Role Of The Thymus In T Cell Homeostasis During Foetal And Postnatal Life In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool e ....The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. It follows that a mixing of the pool of older mature T cells with new ones just released from the thymus will introduce more variability, and hence greater adaptability into the immune system. We have developed techniques for labeling the thymus in vivo and the entire blood leukocyte pool in vivo using the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled cells and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and mature cells and their progeny together with their tissue homing properties and surface markers for periods of many months. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Changes In The Fate Of Thymic Emigrants During Foetal And Postnatal Development In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$62,744.00
Summary
SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a l ....SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. A high rate of continuous substitution of mature T cells in the peripheral pool with freshly arriving recent thymic emigrants exhibiting newly arising TCR not previously existing will produce higher adaptive capabilities for the immune system. We have developed techniques for labeling the thymus in vivo by intra-thymic injection with the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled recent thymic emigrants and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and their progeny together with their tissue homing properties and surface markers for periods of many months after they leave the thymus. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Differential Effects On Fetal Growth And Development Of Repeated Fetal Or Maternal Corticosteroid Treatments
Funder
National Health and Medical Research Council
Funding Amount
$356,849.00
Summary
Injections of synthetic hormones (corticosteroids) to women at risk of early preterm birth reduce the rate of respiratory illness and death in the newborn infant. It is standard clinical practice prior to early preterm birth to give corticosteroids by intramuscular injection to the mother. For many women, however, preterm birth does not occur as expected and it has become common practice to give repeated courses of corticosteroids to women in whom the risk of preterm delivery recurs or continues ....Injections of synthetic hormones (corticosteroids) to women at risk of early preterm birth reduce the rate of respiratory illness and death in the newborn infant. It is standard clinical practice prior to early preterm birth to give corticosteroids by intramuscular injection to the mother. For many women, however, preterm birth does not occur as expected and it has become common practice to give repeated courses of corticosteroids to women in whom the risk of preterm delivery recurs or continues. Using the sheep model, we have shown that repeated doses of corticosteroids, given intramuscularly to the mother, are of benefit to newborn lung function, but also reduce the rate of fetal growth and adversely affect brain development. Evidence from the Western Australian Preterm Infant Cohort Study suggests that birthweight in humans is similarly affected by repeated corticosteroids and is followed by behavioral disorders in childhood. Using sheep, we have shown that repeated injections of corticosteroids given directly to the fetus cause no reduction in birthweight although maturation is still enhanced. This finding of a differential effect of corticosteroids by different routes of administration raises several exciting opportunities and questions. First is the possibility that direct fetal treatment may be of use in humans, if current human trials show that repeated doses cause effects similar to those we have seen in sheep. Secondly, the finding challenges our current understanding of how an individual may be programmed for subsequent health or illness by prenatal events. The proposed study will attempt to explain why corticosteroids given to the mother, but not the fetus, restrict fetal growth. Our hypothesis is that these hormones, when given repeatedly to the mother, adversely affect the ability of the placenta to transfer essential nutrients to the fetus. We will test this hypothesis using pregnant sheep in which catheters have been implanted surgically.Read moreRead less