Specific immunotherapy by the sublingual route for respiratory allergy

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes

The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome

The maturation of excitatory transmission comes about through a developmental period in which dendritic spines are highly motile and their number, form and size are rapidly changing. Surprisingly, although these processes are crucial for the formation of cortical circuitry, little is known about possible alterations of these processes in brain disease. By means of acute in vivo 2-photon imaging we show that the dynamic properties of dendritic spines of layer V cortical neurons are deeply affected in a mouse model of Rett syndrome (RTT) at a time around P25 when the neuronal phenotype of the disease is still mild. Then, we show that 24h after a subcutaneous injection of IGF-1 spine dynamics is restored. Our study demonstrates that spine dynamics in RTT mice is severely impaired early during development and suggest that treatments for RTT should be started very early in order to reestablish a normal period of spine plasticity

Insulin-like growth factor I treatment for cerebellar ataxia: Addressing a common pathway in the pathological cascade?

Although development of transgenic animals overexpressing insulin-like growth factor-I has allowed the establishment of a role of this trophic factor in brain growth, detailed knowledge of the action of insulin-like growth factor-I on different brain areas is still lacking. We now provide evidence for a pleiotrophic role of this growth factor on cerebellar development. Insulin-like growth factor-I produced by cerebellar cultures is a survival factor for Purkinje cells and a mitogen/differentiation factor for cerebellar glioblasts. Trophic effects of insulin-like growth factor-I were observed only during specific developmental stages. In addition, insulin- like growth factor-I increased intracellular Ca2+ levels in Purkinje cells and c-Fos in dividing glioblasts. Survival-promoting effects of insulin-like growth factor-I on Purkinje cells required activation of protein kinase C, while glioblast division induced by insulin-like growth factor-I depended on phosphatidylinosytol 3-kinase activation. We conclude that insulin-like growth factor-I is a paracrine/autotrine pleiotrophic factor for both gila and neurons in the cerebellum. Its effects are mediated by distinct intracellular signals and appear to be specific to the developmental stage of the target cell. Since development of the different cell populations that compose a specific brain territory is not synchronized, the pleiotrophic action of growth factors such as insulin-like growth factor-I may he essential to ontogenetic processes underlying normal brain growth.Peer Reviewe

Insulin-like growth factor I is an afferent trophic signal that modulates calbindin-28kD in adult Purkinje cells

Recent evidence suggests that Purkinje cells are specific targets of insulin-like growth factor I (IGF-I) through their entire life span. During development, Purkinje cell numbers and their calbindin-28kD content increase after IGF-I treatment in culture. In the adult, part of the IGF-I present in the cerebellum is transported from the inferior olive, and modulates Purkinje cell function. We investigated whether IGF-I produced by inferior olive neurons and transported to the contralateral cerebellum through climbing fibers may modulate the levels of calbindin-28kD in the cerebellum of adult animals. Twenty-four hr after injection of an antisense oligonucleotide of IGF-I into the inferior olive, both IGF-I and calbindin-28kD levels in the contralateral cerebellar lobe were significantly reduced, while the number of calbindin-positive Purkinje cells was unchanged. The effect of the antisense on IGF-I levels was fully reversed 3 days after its injection into the inferior olive, with a postinhibitory rebound observed at this time, while calbindin-28kD levels slowly returned to control values. A control oligonucleotide did not produce any change in either IGF-I or calbindin-28kD content in the cerebellum. These results indicate that normal levels of IGF- I in the inferior olive are necessary to maintain appropriate levels of IGF- I in the cerebellum and of calbindin-28kD in the Purkinje cell. These results also extend our previous findings on the existence of an olivo-cerebellar IGF-I-containing pathway with trophic influence on the adult Purkinje cell.Peer Reviewe

Orthograde transport and release of insulin-like growth factor I from the inferior olive to the cerebellum

Insulin-like growth factor I (IGF-I) and its receptor are expressed in functionally related areas of the rat brain such as the inferior olive and the cerebellar cortex. A marked decrease of IGF-I levels in cerebellum is found when inferior olive neurons are lesioned. In addition, Purkinje cells in the cerebellar cortex depend on this growth factor to survive and differentiate in vitro. Thus, we consider it possible that IGF-I forms part of a putative trophic circuitry encompassing the inferior olive and the cerebellar cortex and possibly other functionally connected areas. To test this hypothesis we have studied whether IGF-I may be taken up, transported, and released from the inferior olive to the cerebellum. We have found that 125I-IGF-I is taken up by inferior olive neurons in a receptor-mediated process and orthogradely transported to the cerebellum. Thus, radioactivity found in the cerebellar lobe contralateral to the injection site in the inferior olive was immunoprecipitated by an anti-IGF-I antibody, co-eluted with 125I-IGF-I in an HPLC column, and co-migrated with 125I-IGF-I in an SDS-urea polyacrylamide gel electrophoresis. Time-course studies indicated that orthograde axonal transport is relatively rapid since 30 min after the injection, radiolabeled IGF-I was already detected in the contralateral cerebellum. Furthermore, transport of IGF-I from the inferior olive is specific since when 125I-neurotensin was injected in the inferior olive or when 125I-IGF-I was injected in the pontine nucleus, no radiactivity was found in the contralateral cerebellum. In addition, no specific transport of 125I-IGF-I was found in climbing fiber-deafferented rats or when excess unlabeled IGF-I was co-injected with 125I-IGF-I. We next studied whether IGF-I is released by inferior olive neurons. We found that the release of IGF-I from cerebellar slices of normal rats was significantly greater in response to depolarizing stimuli than that from slices obtained of climbing fiber-deafferented animals. Indeed, in vitro release of IGF-I in response to KCl or veratridine was almost completely abolished in the latter. These data suggest that IGF-I is taken up by inferior olive neurons through IGF-I receptors and transported to the cerebellum through their axons without any major modification. Moreover, the release of IGF-I from the cerebellum after depolarization depends on the presence of climbing fiber afferents. Altogether these results indicate that the olivo-cerebellar pathway is able to take up, orthogradely transport, and release IGF-I. Since a similar process has been described in the visual system for basic fibroblast growth factor (bFGF), we propose that IGF-I, bFGF, and possibly other growth factors may constitute afferent trophic signals involved in plastic mechanisms within specific neural circuitries.Peer Reviewe

Transynaptic modulation by insulin-like growth factor I of dendritic spines in Purkinje cells

Purkinje cells synthesize insulin-like growth factor I and express insulin-like growth factor I receptors during their entire life. An additional source of insulin-like growth factor I for these cells is provided by climbing fiber afferents originating in the inferior olive nucleus. Recently we found that insulin-like growth factor I from the inferior olive is necessary for motor learning processes probably involving Purkinje cell synaptic plasticity. We now studied whether inferior olive insulin-like growth factor I influences the synaptic structure of Purkinje cells, because changes in synaptic morphology are related to neuronal plasticity events. We injected an insulin-like growth factor I antisense in the inferior olive of adult rats, a procedure which we previously found to elicit a significant and reversible decrease of insulin-like growth factor I levels in the contralateral cerebellum. Ultrastructural analysis of the cerebellar cortex of these animals showed a significant reduction in the size of dendritic spines on Purkinje cells of antisense-treated rats compared to controls. The decrease in spine size was linked to a diminished numerical density of dendritic spines on Purkinje cells, without affecting the numerical density of synapses in the molecular layer of the cerebellum. This reduction was not due to a change in the thickness of the molecular layer. Climbing or parallel fiber terminals were also unaffected. Taken together with previous findings, these results support a role for insulin-like growth factor I produced in the inferior olive in the maintenance of Purkinje cell synaptic plasticity.Peer Reviewe