating that hormones of the hypothalamic-pituitary-gonadal (H-PG)
axis, particularly gonadal hormones, influence thymic development and involution.
However, despite extensive research in the past decades, the role of ovarian hormones
in the initiation and maintenance/progression of thymic involution is not fully
understood. Bearing all aforementioned in mind, this dissertation was aimed to elucidate the
role of ovarian hormones in initiation and maintenance/progression of thymic
involuti...on. To this end the effects of single injection of testosterone in critical postnatal
period, which postpones H-P-G axis maturation and affects the gender-specific pattern
of gonadal hormone secretion in adult animals (neonatal androgenization), and ovarian
hormone removal in rats with advanced thymic involutive changes (10-month-old), on
thymic structure and function, were examined in 3-month-old and 11-month-old female
rats, respectively. In addition, the putative indirect, catecholamine-mediated effects of
the neonatal androgenization and ovariectomy on thymopoiesis were explored.
Neonatal androgenization, affecting distinct stages of thymocyte
differentiation/maturation (from progenitor cell entry and differentiation to thymocyte
lineage commitment), increased the efficiency of thymopoiesis and consequently
thymic output (as evidenced by the increased number of recent thymic emigrants in
peripheral blood and spleen), including, most likely, increased output of the cells with
regulatory phenotype (CD4+CD25+FoxP3+ and CD161+TCRαβ+ cells). In addition,
neonatal treatment with testosterone skewed thymocyte lineage commitment towards
CD4-CD8+TCRαβ++ cells (phenotypic defeminization/masculinization of
thymopoiesis). Despite the increased efficiency of thymopoiesis, unaltered relative abundance of thymic epithelial cells (TEC) and the thymic level of IL-6 mRNA, and
reduced thymic level of IL-7 mRNA, indicated, most likely, activation of intrathymic
negative feedback mechanisms limiting TEC proliferation and thymopoiesis in 3-
month-old neonatally androgenized rats.
Ovariectomy at the age of 10 months led to the expansion of TECs and greater
efficiency of thymopoiesis (including generation of cells with regulatory phenotype),
increasing the number of both CD4+ and CD8+ recent thymic emigrants in peripheral
blood and spleen of 11-month-old rats, compared with age-matched controls. However,
despite the regeneration of the thymic epithelial component and increased efficiency of
thymopoiesis, reduced thymic levels of mRNA for IL-6 and IL-7 in ovariectomized rats
indicated activation of intrathymic negative feedback mechanisms limiting the
expansion of IL-6-synthesizing TECs and thymopoietic efficiency in these animals.
In conclusion, the data obtained in this dissertation indicate that neonatal
androgenization alters the kinetics of postnatal thymic development and sex-specific
pattern of thymocyte differentiation/maturation and postpones thymic involution, but,
most likely, does not prevent it completely. The removal of ovarian hormones in female
rats with advanced thymic involutive changes leads to partial reversion of these
changes, and an increase in thymopoietic efficiency of, most likely, limited duration. In
addition, these data indicate that ovarian hormones might affect thymic development/involution not only directly, but also indirectly by diminishing the
efficiency of noradrenaline-mediated modulation of thymopoiesis.
Fakultet:
Универзитет у Београду, Биолошки факултетDatum odbrane:
28-09-2012Projekti:
- Plastičnost imunskog sistema tokom starenja: imunomodulatorni potencijal estrogena (RS-MESTD-Basic Research (BR or ON)-175050)