Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells.

The aim of the present study was to define the point at which mesothelioma T-cell responses fail in order to design better immunotherapies. A murine model of mesothelioma was used which was established with asbestos. Inoculation of tumour cells into syngeneic mice results in progressing tumours with similar histopathology to human mesothelioma. The tumour cells secrete a marker tumour antigen similar to secreted tumour-associated products, such as mesothelin. The mesothelioma microenvironment contains stromal elements including dendritic cells, effector CD8(+) and CD4(+) T-cells, and CD4(+) T-regulatory (Tregs) cells, all of which are activated in situ, implying chronic inflammation. Tumour antigens are rapidly transported to draining lymph nodes wherein tumour-specific T-cell responses are generated. Despite the generation of potent CD8(+) cytotoxic lymphocyte in lymphoid organs, those that infiltrate tumours cannot restrain tumour growth suggesting local suppression. Splenic Tregs did not suppress protective responses in adoptive transfer experiments suggesting that systemic Tregs play little role in regulating anti-mesothelioma immune responses. Finally, removal of CD25(+) Tregs from the tumour site and lymphoid organs did not alter tumour growth with or without interleukin (IL)-2 or IL-21 immunotherapy. Tregs are not potent regulators of anti-mesothelioma immunity and targeting these cells may not improve results.

Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment.

Reductions in dietary fat, saturated fat, and cholesterol have been recommended to reduce the risk of heart disease in our society. The effects of these modifications on human cytokine production and immune responses have not been well studied. 22 subjects > 40 yr of age were fed a diet approximating that of the current American (14.1% of calories as saturated fatty acids, [SFA], 14.5% monounsaturated fatty acids [MUFA], 6.1% [n-6] polyunsaturated fatty acids [PUFA], 0.8% [n-3] PUFA, and 147 mg cholesterol/1,000 calories) for 6 wk, after which time they consumed (11 in each group) one of the two low-fat, low-cholesterol, high-PUFA diets based on National Cholesterol Education Panel (NCEP) Step 2 recommendations (4.0-4.5% SFA, 10.8-11.6% MUFA, 10.3-10.5% PUFA, 45-61 mg cholesterol/1,000 calories) for 24 wk. One of the NCEP Step 2 diets was enriched in fish-derived (n-3) PUFA (low-fat, high-fish: 0.54% or 1.23 g/d eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] [121-188 g fish/d]) and the other low in fish-derived (n-3) PUFA (low-fat, low-fish [0.13% or 0.27 g/d EPA and DHA] [33 g fish/d]). Measurements of in vivo and in vitro indexes of immune responses were taken after each dietary period. Long-term feeding of low-fat, low-fish diet enriched in plant-derived PUFA increased blood mononuclear cell mitogenic response to the T cell mitogen Con A, IL-1 beta, and TNF production and had no effect on delayed-type hypersensitivity skin response, IL-6, GM-CSF, or PGE2 production. In contrast, the low-fat, high-fish diet significantly decreased the percentage of helper T cells whereas the percentage of suppressor T cells increased. Mitogenic responses to Con A and delayed-type hypersensitivity skin response as well as the production of cytokines IL-1 beta, TNF, and IL-6 by mononuclear cells were significantly reduced after the consumption of the low-fat, high-fish diet (24, 40, 45, 35, and 34%, respectively; P < 0.05 by two-tailed Student's t test except for IL-1 beta and TNF, which is by one-tailed t test). Our data are consistent with the concept that the NCEP Step 2 diet that is high in fish significantly decreases various parameters of the immune response in contrast to this diet when it is low in fish. Such alterations may be beneficial for the prevention and treatment of atherosclerotic and inflammatory diseases but may be detrimental with regard to host defense against invading pathogens.

Vitamin E deficiency and impaired cellular immunity related to intestinal fat malabsorption.

This report describes a patient in whom a severe vitamin E deficiency developed secondary to an intestinal malabsorptive disorder. In vivo and in vitro impairment of T-cell function, as well as a polyneuropathy, were observed in conjunction with this vitamin deficiency. Repletion of the vitamin deficiency was associated with marked improvement in the T-cell functions and modest improvement in the neuropathy. Observations in this patient suggest that severe vitamin E deficiency in humans may impair T-cell activity and that correction of the deficient state may reverse these T-cell abnormalities. Further studies will need to be performed to confirm these findings.

Macrophage heterogeneity in normal colonic mucosa and in inflammatory bowel disease.

Immunohistological techniques using monoclonal antibodies were employed to study the morphology and phenotypic expression of macrophage like cells in ulcerative colitis, Crohn's colitis and histologically normal colonic mucosa. The antibody RFD1 identifies interdigitating (antigen presenting) cells whereas RFD7 binds to mature tissue macrophages. In normal colonic mucosa, the majority of cells recognised by these reagents were positive for Class II antigen expression and a median 87% (range 80-95%) were positive for both RFD1 and RFD7, with 6.5% (ranges 1-14%) positive for either antibody alone. There was much greater macrophage heterogeneity in the ulcerative colitis and Crohn's colitis biopsies than in normal mucosa. Clusters of RFD9+ cells (epithelioid cells) were found in Crohn's colitis and, to a lesser extent, in ulcerative colitis. Some Crohn's colitis sections showed replacement of the normal colonic macrophage phenotype with RFD1-RFD7+ cells (classical scavenger macrophages). The degree of this replacement correlated with the histological severity of the disease. By contrast, large numbers of RFD1+ RFD7- cells, with long dendritic processes, were found in intimate association with the lymphoid infiltrates in the lamina propria of the ulcerative colitis sections. Future studies of the factors controlling macrophage differentiation in tissues may help to explain the greater macrophage heterogeneity in inflammatory bowel disease and the differences between ulcerative colitis and Crohn's colitis observed in this study.

A family demonstrating inheritance of the Leach phenotype: a Gerbich-negative phenotype associated with elliptocytosis.

The proposita of a Canadian family and 2 of her sibs have the rare Leach phenotype and provide the first evidence that the Leach phenotype is an inherited condition. Their red cells are Ge: -2, -3 and fail to react, by the antiglobulin test, with the monoclonal antibodies GERO, BRIC 4 and BRIC 10. The minor sialoglycoproteins beta, beta 1 and gamma are apparently absent from their red cell membranes. A proportion of their red cells are elliptocytes indicating that beta and/or beta 1 and/or gamma have a function in maintaining normal red cell shape.

A third example of haemolytic auto-anti-Vel.

A non-transfused, 43 year old Caucasian female presented with acute haemolytic anaemia and splenomegaly. Sections of bone marrow showed erythroid hyperplasia. The patient's red blood cells gave a negative reaction with polyspecific antiglobulin serum, but a positive reaction with specific anti-IgM. A heat eluate prepared from her red cells showed anti-Vel specificity. Her serum agglutinated only Vel-positive cells including her own. All papain pre-treated red cells including her own and Vel-negative cells were completely haemolysed at 37 degrees C. The percentage of haemolysis of Vel-positive cells was greater than that of Vel-negative cells.