Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.

Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.

Animal models of acute lung injury.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(01)06252-3.pdf

Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey

Interleukin 15: biology and relevance to human disease

Regulatory CD4 T cells (Treg) control inflammatory reactions to commensal bacteria and opportunist pathogens. Activation of Treg functions during these processes might be mediated by host-derived proinflammatory molecules or directly by bacterial products. We tested the hypothesis that engagement of germline-encoded receptors expressed by Treg participate in the triggering of their function. We report that the subset of CD4 cells known to exert regulatory functions in vivo (CD45RBlow CD25+) selectively express Toll-like receptors (TLR)-4, -5, -7, and -8. Exposure of CD4+ CD25+ cells to the TLR-4 ligand lipopolysaccharide (LPS) induces up-regulation of several activation markers and enhances their survival/proliferation. This proliferative response does not require antigen-presenting cells and is augmented by T cell receptor triggering and interleukin 2 stimulation. Most importantly, LPS treatment increases CD4+ CD25+ cell suppressor efficiency by 10-fold and reveals suppressive activity in the CD4+ CD45RBlow CD25− subset that when tested ex-vivo, scores negative. Moreover, LPS-activated Treg efficiently control naive CD4 T cell–dependent wasting disease. These findings provide the first evidence that Treg respond directly to proinflammatory bacterial products, a mechanism that likely contributes to the control of inflammatory responses.

https://rupress.org/jem/article-pdf/197/4/403/1144398/jem1974403.pdf

Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide

Background: Food allergy is caused by production of IgE against dietary antigen induced by T H2 response. IL-12 inhibits T H2 responses and strongly suppresses IgE production. We have recently established a murine model for IgE production with a predominant T H2 response induced by feeding antigen. Objective: We here show a suppressive effect of heat-killed Lactobacillus plantarum L-137, a potent inducer of IL-12, on IgE production against naturally fed antigen in a murine model. Methods: The ability of L. plantarum L-137 to induce IL-12 production was examined in vitro and in vivo. DBA/2 mice were fed a casein diet and injected intraperitoneally with L. plantarum L-137 from the beginning of feeding or 2 weeks later. Recombinant mouse IL-12 was also injected 2 weeks after the start of feeding. Casein-specific IgE and IgG1 in plasma were determined by ELISA. Results: L. plantarum L-137 directly induced IL-12 production by the peritoneal macrophages and also stimulated spleen cells to produce both IL-12 and interferon-γ in vitro. In vivo treatment of L. plantarum L-137 also increased the plasma level of IL-12 in mice. Plasma anti-casein IgG1 and IgE levels were gradually elevated in DBA/2 mice fed a casein diet. Administration of L. plantarum L-137 from the beginning of feeding suppressed the elevation of anti-casein IgE levels, whereas the levels of anti-casein IgG1 were rather augmented by L. plantarum L-137. IL-12 production of the peritoneal macrophages was enhanced, but IL-4 production of concanavalin A (Con A)–stimulated spleen cells was suppressed in the L. plantarum L-137–treated mice compared with control mice fed a casein diet. When L. plantarum L-137 was given from 2 weeks after the start of feeding, anti-casein IgE levels were also significantly suppressed, which was similar to the result found in mice treated with IL-12. Conclusion: Our results suggest that L. plantarum L-137, a potent IL-12 inducer, is useful for prevention and treatment of food allergy. (J Allergy Clin Immunol 1998;102:57-64.)

Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen–specific IgE production by stimulation of IL-12 production in mice

Gene expressions of lipopolysaccharide receptors, toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes.

Several cytokines including stem cell factor (SCF) and interleukin (IL)-7 are known to be required for development of gamma delta T cell receptor (TCR) intestinal intraepithelial lymphocytes (i-IEL) in mice. We show here the effects of IL-15 on the proliferation and maintenance of murine gamma delta i-IEL in vitro. gamma delta i-IEL constitutively expressed a high level of IL-15 receptor alpha mRNA and proliferated in response to IL-15 more vigorously than alpha beta i-IEL. V gamma/delta repertoire analysis revealed that IL-15, like IL-2, induced polyclonal expansion of gamma delta i-IEL, whereas gamma delta i-IEL responding to IL-7 showed a V gamma/delta repertoire skewed towards V gamma 1/V delta 4, V delta 5. IL-15 efficiently prevented gamma delta i-IEL from apoptosis induced by growth factor deprivation. This rescue was accompanied by up-regulation of Bcl-2 expression. These results suggest that IL-15 plays important roles in proliferation and maintenance of gamma delta i-IEL.

Interleukin-15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing γδ T cell receptor in mice

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease

We cloned the 5’ upstream region of IL-15 genomic DNA and examined promoter activity in macrophages stimulated with lipopolysaccharide(LPS). The 1.2 kilobase (kb) fragment of the 5’ upstream region contained binding elements for LPS-inducible transcription factors such as NFIL-6 or NF-κB. Determined by luciferase assay following transient transfection in the J774A.1 macrophage cell line, the 1.2 kb of the 5’ upstream region exhibited high promoter activity in response to LPS, while promoter activity was significantly reduced by the 5’ deletion of 313 base pairs containing the NF-κB binding motif. Nuclear protein prepared from LPS-stimulated macrophages formed a complex with the NF-κB binding sequence of the IL-15 promoter. Taken together, the binding of nuclear protein to the NF-κB binding site is required for transcriptional activation of the IL-15 gene in LPS-stimulated macrophages.

Yasunobu Yoshikai

Papers

Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen–specific IgE production by stimulation of IL-12 production in mice

Gene expressions of lipopolysaccharide receptors, toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes.

Interleukin-15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing γδ T cell receptor in mice

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease

The NF-κB binding site is essential for transcriptional activation of the IL-15 gene