Induction of donor-specific unresponsiveness by intrathymic islet transplantation

The application of isolated pancreatic islet transplantation for treatment of diabetes mellitus has been hampered by the vulnerability of islet allografts to immunologic rejection. Rat islet allografts that were transplanted into the thymus of recipients treated with a single injection of anti-lymphocyte serum survived indefinitely. A state of donor-specific unresponsiveness was achieved that permitted survival of a second donor strain islet allograft transplanted to an extrathymic site. Maturation of T cell precursors in a thymic microenvironment that is harboring foreign alloantigen may induce the selective unresponsiveness. This model provides an approach for pancreatic islet transplantation and a potential strategy for specific modification of the peripheral immune repertoire.     

Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes

In the fruit fly Drosophila, four insulin genes are coexpressed in small clusters of cells [insulin-producing cells (IPCs)] in the brain. Here, we show that ablation of these IPCs causes developmental delay, growth retardation, and elevated carbohydrate levels in larval hemolymph. All of the defects were reversed by ectopic expression of a Drosophila insulin transgene. On the basis of these functional data and the observation that IPCs release insulin into the circulatory system, we conclude that brain IPCs are the main systemic supply of insulin during larval growth. We propose that IPCs and pancreatic islet beta cells are functionally analogous and may have evolved from a common ancestral insulin-producing neuron. Interestingly, the phenotype of flies lacking IPCs includes certain features of diabetes mellitus.     

Autoantibodies to a 64-kilodalton islet cell protein precede the onset of spontaneous diabetes in the BB rat

Spontaneous insulin-dependent diabetes mellitus (IDDM) in the BB rat is associated with the presence of antibodies to a 64-kilodalton rat islet cell protein. These protein antibodies appeared in young animals and remained for as long as 8 weeks before the clinical onset of IDDM. Antibodies to a 64-kilodalton human islet cell protein were found to be associated with human IDDM. Detection of the antibodies may therefore be used to predict an early immune reaction against pancreatic B cells.     

Diabetes research. Islet transplants not yet ready for prime time

When researchers in Edmonton, Canada, announced last month that a new procedure for transplanting pancreatic islet cells had freed seven adults with type I diabetes from taking insulin, the results generated a great deal of public enthusiasm. Some important caveats tended to get lost, however. One drawback is that transplant recipients would need to take immunosuppressive drugs for the rest of their lives to keep from rejecting the tissue. But more importantly, even if the benefits of the transplants outweigh the risks of the drugs, there's just not enough islet tissue to go around and there won't be anytime soon.     

Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells

Type 1 diabetes mellitus results from the autoimmune destruction of the beta cells of the pancreatic islets of Langerhans and is recapitulated in the nonobese diabetic strain of mice. In an attempt to rescue islet loss, diabetic mice were made normoglycemic by islet transplantation and immunization with Freund's complete adjuvant along with multiple injections of allogeneic male splenocytes. This treatment allowed for survival of transplanted islets and recovery of endogenous beta cell function in a proportion of mice, but with no evidence for allogeneic splenocyte-derived differentiation of new islet beta cells. Control of the autoimmune disease at a crucial time in diabetogenesis can result in recovery of beta cell function.     

Islet regeneration during the reversal of autoimmune diabetes in NOD mice

Nonobese diabetic (NOD) mice are a model for type 1 diabetes in humans. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. We now show that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet and ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal.     

Interleukin-2 induction of T-cell G1 progression and c-myb expression

In studies to determine the biochemical mechanisms responsible for cell proliferation, synchronized T cells were used as a model for cellular growth control. By metabolic and morphologic criteria, it was found that activation of the T-cell antigen receptor rendered the cells responsive to interleukin-2 (IL-2), but did not move them through the cell cycle. Instead, IL-2 stimulated G1 progression to S phase, or lymphocyte "blastic transformation." During IL-2-promoted G1 progression, expression of the cellular proto-oncogene c-myb was induced transiently at six to seven times basal levels, maximal levels occurring at the midpoint of G1.     

Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution

A cure for type 1 diabetes will probably require the provision or elicitation of new pancreatic islet beta cells as well as the reestablishment of immunological tolerance. A 2003 study reported achievement of both advances in the NOD mouse model by coupling injection of Freund's complete adjuvant with infusion of allogeneic spleen cells. It was concluded that the adjuvant eliminated anti-islet autoimmunity and the donor splenocytes differentiated into insulin-producing (presumably beta) cells, culminating in islet regeneration. Here, we provide data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retain substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity.     

Type 2 diabetes-a matter of beta-cell life and death?

In type 2 diabetes, the beta cells of the pancreas fail to produce enough insulin to meet the body's demand, in part because of an acquired decrease in beta-cell mass. In adults, pancreatic beta-cell mass is controlled by several mechanisms, including beta-cell replication, neogenesis, hypertrophy, and survival. Here, I discuss evidence supporting the notion that increased beta-cell apoptosis is an important factor contributing to beta-cell loss and the onset of type 2 diabetes. Interestingly, a key signaling molecule that promotes beta-cell growth and survival, insulin receptor substrate 2 (IRS-2), is a member of a family of proteins whose inhibition contributes to the development of insulin resistance in the liver and other insulin-responsive tissues. Thus, the IRS-2 pathway appears to be a crucial participant in the tenuous balance between effective pancreatic beta-cell mass and insulin resistance.     

Prolactin stimulation of maternal behavior in female rats

Inexperienced, hypophysectomized female rats treated with steroids were used in experiments to investigate the roles of the pituitary gland and prolactin in the expression of maternal behavior. Administration of ovine prolactin or treatment with ectopic pituitary grafts, which release prolactin into the circulation, stimulated maternal care in these females toward rat young. Steroid treatment alone, while stimulating maternal behavior in rats with intact pituitary glands, did not facilitate maternal responsiveness in hypophysectomized females. These findings indicate a stimulatory behavioral role for pituitary prolactin in the establishment of maternal care and suggest that exposure to prolactin during pregnancy helps to stimulate the immediate onset of maternal behavior at parturition.     

Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant

Insulin-dependent diabetes mellitus (IDDM) is caused by a specific loss of the insulin-producing beta cells from pancreatic Langerhans islets. It has been proposed that aberrant expression of major histocompatibility complex (MHC) class II molecules on these cells could be a triggering factor for their autoimmune destruction. This proposal was tested in transgenic mice that express allogeneic or syngeneic class II molecules on the surface of islet cells at a level comparable with that normally found on resting B lymphocytes. These animals do not develop diabetes, nor is lymphocyte infiltration of the islets observed. This immunological inactivity does not result from tolerance to the "foreign" class II molecules.     

牛初乳提取物(BCE)对成骨细胞增殖及胎鼠骨骼发育的影响

ＮＩＨ小鼠孕期连续服用牛初乳提取物（ＢＣＥ）、活性钙和蒸馏水,孕后第１８天解剖母鼠,检查胎鼠骨骼发育情况。结果表明,ＢＣＥ能显著促进胎鼠骨骼的生长发育,比单纯补钙更有效。用离体培养的新生大鼠头盖骨成骨细胞检测不同浓度的ＢＣＥ和表皮生长因子（ＥＧＦ）的促细胞增殖作用时发现,ＢＣＥ浓度在２μｇ／ｍＬ至２０ｍｇ／ｍＬ之间递增时,其促细胞增殖作用随之加强,继续提高浓度则对细胞增殖产生抑制作用;不同浓度的ＥＧＦ也有促细胞增殖作用,但ＥＧＦ的剂量曲线比较平缓,提示ＢＣＥ的促细胞增殖作用是多种生长因子协同作用的结果。实验结果表明ＢＣＥ具有促进骨骼发育的作用。     

大口黑鲈胰腺的组织学观察

采用组织切片和免疫组化技术对大口黑鲈的胰腺进行了组织学观察。经H-E染色和G-醛复红染色了的切片显示:大口黑鲈腹腔中10多个肉眼可见的黄白色颗粒物其实是被一层结缔组织和外分泌胰腺包裹着的胰岛结构,其中最大的一个即为主岛;还有许多肉眼不可见的胰岛结构被埋藏于总胆管的管壁中;肝脏中有外分泌胰腺的存在与分布。过氧化物酶标记的链霉卵白素免疫组化切片和图像分析显示:B细胞主要集中胰岛的中央区;A细胞分布于胰岛的全部。本研究的结论为:大口黑鲈的内分泌胰腺主要分布于总胆管周围,外分泌胰腺除了包裹于胰岛之外也分布于肝脏中,胰腺的分布属于弥散型。     

Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin

Neurogenesis occurs in the olfactory system of the adult brain throughout life, in both invertebrates and vertebrates, but its physiological regulation is not understood. We show that the production of neuronal progenitors is stimulated in the forebrain subventricular zone of female mice during pregnancy and that this effect is mediated by the hormone prolactin. The progenitors then migrate to produce new olfactory interneurons, a process likely to be important for maternal behavior, because olfactory discrimination is critical for recognition and rearing of offspring. Neurogenesis occurs even in females that mate with sterile males. These findings imply that forebrain olfactory neurogenesis may contribute to adaptive behaviors in mating and pregnancy.     

Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity

The transition of cells from an epithelial to a mesenchymal phenotype is a critical event during morphogenesis in multicellular organisms and underlies the pathology of many diseases, including the invasive phenotype associated with metastatic carcinomas. Transforming growth factor beta (TGFbeta) is a key regulator of epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms that control the dissolution of tight junctions, an early event in EMT, remain elusive. We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. Phosphorylation of Par6 is required for TGFbeta-dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions. These studies define how an extracellular cue signals to the polarity machinery to control epithelial cell morphology.     

猪母体营养对子代生长发育和肉质的影响

文章根据本实验室近几年的研究工作,对母猪营养与子代肉品质间的母体效应与子代补偿作用及其机理进行了总结分析。试验观测了母猪妊娠期与哺乳期营养对子代猪出生、断奶和出栏不同阶段生长性能、内脏器官发育、胴体品质、肉质性状等方面的影响,阐述了母猪妊娠期和哺乳期营养是否对后代产生母体效应、母体效应的延续性以及子代后续生长过程中是否...     

H-2 antigen class: effect on mouse islet allograft rejection

Rejection of mouse pancreatic islet allografts occurred in a high percentage of donor recipient combinations identical for H-21-region antigens and differing at H-2K and H-2K + H-2D without I-region disparities. The results suggest that disparities in major histocompatibility complex antigens of class I (H-2K and H-2D) alone are capable of eliciting islet allograft rejection, and that lack of a stimulus from class II (I-region) alloantigens does not ensure permanent islet allograft survival.     

胚胎着床期间母-胎对话研究进展

哺乳动物胚胎着床时,母体和胚胎之间进行精密的分子对话和信号交换,以使两者达到协调。母体和胚胎来源的类固醇激素、生长因子、细胞因子、整合素等在胚胎着床及母体妊娠识别过程中发挥着重要的作用,使母体-胎儿间形成一个紧密联系的对话体系。综述了胚胎着床过程中母-胎对话的研究进展。