Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus.

The zinc-finger protein Ikaros is a key player in T-cell development and a potent tumor suppressor in thymocytes. To understand the molecular basis of its function, we disabled Ikaros activity in vivo using a dominant negative Ikaros transgene (DN-IkTg). In DN-IkTg mice, T-cell development was severely suppressed, and positively selected thymocytes clonally expanded, resulting in a small thymus with a heavily skewed T-cell receptor (TCR) repertoire.

CD4 co-receptor dependent signaling promotes competency for re-stimulation induced cell death of effector T cells.

The elimination of activated T cells by FAS-mediated signaling is an important immunoregulatory mechanism used to maintain homeostasis and prevent tissue damage. T cell receptor-dependent signals are required to confer sensitivity to FAS-mediated re-stimulation-induced cell death (RICD), however, the nature of these signals is not well understood. In this report, we show, using T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene, that CD4-dependent signaling events are a critical part of the competency signal required for RICD.

In vitro culture of chondrocytes in a novel thermoreversible gelation polymer scaffold containing growth factors.

In this study we examined the potential of a novel thermoreversible gelation polymer (TGP) to act as a 3-D hydrogel scaffold and deliver both chondrocytes and growth factors. Chondrocytes obtained from bovine articular cartilage were studied as a suspension in TGP chilled to 4 degrees C, in the presence or absence of the growth factors IGF-1 and/or TGF beta2. The cold cell/aqueous suspensions were injected into a cylindrical mold and cultured at 37 degrees C for up to 16 weeks.

CD4-dependent signaling is required for a late checkpoint during Th2 development associated with resistance to activation-induced cell death.

Previous studies have found that class II-restricted T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene have a specific defect in the development of Th2 effector cells; however, the reason for this defect was not clear. Following stimulation with a high potency peptide and exogenous IL-4, CD4-dependent signaling is required for optimal generation of a Th2 effector population. However, initial IL-4 and GATA-3 transcription is appropriately induced, suggesting that the initial stages of Th2 development are intact and independent of CD4 after priming with a strong agonist peptide.

Tissue-engineered trachea from sheep marrow stromal cells with transforming growth factor beta2 released from biodegradable microspheres in a nude rat recipient.

Objective: The purpose of this study was to evaluate the feasibility of using autologous sheep marrow stromal cells cultured onto polyglycolic acid mesh to develop helical engineered cartilage equivalents for a functional tracheal replacement. We also explored the potential benefit of local delivery of transforming growth factor beta 2 with biodegradable gelatin microspheres.

Methods: Bone marrow was obtained by iliac crest aspiration from 6-month-old sheep and cultured in monolayer for 2 weeks.

Akt decreases lymphocyte apoptosis and improves survival in sepsis.

Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality of the disorder. The serine/threonine kinase Akt is a key regulator of cell proliferation and death. The purpose of this study was to determine whether overexpression of Akt would prevent lymphocyte apoptosis and improve survival in sepsis.

Role of apoptotic cell death in sepsis.

Sepsis is the leading cause of morbidity and mortality in critically ill patients in many intensive care units. The pathophysiology of organ failure and death in patients with sepsis remain elusive. This review focuses on recent advances in our understanding of the mechanisms of cell death in sepsis, the types of cells that are dying and the consequences on immunity.

Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells.

Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival of B and T cells. Although proper function of dendritic cells is essential to host control of invading pathogens, few studies have examined the impact of sepsis on dendritic cells. The purpose of this study was to determine the effect of sepsis on splenic interdigitating dendritic cells (IDCs) and follicular dendritic cells (FDCs) using a clinically relevant animal model.

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis.

In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model.

Endothelial cell apoptosis in sepsis.

Objective: To discuss a potential role for endothelial cell apoptosis in the pathogenesis of sepsis.

Data Sources: Studies published in biomedical journals and studies from the authors' laboratory.

Study Selection: In vitro and in vivo studies of endothelial cell apoptosis in endotoxin and sepsis models.

Overexpression of Bcl-2 in the intestinal epithelium improves survival in septic mice.

Objectives: The aim of this study was to determine whether decreasing intestinal epithelial apoptosis in sepsis would alter mortality rates. The roles of the antiapoptotic protein Bcl-2 and the "executioner" protease caspase-3 in sepsis-induced gut cell death also were evaluated.

Design: Prospective, randomized, controlled trial.

Depletion of dendritic cells, but not macrophages, in patients with sepsis.

Dendritic cells (DCs) are a group of APCs that have an extraordinary capacity to interact with T and B cells and modulate their responses to invading pathogens. Although a number of defects in the immune system have been identified in sepsis, few studies have examined the effect of sepsis on DCs, which is the purpose of this study. In addition, this study investigated the effect of sepsis on macrophages, which are reported to undergo apoptosis, and MHC II expression, which has been noted to be decreased in sepsis.