Malignant and non-malignant lung tissue areas are differentially populated by natural killer cells and regulatory T cells in non-small cell lung cancer.

Even though the lung represents a special immune compartment with the capacity of a high inflammatory response, ineffective anti-tumour immunity is common in lung-associated malignancies. We asked whether a differential composition of the immune cell infiltrate in malignant (MLTAs) and non-malignant lung tissue areas (N-MLTAs) exists and might potentially contribute to this effect. We performed a comparative analysis of immune cells residing in MLTAs and N-MLTAs of non-small cell lung cancer (NSCLC) patients. To this end, we used immunophenotyping and functional analyses on directly isolated immune cells and tissue arrays on archived paraffin-embedded specimens. A strong T cell infiltration was prominent in both tissue compartments whereas CD4(+)CD25(+)CD127(-) T regulatory cells were present in MLTAs only. Nonetheless, concurrent functional ex vivo T cell analyses revealed no significant difference between T cells of MLTA and N-MLTA, suggesting that tumour-infiltrating T cells were not functionally impaired. Interestingly, T cell infiltration was less pronounced in specimens with a high neutrophilic infiltrate. NK cell infiltration was strikingly heterogenous between MLTA and N-MLTA. While NK cells were almost absent in the malignant tissue regions, non-malignant counterparts were selectively populated by NK cells and those NK cells showed strong cytotoxic activity ex vivo. We report that malignant and non-malignant tissue areas in NSCLC are selectively infiltrated by certain immune cell types with NK cells being displaced from the tumour tissue. These phenomena have important implications for tumour immunology of NSCLC and should be considered for the development of future immunologic intervention therapies.

The maturation of the acetylcholine system in the dentate gyrus of gerbils (Meriones unguiculatus) is affected by epigenetic factors.

The current study investigated the influence of impoverished rearing (IR) conditions and a single early methamphetamine challenge (MA; 50 mg/kg i.p.) on day 14 on the postnatal maturation of acetylcholinesterase-positive (AChE+) fibres in the hippocampal dentate gyrus (DG) of gerbils (Meriones unguiculatus). The layer-specific densities of histochemically stained AChE+ fibres were quantified in two planes of the left and right DG in young adults (day 90). Compared to enriched reared (ER) animals, the AChE+ fibre densities turned out to be higher in both the septal and the temporal plane of both hemispheres in saline treated IR and MA treated ER gerbils. The temporal plane was slightly more affected than the septal plane. In IR animals, MA treatment selectively diminished the AChE+ fibre densities in the subgranular layer of both left and right temporal DG. In conclusion, the maturation of AChE+ fibres is vulnerable to both rearing conditions and early MA challenge. The results correlate with our previous studies on the dentate cell proliferation rates and the serotonergic innervation, two parameters which are similarly affected by the experimental design. Thus, disturbances of the ACh system may impair the hippocampal plasticity and hippocampus-related cognitive and emotional function.

Developmentally induced imbalance of dopaminergic fibre densities in limbic brain regions of gerbils ( Meriones unguiculatus).

It is well established that epigenetic factors influence the maturation of neurotransmitter systems. Social isolation as well as an early intervention with methamphetamine (MA) lead to a diminished maturation of dopaminergic (DA) fibres in cortical and striatal areas in the brain of Mongolian gerbils. The aim of this study was to prove whether isolated rearing (IR) and the application of a single dose of MA on postnatal day 14 affect the maturation of DA fibres in caudal limbic areas. Therefore the DA fibre densities were quantified in the dorsolateral and ventrolateral entorhinal cortex (EC), the ventral subiculum (SUB) and in three amygdala nuclei - the basolateral (BLA), the lateral (LA) and the central (CA) nucleus. Our results showed that IR and an early MA application led to an increase of DA fibre densities in various caudal limbic areas. Whereas the BLA was affected by both IR and MA, the LA and the medial left CA were only influenced by MA in IR animals. The DA fibre surplus in the ventrolateral EC was significant in MA treated ER and IR animals in the left and right hemisphere, respectively. The SUB and the dorsolateral EC remained unaffected by both epigenetic factors. Altogether, the BLA seems to be the area which responds most sensitively to IR and MA. Previous studies in our laboratory showed a suppressive maturation of DA fibres in the prefrontal cortex (PFC) and nucleus accumbens (NAC) induced by the same set of epigenetic factors. Thus, due to the close functional connection between the PFC and limbic areas, it could be assumed that the suppressive maturation of prefrontal DA fibres implicates an enhancement of DA innervation densities in caudal limbic areas. Imbalances in the morphology and physiology of the different DA projections are suggested here to be crucial in the aetiology of schizophrenia.

Epigenetic factors differentially influence postnatal maturation of serotonin (5-HT) innervation in cerebral cortex of gerbils: interaction of rearing conditions and early methamphetamine challenge.

The effects of disjunctive environmental deprivation combined with a single methamphetamine (MA) challenge on postnatal maturation of the serotonin (5-HT) innervation pattern in cerebral cortex of gerbils were studied. Gerbils were assigned to either enriched (ER) or impoverished (IR) environmental rearing conditions. On postnatal day 110, 5-HT was immunostained. The 5-HT innervation pattern of the brain was qualitatively evaluated and provided in graphic form. The densities of 5-HT fibres were quantified in areas of prefrontal, insular, frontal, parietal, and entorhinal cortices of the right hemisphere using digital image analysis. The early MA challenge led to an overshoot of the fibre density in medial and orbital prefrontal cortex and entorhinal cortex of ER animals. IR animals mostly resisted MA effects except of a restraint of the innervation of the insular cortex. In comparison to enriched rearing, restricted rearing caused overshoot maturation of 5-HT innervation in insular and entorhinal cortices. The present data provide evidence for a region-specific postnatal vulnerability of the maturing 5-HT innervation, namely in association cortices. In contrast, both sensory and motor cortices showed no significant changes at all. The results are discussed in context with previously presented findings of alterations of the cortical dopamine innervation depending on both epigenetic factors. In conclusion, both experimental variables together give new insight into raphe-cortical plasticity that may contribute to a better understanding of the role of 5-HT fibre systems in structural maturation of the cortex. Postnatal environment may be involved in individual vulnerability of a variety of mental disorders during adolescence and aging.

Differential influence of rearing conditions and methamphetamine on serotonin fibre maturation in the dentate gyrus of gerbils (Meriones unguiculatus).

Environmental experience and drugs are two parameters that affect the maturation of neurotransmitter systems. The influence of impoverished rearing (IR) versus enriched rearing (ER) was compared in conjunction with postnatal methamphetamine (MA) treatment. The densities of immunostained 5-HT fibres were quantified in septal and temporal regions of the hippocampal dentate gyrus (DG) in young adult gerbils. In the IR group, 5-HT fibre densities were significantly increased in the molecular, granular and polymorphic layers of the DG in the temporal plane. After postnatal MA treatment, the 5-HT fibre density in the ER group reached a level equivalent to that of the IR group in nearly all respects. Under IR conditions, the pharmacological intervention significantly increased the maturation of fibre densities in septal layers only in the right hemisphere with no significant alterations in the left hemisphere and in temporal regions of either hemisphere. According to our previous studies on hippocampal neurogenesis, adaptations of 5-HT fibre densities partly proved to be positively correlated to cell proliferation rates for each of the specific conditions. Thus, the induced MA sensitivity, caused by pharmacological intervention at day 14, was manifested as direct interaction of 5-HT fibre maturation and cell proliferation in dependence of environmental factors. Both IR and MA together give us a better understanding of raphe-hippocampal plasticity and offer new perspectives for pharmacological studies on the 5-HT participation in mental disorders.