Interleukin-1 and interleukin-1 antagonism.

Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions Here, we review these findings on the environmental modulators of pathogenesis and gene-environment interactions in CNS disorders, and discuss their therapeutic implications

Enriched environments, experience-dependent plasticity and disorders of the nervous system.

Publisher Summary It is known for some time that malignant transformation of human cells may be associated with the appearance of tumor associated antigens (TAA). Decades of research have been aimed at the identification of TAA that can serve as targets for the immunotherapy of malignant diseases. The dramatic progress in the understanding of molecular basis of target cell recognition by cytotoxic T lymphocytes (CTL) has provided the background to design effective strategies to identify TAA recognized by CTL on tumor cells. The extensive application of these strategies by a number of investigators has resulted in the identification of various families of TAA on various types of solid tumors. Mouse tumor models have played an important role in elucidating the mechanisms by which the immune system interacts with tumor cells and eradicates cancer. The second line of evidence is represented by the phenomenon of a “mixed response.” A mixed response occurs rather frequently in patients with metastases, although its actual frequency is not documented. Mixed responses are characterized by the different behavior of synchronous metastases in response to T cell-based immunotherapy. This important finding suggests that TAA-specific CTL may be present in some cancer patients but are unable to attack tumor cells due to the presence of inhibitory receptors.

Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance.

Can an abundantly expressed molecule be a reliable marker for the cancer-initiating cells (CICs; also known as cancer stem cells), which constitute the minority of cells within the mass of a tumour? CD44 has been implicated as a CIC marker in several malignancies of haematopoietic and epithelial origin. Is this a fortuitous coincidence owing to the widespread expression of the molecule or is CD44 expression advantageous as it fulfils some of the special properties that are displayed by CICs, such as self-renewal, niche preparation, epithelial-mesenchymal transition and resistance to apoptosis?

CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?

Advances in the fields of cognitive and affective developmental neuroscience, developmental psychopathology, neurobiology, genetics, and applied behavior analysis have contributed to a more optimistic outcome for individuals with autism spectrum disorder (ASD). These advances have led to new methods for early detection and more effective treatments. For the first time, prevention of ASD is plausible. Prevention will entail detecting infants at risk before the full syndrome is present and implementing treatments designed to alter the course of early behavioral and brain development. This article describes a developmental model of risk, risk processes, symptom emergence, and adaptation in ASD that offers a framework for understanding early brain plasticity in ASD and its role in prevention of the disorder.

Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder.

The importance of environment in the regulation of brain, behaviour and physiology has long been recognized in biological, social and medical sciences. Animals maintained under enriched conditions have clearly been shown to have better learning abilities than those maintained under standard conditions. However, the effects of environmental enrichment (EE) on immunity and emotionality have been less documented and remain questionable. Therefore, we investigated the effect of EE on natural killer (NK) cell activity, psychological stress responses and behavioural parameters. Male C3H mice were housed either in enriched or standard conditions for 6 weeks. Behaviour was then examined by the grip-strength test, staircase and elevated plus maze, and corticosterone levels and NK cell activity were measured. Furthermore, animals exposed to the stress paradigm, achieved by electric shock with reminders, were tested for freezing time in each reminder. Corticosterone levels were also measured. The EE mice showed decreased anxiety-like behaviour and higher activity compared to standard mice, as revealed by a greater percentage of time spent in the open arms of the elevated plus maze, and a higher rate of climbing the staircase. A shorter freezing time in the stress paradigm and no corticosterone level reactivity were measured in EE mice. In addition, NK cell activity in spleens of EE mice was higher than that demonstrated in those of standard mice. Thus, EE has a beneficial effect on anxiety-like behaviour, stress response and NK cell activity. The effect on NK cell activity is promising, due to the role of NK cells in host resistance.

Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity.

Two clones of the 3LL Lewis lung carcinoma, a low-metastatic clone A9 and a high-metastatic clone D122, were studied for MHC expression and immunogenic properties. Using monoclonal antibodies, we demonstrated that the A9 clone expresses both the H-2Kb and the H-2Db, whereas the D122 expresses only the H-2Db, and lacks the expression of the H-2Kb encoded molecules. Cells of the low-metastatic clone A9 grew progressively in syngeneic (C57BL/6J) or in F1 mice, but were rejected in allogeneic recipients. The high-metastatic D122 grew progressively in all mouse strains tested, yet metastases were formed only in syngeneic recipients. When H-2 recombinant mice were used, the A9 again manifested a significantly greater immunogenic potency than the metastatic D122, which grew in all 4 recombinants tested. Metastases, however, were formed in B10HTG and to a lesser extent in B10A(4R), thus indicating that metastasis formation is restricted by both C57BL background and H-2Db sub region. We subsequently tested whether the higher immunogenicity of the H-2Kb-positive A9 cells is expressed also in syngeneic mice, to examine whether this could account for its low metastatic phenotype. We found that immunization by A9 cells significantly inhibited the growth of a subsequent A9 graft and even of D122, yet D122 did not retard the growth of secondary D122 or A9 cells. The increased immunogenic effect was expressed also in the generation of syngeneic cytotoxic lymphocytes by A9 but not by D122 cells. We suggest that expression of H-2K molecules on the 3LL clones, immunogenicity and the metastatic phenotype are causally related in this system.

The differential expression of H-2K versus H-2D antigens, distinguishing high-metastatic from low-metastatic clones, is correlated with the immunogenic properties of the tumor cells.

Bispecific antibodies, in contrast to conventional monoclonal antibodies, can bind simultaneously two different antigens. Taking advantage of this virtue, they are mostly designed for immune effector cell redirection to tumors and for radionuclide pretargeting to tumors. Bispecific antibodies of the first generation were produced by chemical cross-linking or cell-fusion technologies. More recently, the application of genetic engineering technologies gave rise to numerous formats of bispecific antibody fragments and whole IgG molecules. Because bispecific antibodies enable therapeutic strategies that are not possible with conventional monoclonal antibodies, they attract strong interest. Several bispecific antibody formats have already shown clinical efficacy in cancer patients, catalyzing efforts to translate the imaginative bispecific antibody concepts into effective therapies.

Bispecific antibodies for cancer therapy

Mouse thymus-derived (T) lymphocytes are distinguished from other lymphoid cell populations by cell surface markers. Among these, the Lyt-1, Lyt-2, and Lyt3 antigens have been extensively characterized (Boyse et al. 1968, 1971, Itakura et al. 1972). T lymphocytes with different functions can be distinguished by their Lyt phenotype (Cantor & Boyse 1975a, Shiku et al. 1975). It has been widely accepted that helper T lymphocytes and delayed-type hypersensitivity effector cells express the Lyt 1*2̂ 3\" phenotype, whereas cytotoxic T lymphocytes (CTL) and suppressor cells express the Lyt r2*3* phenotype. Recent findings indicate that all T cells bear Lyt-1 antigens, and thus CTL, express the Lyt 1*2*3* phenotype (Shiku et al. 1976, Wettstein et al. 1979, Nakayama et al. 1979, Ledbetter et al. 1980). In spite of the disagreement regarding the absolute amounts of Lyt-1 and Lyt-2/3 on the cell surface, there is little doubt, that by using anti-Lyt antibodies and complement to deplete antigen-bearing cells, different T cell functional populations can be demonstrated.

Effects of anti-Lyt antibodies on T-cell functions.

Complement- and cell-mediated killing utilize related effector proteins (C8/C9 and perforin, respectively), suggesting that proteins which protect cells against complement- and cell-mediated attack may also be similar. In homologous complement-mediated killing two protective proteins, which are anchored to the cell membrane by phosphatidylinositol glycan (PIG) tails, are known. To study whether similar PIG-tailed proteins protect against lymphocyte-mediated killing, nucleated cell lines with a mutation in the biosynthesis of the PIG anchor were used. It was found that PIG-tailed membrane proteins restrict homologous complement-mediated lysis but not three different types of cell-mediated killing or lysis by purified perforin. Furthermore, E from patients with an acquired defect in PIG tail biosynthesis did not differ from normal E in sensitivity to antibody-dependent cell-mediated cytotoxicity, in spite of their increased sensitivity to human C8 and C9.

Nurit Hollander

Papers

Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity.

The differential expression of H-2K versus H-2D antigens, distinguishing high-metastatic from low-metastatic clones, is correlated with the immunogenic properties of the tumor cells.

Bispecific antibodies for cancer therapy

Effects of anti-Lyt antibodies on T-cell functions.

Distinct restriction of complement- and cell-mediated lysis.