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Birthweight and adult disease: supporting evidence from the United States
A.6
Placenta (1996), Vol. 17
Birthweight and Adult Disease:Supporting Evidencefrom the United States. J. Rich-Edwards, Department of Medicine, Harvard Medical School, Cambridge, MA, U.S.A.
Immunoregulation by cytokines of T cell subsets. T.R. Mosmann, S. Sad, L. Li, *D. Kagi, “H. Hengartner, R.C. Bleackley, L. Krishnan, M. Belosevic and L.J. Guilbert, Univ. of Alberta, Edmonton, *Ontario Cancer Institute, Toronto, “Univ of Zurich, Switzerland
The work of David Barker and colleagues linking fetal and infant growth to adult disease has been controversial, in part due to lack of control for potentially confounding factors associated with socioeconomic status. Our research group sought to replicate these findings in three large follow-up cohorts that together comprise over 250,000 US. female and male health professionals. Extensive information on adolescent and adult health behaviors has been collected on these cohorts for as long as 20 years. Despite control for childhood socioeconomic status as well as adult socioeconomic status, diet and health behaviors, we have observed associations between birthweight and adult disease that are similar to those reported by Barker et al. These include inverse associations between birth-weight and hypertension, non-insulin dependent diabetes and non-fatal cardiovascular disease. We have also observed a direct association between birthweight and breast cancer. While these data suggest that the association between fetal growth and adult disease is real, they do not indicate whether the cause is environmental or genetic in origin.
In addition to the Thl and Th2 subsets that are major regulatorsof immune responses,there is considerable further diversity in T cell cytokine patterns. Additional T cell cytokine patterns exist, and non-T cells can also be major sourcesof ‘Thl’ or ‘Th2’ cytokines during immune responses. These cytokines can vary in different locations, and can change rapidly as an immune responseprogresses. CD8 T cells also express either Thl-like (Tel) or ThZ-like (Tc2) cytokines. Both Tel and Tc2 cells are highly cytotoxic via perforin and Faspathways. Both kill B cells, and so do not provide cognate help, although Tc2 cells provide bystander help. Thl and Tel (but not Th2) cells induce DTH, and Thl cytokines are associatedwith DTH in vivo. Surprisingly, Tc2 cells also mediate DTH, although they continue to express Th2 cytokines in vivo. Both Tel and Tc2 cells induce edema and infiltration of neutrophils, eosinophils and macrophages. Cytotoxicity is not absolutely required for induction of DTH by Tc2 cells. C&-mediated responsesare selectivelysuppressed during pregnancy,possibiy becauseThl cytokinesh-armthe nlacenta.whereasthe Th2 cvtokine IL10 is nrotective. The strong Thl response agaiist Leishmania major increases fetal resorption and placental IFNy. Implantations are reduced during Thl but not Th2 responses against L. major. Conversely, pregnancy impairs the anti-l. major IFNy response, and leads to parasitepersistence. Overall, these results support a model of selective and mutual inhibition of Thl responsesand pregnancy.
The Effect of Granulocy&-Macrophage Factor (GM-CSF) gene knockout
Macrophuges:
Colony on pregnancy
Stimulating in mice.
S.A. Robertsonand R.F. Seamark, Department of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia. GM-CSF has been identified as a potentially important mediator of intercellular communication in the female reproductive tract, with principal targets being uterine myeloid leukocytes, and trophoblast cells of the developing placenta. To investigate the physiological significance of this cytokine, the fertility of genetically GM-CSF-deficient (GM-/-) mice has been examined. Implantation rates were normal in GM-/- mice and viable pups were produced, suggesting either that GM-CSF does not have a critical role in pregnancy, or that other cytokines can compensate for its absence. However, the mean litter sizes of GM-/- x GM-Ibreeding pairs were 25% smaller at weaning than those of GM+Ix GM+/- pairs, with a disproportionate loss of male pups. This
effect wasnot apparentwhen GM-/- damswerematedwith GM+/+ studs. On day 17 of pregnancy, the number of resorbing and malformed fetuses was higher in GM-/- dams mated with GM-/- studs (21%) or GM+/- studs (1 S%), but was similar to control rates in GM-/- dams mated with GM+/+ studs (10%). Fetal weights and fetal:placental weight ratios were reduced in GM-/- dams mated with GM-/- or GM+/- studs, and when PCR was used to genotype the embryonictissue, GM-/- fetuses were smaller than GM+/- fetuses. Thus a progressive loss of fetal viability occurs during the second half of gestation and perinatally in the absence of maternal GM-CSF, with the detrimental effects being most evident when the conceptus is concomitantly GM-CSF deficient. These findings indicate that maternal and / or fetal GM-CSF is required for optimal growth and survival of the murine fetus.
L
A
liophic
Roles
in Reproduction.
P. E. Cohen, L. Zhu and J.W. Pollard. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461. Mice homozygous for the null mutation, csfmop, lack the mononuclear phagocyte growth factor, colony stimulating factor-l (CSF-1 ), and consequently have severely depleted macrophage numbers. Analysis of these mice revealed unexpected r8les for CSF-I in gonadal function, characterized by a perturbation of steroidogenesis and a signif’icantlyreduced production of gametesas compared to wild type mice. In the gonads the major site of action of CSF-1 is on macrophages suggestingthat CSF-1 exerts its action on gonadal function through trophic factors synthesizedby macrophages.
Placenta (1996), Vol. 17
Birthweight and Adult Disease:Supporting Evidencefrom the United States. J. Rich-Edwards, Department of Medicine, Harvard Medical School, Cambridge, MA, U.S.A.
Immunoregulation by cytokines of T cell subsets. T.R. Mosmann, S. Sad, L. Li, *D. Kagi, “H. Hengartner, R.C. Bleackley, L. Krishnan, M. Belosevic and L.J. Guilbert, Univ. of Alberta, Edmonton, *Ontario Cancer Institute, Toronto, “Univ of Zurich, Switzerland
The work of David Barker and colleagues linking fetal and infant growth to adult disease has been controversial, in part due to lack of control for potentially confounding factors associated with socioeconomic status. Our research group sought to replicate these findings in three large follow-up cohorts that together comprise over 250,000 US. female and male health professionals. Extensive information on adolescent and adult health behaviors has been collected on these cohorts for as long as 20 years. Despite control for childhood socioeconomic status as well as adult socioeconomic status, diet and health behaviors, we have observed associations between birthweight and adult disease that are similar to those reported by Barker et al. These include inverse associations between birth-weight and hypertension, non-insulin dependent diabetes and non-fatal cardiovascular disease. We have also observed a direct association between birthweight and breast cancer. While these data suggest that the association between fetal growth and adult disease is real, they do not indicate whether the cause is environmental or genetic in origin.
In addition to the Thl and Th2 subsets that are major regulatorsof immune responses,there is considerable further diversity in T cell cytokine patterns. Additional T cell cytokine patterns exist, and non-T cells can also be major sourcesof ‘Thl’ or ‘Th2’ cytokines during immune responses. These cytokines can vary in different locations, and can change rapidly as an immune responseprogresses. CD8 T cells also express either Thl-like (Tel) or ThZ-like (Tc2) cytokines. Both Tel and Tc2 cells are highly cytotoxic via perforin and Faspathways. Both kill B cells, and so do not provide cognate help, although Tc2 cells provide bystander help. Thl and Tel (but not Th2) cells induce DTH, and Thl cytokines are associatedwith DTH in vivo. Surprisingly, Tc2 cells also mediate DTH, although they continue to express Th2 cytokines in vivo. Both Tel and Tc2 cells induce edema and infiltration of neutrophils, eosinophils and macrophages. Cytotoxicity is not absolutely required for induction of DTH by Tc2 cells. C&-mediated responsesare selectivelysuppressed during pregnancy,possibiy becauseThl cytokinesh-armthe nlacenta.whereasthe Th2 cvtokine IL10 is nrotective. The strong Thl response agaiist Leishmania major increases fetal resorption and placental IFNy. Implantations are reduced during Thl but not Th2 responses against L. major. Conversely, pregnancy impairs the anti-l. major IFNy response, and leads to parasitepersistence. Overall, these results support a model of selective and mutual inhibition of Thl responsesand pregnancy.
The Effect of Granulocy&-Macrophage Factor (GM-CSF) gene knockout
Macrophuges:
Colony on pregnancy
Stimulating in mice.
S.A. Robertsonand R.F. Seamark, Department of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia. GM-CSF has been identified as a potentially important mediator of intercellular communication in the female reproductive tract, with principal targets being uterine myeloid leukocytes, and trophoblast cells of the developing placenta. To investigate the physiological significance of this cytokine, the fertility of genetically GM-CSF-deficient (GM-/-) mice has been examined. Implantation rates were normal in GM-/- mice and viable pups were produced, suggesting either that GM-CSF does not have a critical role in pregnancy, or that other cytokines can compensate for its absence. However, the mean litter sizes of GM-/- x GM-Ibreeding pairs were 25% smaller at weaning than those of GM+Ix GM+/- pairs, with a disproportionate loss of male pups. This
effect wasnot apparentwhen GM-/- damswerematedwith GM+/+ studs. On day 17 of pregnancy, the number of resorbing and malformed fetuses was higher in GM-/- dams mated with GM-/- studs (21%) or GM+/- studs (1 S%), but was similar to control rates in GM-/- dams mated with GM+/+ studs (10%). Fetal weights and fetal:placental weight ratios were reduced in GM-/- dams mated with GM-/- or GM+/- studs, and when PCR was used to genotype the embryonictissue, GM-/- fetuses were smaller than GM+/- fetuses. Thus a progressive loss of fetal viability occurs during the second half of gestation and perinatally in the absence of maternal GM-CSF, with the detrimental effects being most evident when the conceptus is concomitantly GM-CSF deficient. These findings indicate that maternal and / or fetal GM-CSF is required for optimal growth and survival of the murine fetus.
L
A
liophic
Roles
in Reproduction.
P. E. Cohen, L. Zhu and J.W. Pollard. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461. Mice homozygous for the null mutation, csfmop, lack the mononuclear phagocyte growth factor, colony stimulating factor-l (CSF-1 ), and consequently have severely depleted macrophage numbers. Analysis of these mice revealed unexpected r8les for CSF-I in gonadal function, characterized by a perturbation of steroidogenesis and a signif’icantlyreduced production of gametesas compared to wild type mice. In the gonads the major site of action of CSF-1 is on macrophages suggestingthat CSF-1 exerts its action on gonadal function through trophic factors synthesizedby macrophages.