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Fetal and neonatal environment has influence on brain development
Gene therapy blocked by strong immune response A
promising
approach
gene
therapy
has been found to elicit a strong immune response that quickly eliminates gene-modified cells, which suggests that it may be much more difficult than previously realised to develop effective genetic therapies (Riddell et al Nature Medicine 1996; 2: 216-23). The paper comes out of a clinical trial in Seattle to determine whether infusions of autologous CD8 HIV-
specific cytotoxic (CTLs), genetically
T
lymphocytes
modified with a retrovirus vector that transduces a double gene, can bolster an HIVinfected patient’s immune response to the virus. The first gene is a marker gene encoding for hygro-
mycin phosphotransferase (Hy). The second is a suicide gene encoding for herpes virus thymidine kinase (TK).Viral TK in the modified cells allows for their quick elimination with ganciclovir should toxicity develop during treatment. In previous studies with retrovirus vectors, gene-modified cells were found to persist for some time without inducing host immunity, but it is clear whether these cells were expressing the proteins encoded by the transduced genes. In addition, patients in those studies were not
view that finding the gene is all that is necessary to eradicate important conditions such as schizophrenia or pre-eclampsia is pervasive. The three-day Nobel Symposium in Stockholm on Jan 22-24 entitled "Genetic versus environmental determination of human behaviour and health" evaluated the respective roles of genes and environment as regulators of development. Influences on brain development was a recurrent theme at the meeting. Impulse activity within developing nerve cells increases nerve growth factor and brain-derived growth factor mRNA in the brain. Thus activity of the developing brain induced by intrauterine environmental stimuli modifies development of neurons. These stimuli include circulating growth factors such as insulin-like growth factors, whose production is regulated by metabolite availability to the fetus.
Long-term potentiation (LTP) produced by repeated stimulation of nerve cells at high frequencies produces cell excitability changes that last for minutes to hours. When rat brain cells are stimulated in vivo to develop LTP and then placed in vitro 40 min later, more spine-tospine connections can be observed between nerve cells. Thus LTP constitutes another mechanism by which environmentally altered fetal neural activity can modify neurons and brain circuits. Dr Bruce McEwen from the Rockefeller University, New York,
314
"there was effective transfer and persistence of HyTK-modified CTLs after the first two infusions but rapid clearance after the third and fourth infusions. Further study found that these patients had developed cytolytic reactivity for HyTK-transduced cells. The magnitude of the CTL response elicited to Hy and TK was "substantial". The findings suggest that strategies to render genemodified cells less susceptible to host immune surveillance will be
severely immunosuppressed. In the Seattle study, six HIVseropositive patients were infused
required.
with the modified CD8 CTLs in
Michael McCarthy
Fetal and neonatal environment has influence
The responsible
escalating doses given fortnightly. In five of the six patients four
focused attention on how adrenal and sex steroids and thyroxine can permanently modify brain structure and function. When newborn female rats are given a single dose of an androgen in the first 5 days of life, on reaching puberty their ovaries are full of growing follicles, but their brains do not deliver the cyclic ovulatory surge of hormones. If the androgen is given a little later in life, say around 20 days after birth, there is no permanent effect. In the case of glucocorticoids rats exposed to high concentrations before birth respond to stress in later life by increased glucocorticoid secretion. Perinatal brain exposure to excessive amounts of glucocorticoid leads to premature brain ageing. By contrast, postnatal stress decreases both later stress reactivity and ageing, probably through secretion of thyroxine. After steroid administration, structural changes can be seen in the large hippocampal pyramidal cells. The hippocampus plays a central role in memory and learning. Monkey studies show that subordinate animals subjected to the stress of forced companionship with domi-
monkeys rapidly lose hippocampal neurons, which raises questions relating to consequences of developmental stress in utero and chronic therapy with glucocorticoids. Robin Murray presented convincing data to suggest that prenatal factors have a role in the aetiology of schizophrenia. Head circumference at birth is significantly smaller in individuals who will develop schizonant
on
brain
development
In one set of twin newborn babies with signs of cerebral damage the baby with the lesser total amount of damage was the baby who developed schizophrenia; however, the corpus callosum of the twin who became schizophrenic was affected. Does early diet also programme neurodevelopment? In a randomised multicentre study by the MRC Dunn Nutrition Unit and the University of Cambridge department of paediatrics, human or formula milk was given by intragastric tube to preterm human infants, whose mental and
phrenia.
psychomotor
development
was
assessed at 18 months of age. Those fed unsupplemented donor milk for the first few weeks of life were more advanced in their development than those fed standard term formula. Surprisingly, although breast milk contained fewer calories and nutrients than did enriched preterm formula, babies fed breast milk did as well as babies on the enriched formula. Breast milk may therefore contain factors that ameliorate any disadvantage resulting from its lower nutrient content. It is fitting that these issues were discussed at the Karolinska Institute to celebrate the 150th anniversary of the appointment of the first professor of paediatrics in the world, Fredrik Theodor Berg. The meeting played a critical part in furthering the new concepts that have arisen to challenge entrenched ideas of the origins of health and disease. Peter W Nathanielsz
promising
approach
gene
therapy
has been found to elicit a strong immune response that quickly eliminates gene-modified cells, which suggests that it may be much more difficult than previously realised to develop effective genetic therapies (Riddell et al Nature Medicine 1996; 2: 216-23). The paper comes out of a clinical trial in Seattle to determine whether infusions of autologous CD8 HIV-
specific cytotoxic (CTLs), genetically
T
lymphocytes
modified with a retrovirus vector that transduces a double gene, can bolster an HIVinfected patient’s immune response to the virus. The first gene is a marker gene encoding for hygro-
mycin phosphotransferase (Hy). The second is a suicide gene encoding for herpes virus thymidine kinase (TK).Viral TK in the modified cells allows for their quick elimination with ganciclovir should toxicity develop during treatment. In previous studies with retrovirus vectors, gene-modified cells were found to persist for some time without inducing host immunity, but it is clear whether these cells were expressing the proteins encoded by the transduced genes. In addition, patients in those studies were not
view that finding the gene is all that is necessary to eradicate important conditions such as schizophrenia or pre-eclampsia is pervasive. The three-day Nobel Symposium in Stockholm on Jan 22-24 entitled "Genetic versus environmental determination of human behaviour and health" evaluated the respective roles of genes and environment as regulators of development. Influences on brain development was a recurrent theme at the meeting. Impulse activity within developing nerve cells increases nerve growth factor and brain-derived growth factor mRNA in the brain. Thus activity of the developing brain induced by intrauterine environmental stimuli modifies development of neurons. These stimuli include circulating growth factors such as insulin-like growth factors, whose production is regulated by metabolite availability to the fetus.
Long-term potentiation (LTP) produced by repeated stimulation of nerve cells at high frequencies produces cell excitability changes that last for minutes to hours. When rat brain cells are stimulated in vivo to develop LTP and then placed in vitro 40 min later, more spine-tospine connections can be observed between nerve cells. Thus LTP constitutes another mechanism by which environmentally altered fetal neural activity can modify neurons and brain circuits. Dr Bruce McEwen from the Rockefeller University, New York,
314
"there was effective transfer and persistence of HyTK-modified CTLs after the first two infusions but rapid clearance after the third and fourth infusions. Further study found that these patients had developed cytolytic reactivity for HyTK-transduced cells. The magnitude of the CTL response elicited to Hy and TK was "substantial". The findings suggest that strategies to render genemodified cells less susceptible to host immune surveillance will be
severely immunosuppressed. In the Seattle study, six HIVseropositive patients were infused
required.
with the modified CD8 CTLs in
Michael McCarthy
Fetal and neonatal environment has influence
The responsible
escalating doses given fortnightly. In five of the six patients four
focused attention on how adrenal and sex steroids and thyroxine can permanently modify brain structure and function. When newborn female rats are given a single dose of an androgen in the first 5 days of life, on reaching puberty their ovaries are full of growing follicles, but their brains do not deliver the cyclic ovulatory surge of hormones. If the androgen is given a little later in life, say around 20 days after birth, there is no permanent effect. In the case of glucocorticoids rats exposed to high concentrations before birth respond to stress in later life by increased glucocorticoid secretion. Perinatal brain exposure to excessive amounts of glucocorticoid leads to premature brain ageing. By contrast, postnatal stress decreases both later stress reactivity and ageing, probably through secretion of thyroxine. After steroid administration, structural changes can be seen in the large hippocampal pyramidal cells. The hippocampus plays a central role in memory and learning. Monkey studies show that subordinate animals subjected to the stress of forced companionship with domi-
monkeys rapidly lose hippocampal neurons, which raises questions relating to consequences of developmental stress in utero and chronic therapy with glucocorticoids. Robin Murray presented convincing data to suggest that prenatal factors have a role in the aetiology of schizophrenia. Head circumference at birth is significantly smaller in individuals who will develop schizonant
on
brain
development
In one set of twin newborn babies with signs of cerebral damage the baby with the lesser total amount of damage was the baby who developed schizophrenia; however, the corpus callosum of the twin who became schizophrenic was affected. Does early diet also programme neurodevelopment? In a randomised multicentre study by the MRC Dunn Nutrition Unit and the University of Cambridge department of paediatrics, human or formula milk was given by intragastric tube to preterm human infants, whose mental and
phrenia.
psychomotor
development
was
assessed at 18 months of age. Those fed unsupplemented donor milk for the first few weeks of life were more advanced in their development than those fed standard term formula. Surprisingly, although breast milk contained fewer calories and nutrients than did enriched preterm formula, babies fed breast milk did as well as babies on the enriched formula. Breast milk may therefore contain factors that ameliorate any disadvantage resulting from its lower nutrient content. It is fitting that these issues were discussed at the Karolinska Institute to celebrate the 150th anniversary of the appointment of the first professor of paediatrics in the world, Fredrik Theodor Berg. The meeting played a critical part in furthering the new concepts that have arisen to challenge entrenched ideas of the origins of health and disease. Peter W Nathanielsz