Role of lymphokines in immunoregulatory function of mucosal T cells in humans and nonhuman primates

The findings presented above and in other studies provide substantial evidence that lymphocytes in the intestinal lamina propria differ from lymphocyte populations in the circulation or in other tissue sites in a number of ways. First, lamina propria lymphocytes are phenotypically distinct and have evidence of activation. Lymphocytes in the intestinal lamina propria are different in their potential for expression of lymphokine gene products, since activated cells from the lamina propria have high expression of mRNA for IL-2, IL-4, IL-5 and IFN-gamma in comparison to circulating lymphocytes. Mesenteric lymph node T cells also differ from circulating lymphocytes in their high expression of IL-4 and IL-5 mRNA. A further difference between mesenteric lymph node and lamina propria T cells is that the former are capable of proliferating in response to IL-4, whereas the latter are not. These phenotypic and mRNA differences of lamina propria lymphocytes also correlate well with their high helper activity in vitro for immunoglobulin synthesis in the pokeweed mitogen system. Finally, lamina propria T cells at a site of inflammation are able to provide high helper activity in response to specific antigens. These observations are all consistent with the conclusion that T cells in the lamina propria are pleomorphic, but are highly enriched for subpopulations of activated memory cells that are geared for effector functions. These functions are likely to be critical in maintaining normal host defense in the mucosal environment.     

Cytokine secretion induced by superantigens in peripheral blood mononuclear cells, lamina propria lymphocytes, and intraepithelial lymphocytes.

Superantigens are potent inducers of T-cell proliferation and induce a broad range of cytokines, including tumor necrosis factor (TNF), gamma interferon, and interleukin 2 (IL-2). In the present study, we compared the abilities of different staphylococcal superantigens (staphylococcal enterotoxin B [SEB], staphylococcal enterotoxin E [SEE], and toxic shock syndrome toxin 1 [TSST-1]) to stimulate distinct cytokine profiles in peripheral blood mononuclear cells (PBMC), lamina propria lymphocytes (LPL), and intraepithelial lymphocytes (IEL). One million PBMC, LPL, and IEL were stimulated with various concentrations of superantigen (10 to 0.001 ng/ml) for 24, 48, and 72 h. Maximum cytokine production by PBMC, LPL, and IEL was observed for all three superantigens at 48 h at a concentration of 1 ng/ml. In PBMC, SEE and TSST-1 stimulated more IL-2 and gamma interferon than SEB. SEE and TSST-1 also stimulated more TNF and IL-4 production than SEB. In contrast, SEB stimulated more IL-6 than either SEE or TSST-1. In LPL, there was no SEE-induced IL-2 or IL-4 production, but IL-6, TNF, and gamma interferon were induced. SEB similarly induced no IL-2 or gamma interferon from the LPL, but IL-4, IL-6, and TNF were detected. TSST-1 stimulation of LPL resulted in IL-2 and TNF production but no IL-4, IL-6, or gamma interferon. In IEL, SEE induced no IL-2, IL-4, or gamma interferon but produced IL-6 and TNF, while SEB stimulation resulted in no IL-2 or gamma interferon but did result in detectable IL-4, IL-6, and TNF. Taken together, these data indicate that there are significant differences in the cytokine profiles induced by superantigens in LPL and IEL compared with those in PBMC, and these differences may relate to differences in activation requirements.     

Selective expansion of specific T cell receptors in the inflamed colon of Crohn's disease.

To identify disease-specific T cell changes that occur in Crohn's disease (CD), the T cell receptor BV repertoires of lamina propria lymphocytes (LPL) isolated from both the inflamed and "disease-inactive" colons of seven CD patients were compared by the quantitative PCR and DNA sequence analysis. It was observed that the BV repertoires of LPL isolated from the disease-active and disease-inactive parts of the colon from the same individual were very different. Furthermore, nearly all of the differences occurred in CD4+ LPL, with very few differences in the CD8+ population of LPL. Although the pattern of BV segments that was increased in disease-active tissue relative to disease-inactive tissue was different for all seven CD patients, there were several BV segments that increased uniformly in the disease-active tissue of all seven individuals. CDR3 length analysis and DNA sequencing of these BV segments revealed that in six of the seven CD patients there was a striking degree of oligoclonality that was absent from disease-inactive tissue of the same individual. These observations suggest that at least some of the inflammation in CD is the result of responses by CD4+ T cells to specific antigens. The isolation of such inflammation-specific CD4+ T cells may make it possible to identify the antigens that are responsible for the inflammatory process in CD and provide a better understanding of its pathogenesis.     

Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry

To assess whether gender influenced the outcome of percutaneous transluminal coronary angioplasty (PTCA), we analyzed data from the NHLBI PTCA Registry. Early results were compared in 705 women and 2374 men. Women were older (p less than .01) and had more unstable angina (p less than .01), and class 3 or 4 angina (p less than .01). Men had more multivessel disease (p less than .01), prior bypass surgery (p less than .01), and abnormal left ventricular function (p less than .05). Women had a lower angiographic success rate (60.3 vs 66.2%; p less than .01) and had a lower clinical success rate (56.6% vs 62.2%; p less than .01). More women had complications (27.2% vs 19.4%; p less than .01), but overall frequency of major complications (death, myocardial infarction, emergency surgery) was not different (9.8% vs 9.3%). Women had a higher incidence of coronary dissection (p less than .05) and higher in-hospital mortality (1.8% vs 0.7%; p less than .01). PTCA-related mortality was nearly six times higher in women (1.7% vs 0.3%; p less than .001) and mortality with emergency surgery was more than five time higher (17.4% vs 3.2%; p less than .001). Multivariate analysis indicated that female gender was an independent predictor for lower success (p less than .05) and early mortality (p less than .05) and was the only baseline predictor for PTCA-related mortality.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex differences in face processing are mediated by handedness and sexual orientation

Previous research has demonstrated sex differences in face processing at both neural and behavioural levels. The present study examined the role of handedness and sexual orientation as mediators of this effect. We compared the performance of LH (left-handed) and RH (right-handed) heterosexual and homosexual male and female participants on a face recognition memory task. Our main findings were that homosexual males have better face recognition memory than both heterosexual males and homosexual women. We also demonstrate better face processing in women than in men. Finally, LH heterosexual participants had better face recognition than LH homosexual participants and also tended to be better than RH heterosexual participants. These findings are consistent with differences in the organisation and laterality of face-processing mechanisms as a function of sex, handedness, and sexual orientation.     

The LDLR locus in Alzheimer's disease: a family-based study and meta-analysis of case-control data

Genetic linkage studies suggest the presence of an Alzheimer's disease (AD) risk gene on chromosome 19, acting independently of apolipoprotein E (apoE), a known AD risk factor on 19q13. The low density lipoprotein receptor (LDLR) is an interesting candidate because it maps within the linked interval, and is intimately involved in cholesterol homeostasis and the function of apoE. We tested three previously reported single nucleotide polymorphisms (SNPs) within LDLR in a large sample of discordant sibships from multiplex AD families, and failed to find evidence for genetic association with disease risk. In addition, we performed meta-analyses for SNP rs5925 on published data from five independent case control samples, but did not detect any significant summary odds ratios. Based on our data, it seems unlikely that these genetic variants in LDLR make a significant contribution to AD risk in the general population.     

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.