It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell–dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell–reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell–specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd– or I-Ag7–restricted beta cell–specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2–deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2−/− 4.1-NOD mice, which only bear beta cell–specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2−/− 8.3-NOD mice, which only bear beta cell–specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2+ 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2−/− 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell–cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell–derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell– specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell–reactive CD8+ T cells to islets requires the assistance of beta cell–reactive CD4+ T cells.

Objective: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.Methods: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies:

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Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4 ؉ and CD8؉ T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8 ؉ T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, we define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2K d -restricted CD8 ؉ T cell specificity (NY8.3) that uses a T cell receptor ␣ (TCR␣) rearrangement frequently expressed by CD8 ؉ T cells propagated from the earliest insulitic lesions of NOD mice (V␣17-J␣42 elements, often joined by the N-region sequence M-R-D͞E Development of autoimmune insulin-dependent diabetes (IDDM) in nonobese diabetic (NOD) mice is the result of an ill-defined CD4 ϩ and CD8 ϩ T cell-dependent process against the pancreatic beta cells (1, 2). Although the role of T cells as effectors of beta cell destruction in diabetes is well established, the nature of the antigens, cells, and mechanisms that initiate diabetogenesis in susceptible mice remains poorly understood.Adoptive T cell transfer studies by using spleen cells from prediabetic NOD mice have shown that transfer of diabetes into immunodeficient NOD mice requires both CD4 ϩ and CD8 ϩ T cells (3-6). However, splenic CD4 ϩ T cells from diabetic mice and preactivated beta cell-specific CD4 ϩ T cell clones can home into pancreatic islets and kill beta cells in the absence of CD8 ϩ T cells (6-9). Because beta cells do not express MHC class II molecules (10), it has been proposed that naive autoreactive CD4 ϩ T cells differentiate into effector cells by engaging autoantigens shed from the beta cells by a prior insult, in the context of MHC class II molecules on local antigen-presenting cells (11,12).Studies of ␤2-microglobulin-deficient (␤2 m Ϫ/Ϫ) and anti-CD8 mAb-treated NOD mice (13-16), which do not develop islet inflammation or diabetes, have suggested that the initial insult that triggers the shedding of beta cell autoantigens is mediated by beta cell-cytotoxic CD8 (20). Furthermore, the majority of the islet-associated CD8 ϩ T cells of transgenic NOD mice expressing the TCR␤ chain of a CD8 ϩ clonotype that uses a representative TCR␣-CDR3 sequence (NY8.3) were found to express a TCR␣ chain sequence that was identical to the one used by the clonotype donating the TCR␤ transgene (25). Strikingly, DiLorenzo et al. (26) have recently shown that a significant fraction of the CD8 ϩ T cells that can be propagated from the earliest insulitic lesions of NOD mice use TCR␣ chains that are very similar, or even identical, to those used by the CD8 ϩ T cells that we had previously isolated from diabetic NOD mice and 8.3-TCR␤-transgenic NOD mice (V␣17 and J␣42 elements joined by the N-region sequence M-R-D͞E) (20,25). Studies of 8.3-TCR␣␤-transgenic NOD mice have demonstrated that this beta cell-reactive TCR heterodimer is in fact highly pathogenic, e...

Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic β cells by T lymphocytes. It is believed that CD8 + cytotoxic T lymphocytes (CTLs) effect the initial β-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of β cell-reactive CD8 + T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8 + CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2K d complex on β cells, to effect β-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-β-cell targets via both perforin and Fas, but they killed NOD β cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8 + CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill β cells in a Fas-dependent and perforin-independent manner.

A 3D non-uniform bandwidth frequencyplanar (NUB-FP) filter bank structure is described, having a steady-state frequency response with a 3D stop band that approximates that of a wide band 3D cone.Equivalently, the 3D pass band ideally surrounds a 3D plane and has a 3D bandwidth that is approximately proportional to distance from the origin in the 3D frequency space. It is shown that the proposed NUB-FP filter bank is useful for the selective filtering of 3D spatio-temporal constant velocity signals (Le. linear trajectory signals) and yields improved results over that of conventional 3D frequency-planar (FP) velocity fdters. An example is given that yields improved moving high-frequency object details in a de-noised video sequence.

Robot-assisted cystectomy surgery may be advantageous for patients. The purpose of this study was to compare anesthetic management and outcomes in patients undergoing robot-assisted versus open radical cystectomy. In a retrospective review of 256 cystectomy procedures, procedure duration, blood loss, respiratory parameters, recovery room opiate consumption, pain scores and antiemetic use in the recovery room, and hospital length of stay were compared. After exclusions, 96 robot-assisted and 102 open procedures were analyzed. Anesthesia and surgery duration were significantly longer in the robot-assisted group, while the length of hospital stay was significantly shorter in the robot-assisted group: 7.1 ± 5.8 versus 9.8 ± 5.03 days, p = 0.0005. Estimated blood loss was 601.8 ± 491.4 ml in the open group versus 257.7 ± 164.3 ml in the robot-assisted group, p < 0.0001. Recovery room opiate consumption was significantly less in the robot-assisted group: 9.5 ± 8.9 versus 12.6 ± 9.9 mg (morphine equivalents), p = 0.02. The highest recorded respiratory rate was significantly higher in the robot-assisted group, as was the highest recorded peak airway pressure. Among patients with arterial blood gas data, the highest arterial partial pressure of CO2 was significantly greater in the robot-assisted group than in the open surgery group: 42.6 ± 5.6 versus 37.4 ± 4.8 mmHg CO2, p = 0.0001. Surgeons and anesthesia providers can expect robot-assisted radical cystectomy surgery to last longer than traditional open surgery, but to be associated with less pain and blood loss. Positioning and abdominal insufflation for robot-assisted surgery may contribute to ventilation challenges.

The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.