Prevention of diabetes by FTY720-mediated stabilization of peri-islet tertiary lymphoid organs.

ObjectiveThe nonobese diabetic (NOD) mouse is a well-established mouse model of spontaneous type 1 diabetes, which is characterized by an autoimmune destruction of the insulin-secreting pancreatic beta-cells. In this study, we address the role of tertiary lymphoid organs (TLOs) that form in the pancreas of NOD mice during disease progression.MethodsWe developed a model designed to "lock" lymphocytes in the pancreatic lymph node (PLN) and pancreas by the use of FTY720, which blocks the exit of lymphocytes from lymph nodes. A combination of flow cytometry, immunofluorescence, and analysis of clinical scores was used to study the effects of long-term FTY720 treatment on TLO development and development of diabetes.ResultsContinuous treatment of NOD mice with FTY720 prevented diabetes development even at a time of significant insulitis. Treatment withdrawal led to accelerated disease independent of the PLN. Interestingly, naive T-cells trafficked to and proliferated in the TLOs. In addition, morphological changes were observed that occurred during the development of the disease. Remarkably, although the infiltrates are not organized into T/B-cell compartments in 8-week-old mice, by 20 weeks of age, and in age-matched mice undergoing FTY720 treatment, the infiltrates showed a high degree of organization. However, in naturally and FTY720-induced diabetic mice, T/B-cell compartmentalization was lost.ConclusionOur data show that TLOs are established during diabetes development and suggest that islet destruction is due to a loss of TLO integrity, which may be prevented by FTY720 treatment

Black Farmers and the Economic and Social Conditions Where They Live: Some Policy Implications

Black farmers tend to live in southern counties where nonfarm employment opportunities are limited. These counties have grown slowly, much more slowly than southern metropolitan areas. In counties with concentrations of black farmers, blacks face severe economic and social conditions. They have a higher incidence of poverty, less education, and higher unemployment than other blacks in the South. In addition, blacks in these counties lag far behind whites in socioeconomic status. Economic growth and socioeconomic conditions in counties with black farmers vary considerably by region. Strategies to address the black farm crisis must consider both the characteristics of black farmers, such as their advanced age, and the economic and social conditions of areas where they live

The Presidential Primary: A Faulty Process

The system of presidential primary elections has in effect created a nonsystem for selecting party candidates for the highest office in the nation. Personality has become the substitute for program content, and campaign spending coupled with the influence of the media counts for more than the candidates\u27 experience, knowledge, expertise, administrative ability, and attachment to the policies and programs of their respective political party. In large measure the current presidential primary system has failed in its objective to advance the democratic process within the political parties while undermining the effectiveness of the parties and the importance of activists, the party regulars. It is altogether fair to allege that the democratic values we cherish as a nation are not being reinforced by the primary system. This article proposes that we reexamine the process for selecting each party\u27s presidential candidate in search of a better way

Negative Regulation of T Cell Receptor–Lipid Raft Interaction by Cytotoxic T Lymphocyte–associated Antigen 4

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is an essential negative regulator of T cell activation. Recent evidence suggests that CTLA-4 association with the immunological synapse during contact with antigen-presenting cells is important for its inhibitory function. In the present study, we observed a direct interaction of CTLA-4 with the phosphorylated form of T cell receptor (TCR)ζ within the glycolipid-enriched microdomains associated with the T cell signaling complex. In this setting, CTLA-4 regulated the accumulation/retention of TCRζ in the signaling complex, as the lipid raft fractions from CTLA-4KO T cells contained significantly higher amounts of the TCR components when compared with wild-type littermates. In contrast, coligation of CTLA-4 with the TCR during T cell activation selectively decreased the amount of TCRζ that accumulated in the rafts. These results suggest that CTLA-4 functions to regulate T cell signaling by controlling TCR accumulation and/or retention within this a critical component of the immunological synapse

The Value of Measuring Eustachian Tube Aeration on Temporal Bone CT in Patients with Chronic Otitis Media

ObjectivesTo evaluate that the cross-sectional area of the air space in the Eustachian tube (ET) on computed tomography (CT) images could be useful for predicting the postoperative aeration of the middle ear.MethodsThe patient group consisted of 80 patients (80 ears) with chronic otitis media and who underwent middle ear surgery from 2006-2007 and who were followed up for more than 1 yr. The control group consisted of 100 ears of 50 individuals with normal tympanic membranes and who underwent CT for other causes (such as tinnitus or hearing loss). The largest cross-sectional areas of the aerated ET were measured on the coronal images of the temporal bone CT by a single otologist using the computer-based "Region of Interest" picture archiving and communications system. The patient group was divided into two subgroups, 1) those with good postoperative aeration and 2) those with poor postoperative aeration. The largest cross-sectional areas of the aerated ETs were compared between the patients and the controls, and between the patients with good aeration and the patients with poor aeration.ResultsThe mean cross-sectional areas significantly differed between the patient group and the control group, and between the good and poor aeration subgroups (P<0.05 each). The mean area of the poor aeration subgroup was smaller than that of the control group (P<0.05), but the mean area of the good aeration subgroup did not significantly differ from that of the controls.ConclusionThe cross-sectional area of the aerated ET, as measured on the preoperative coronal images of temporal bone CT scans, may be useful for predicting the postoperative condition of the tympanic cavity

Sequential development of interleukin 2–dependent effector and regulatory T cells in response to endogenous systemic antigen

Transfer of naive antigen-specific CD4+ T cells into lymphopenic mice that express an endogenous antigen as a systemic, secreted protein results in severe autoimmunity resembling graft-versus-host disease. T cells that respond to this endogenous antigen develop into effector cells that cause the disease. Recovery from this disease is associated with the subsequent generation of FoxP3+CD25+ regulatory cells in the periphery. Both pathogenic effector cells and protective regulatory cells develop from the same antigen-specific T cell population after activation, and their generation may occur in parallel or sequentially. Interleukin (IL)-2 plays a dual role in this systemic T cell reaction. In the absence of IL-2, the acute disease is mild because of reduced T cell effector function, but a chronic and progressive disease develops late and is associated with a failure to generate FoxP3+ regulatory T (T reg) cells in the periphery. Thus, a peripheral T cell reaction to a systemic antigen goes through a phase of effector cell–mediated pathology followed by T reg cell–mediated recovery, and both require the growth factor IL-2