CD8-positive/T-cell receptor-negative (CD8 ؉ /TCR ؊ ) graft facilitating cells (FCs) are a novel cell population in bone marrow that potently enhance engraftment of hemopoietic stem cells (HSCs). Previously, we showed that the CD11c ؉ /B220 ؉ / CD11b ؊ plasmacytoid-precursor dendritic cell (p-preDC) FC subpopulation plays a critical but nonredundant role in facilitation. In the present study, we investigated the mechanism of FC function. We report that FCs induce antigen-specific CD4 ؉ / CD25 ؉ /FoxP3 ؉ regulatory T cells ( IntroductionRecently, a great deal of interest has focused on the therapeutic potential of cell-based therapies to induce tolerance. Of greatest interest is the subpopulation of bone marrow-derived plasmacytoidprecursor dendritic cells (p-preDCs) and the regulatory T cells (Tregs) that they induce. A major limitation to the use of p-preDCs and Tregs in vivo has been the failure to identify an approach to prevent them from losing their tolerogenic properties and becoming immunogenic after transplantation. We recently demonstrated that CD8␣-positive/T-cell receptor-negative (CD8␣ ϩ /TCR Ϫ ) graft facilitating cells (FCs) enhance the engraftment of hematopoietic stem cells (HSCs) and tolerance induction in allogeneic recipients. [1][2][3] FCs suppress graft-versus-host disease (GVHD) in vivo by producing CD4 ϩ /CD25 ϩ /FoxP3 ϩ Tregs 4 and induce Tregs in vitro in the presence of CpG. 5 The majority of CD8␣ ϩ /TCR Ϫ FCs share the B220 ϩ /CD11c ϩ /CD11b Ϫ p-preDC phenotype, and we have demonstrated the first in vivo engraftment-enhancing and tolerancepromoting effect of the p-preDC FC subpopulation. 2 Although removal of p-preDC FCs from total FCs completely abrogates facilitation, p-preDC FCs alone do not replace FCs to provide the full in vivo biologic effect of facilitation. The mechanism of FC function has yet to be precisely characterized.CD4 ϩ /CD25 ϩ /FoxP3 ϩ Tregs play a critical role in the maintenance of self-tolerance. 6 Defects in Treg development or homeostasis result in systemic autoimmunity, 7 whereas adoptive transfer of Tregs as a therapeutic method can control ongoing autoimmune diseases. [8][9][10] Recently, several studies have demonstrated an important role for Tregs in mediating transplantation tolerance in animal models, 11-14 but little is known about the mechanism of Treg development and homeostasis. [15][16][17] p-preDCs may be important in the generation of Tregs, as evidenced by their potential to facilitate engraftment of HSCs 2,18 and to prolong heart allograft survival. 19,20 In addition, in vitro activation of p-preDCs with CpGoligodeoxynucleotides (CpG-ODNs) induces the production of Tregs in vitro. 5,21 We therefore evaluated whether the mechanism of FC function in vivo is to induce Tregs.In the present study, we first evaluated whether FCs enhance allogeneic HSC engraftment in diabetes-prone nonobese diabetic (NOD) mice. Second, we investigated whether FCs induce the production of Tregs and examined their function using in vivo transplantation models and in vitr...

Background and Objectives:Bariatric surgery has been shown to be an effective weight loss treatment for the morbidly obese, but some primary care physicians remain hesitant about postoperative treatment and management of patients who have undergone the surgery and recommend it to their obese patients infrequently. The purpose of this study was to evaluate perceptions of primary care physicians of the role of bariatric surgery in the management of obese patients and to identify possible barriers to treatment.Methods:A survey of PCPs within our institution was conducted to determine attitudes, knowledge, and practices regarding the treatment of morbidly obese patients, with a specific focus on identifying factors that influence referral patterns for bariatric surgery.Results:Among 161 eligible PCPs, 57 (35.4%) responded. Most respondents (59%) reported that at least 1 in 4 of their patients had a BMI ≥35 kg/m2. Although 39% thought that diet and exercise were an effective means of sustained weight loss, only 12% were satisfied with prescribing nonsurgical interventions. Sixty-three percent agreed that bariatric surgery is generally effective in the long term. All respondents were aware of the commonly established benefits, including improvement of diabetes, hypertension, and hyperlipidemia. In addition, 65% were familiar with the indications for bariatric surgery, and 70% felt comfortable discussing it with patients as a treatment option. Fewer than half of the respondents felt confident in providing postoperative management. Cost was a perceived limitation, with 53% reporting that most of their patients could not afford bariatric surgery.Conclusions:The general attitude of PCPs toward bariatric surgery is supportive. Physicians are largely aware of the indications and benefits; however, far fewer are comfortable in management of patients after surgery. A lack of supplemental information and concerns regarding the cost of surgery can impede treatment and referrals.

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BACKGROUND The role of bone marrow (BM)-derived cells in pancreatic β-cell regeneration remains unresolved. Here we examined whether BM-derived cells are recruited to the site of moderate pancreatic injury and contribute to β-cell regeneration. METHODS Low-dose streptozotocin (STZ) treatment was utilized to induce moderate pancreatic damage and hyperglycemia. Enhanced green fluorescent protein-positive (EGFP+) BM chimeras were evaluated for β-cell regeneration after STZ treatment. RESULTS To test the hypothesis that pancreatic tissue injury induces an SDF-1 gradient to chemoattract the stem cells, we evaluated the expression of mRNA for SDF-1 in damaged pancreatic tissue. SDF-1 was significantly increased in the pancreas after damage, peaking day 10. The majority of BM cells expressing mRNA for pancreatic development markers were detected in the subpopulation of CD45−/Sca-1+/Lin− very small embryonic-like (VSEL) cells. VSEL cells mobilized from BM to peripheral blood (PB) in response to pancreatic damage, peaking in PB at day 5, and were highly enriched in the pancreas 10–15 days after STZ treatment. To confirm a role for BM-derived cells in pancreatic β-cell regeneration, we prepared EGFP+→ B6 chimeras. In the EGFP+ chimeras, EGFP+ cells were detected around duct and islets and were positive for insulin after STZ treatment. However, STZ-induced hyperglycemia was reduced only transiently (49 to 77 days) after pancreatic injury. CONCLUSIONS These data suggest that VSEL cells are mobilized into injured pancreatic tissue and contribute to β-cell regeneration. Transplantation of BM-derived cells improves the function of injured pancreas, although the response is not sufficient to restore sustained normoglycemia.

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