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 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.     

Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice

Chong et al., Nishio et al., and Suri et al. (Reports, 24 March 2006, pp. 1774, 1775, and 1778) confirmed that treating nonobese diabetic (NOD) mice with an immune adjuvant and semisyngenic spleen cells can reverse the disease but found that spleen cells did not contribute to the observed recovery of pancreatic islets. We show that islet regeneration predominately originates from endogenous cells but that introduced spleen cells can also contribute to islet recovery.     

Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone

Nonobese diabetic (NOD) mice develop an autoimmune form of diabetes, becoming hyperglycemic after 3 months of age. This process was accelerated by injecting young NOD mice with CD4+ islet-specific T cell clones derived from NOD mice. Overt diabetes developed in 10 of 19 experimental animals by 7 weeks of age, with the remaining mice showing marked signs of the disease in progress. Control mice did not become diabetic and had no significant pancreatic infiltration. This work demonstrates that a CD4 T cell clone is sufficient to initiate the disease process in the diabetes-prone NOD mouse.     

Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration

Autoimmune destruction of beta cells is the predominant cause of type 1 diabetes mellitus (T1DM) in humans and is modeled in non-obese diabetic (NOD) mice. Many therapeutic interventions prevent the development of T1DM in NOD mice, but few can induce its reversal once established. Intervention with Freund's complete adjuvant, semi-allogeneic splenocytes, and temporary islet transplantation has been reported to cure NOD mice of established T1DM. Using the same approach, we report here that this treatment cured 32% of NOD mice of established diabetes (>340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes.     

NOD小鼠的遗传学特性和部分生物学特性观察

应用定期测定NOD小鼠的体重、血糖，统计繁殖特性，绘制生长曲线图，检测遗传位点，镜检病理学特征等方法，对NOD小鼠的遗传学特性和部分生物学特性进行了研究。结果显示：4－32周龄♀、♂小鼠有明显统计学差异（P＜0．01）。非糖尿病小鼠的受孕率为86．7％，而糖尿病小鼠的受孕率仅为53．3％，两组也差异显著（P＜0．05）。小鼠发病后体重随周龄的增长而急剧下降，至死亡时平均体重仅为发病前的60％。NOD（14♀）小鼠从发病到死亡的平均存活时间为22d。NOD小鼠只有在所有胰岛完全或近乎完全破坏时才发生糖尿病，若仍存有少量未萎缩的胰岛，其血糖水平维持于正常范围内。NOD小鼠在所检测的生化标志基因位点上，等位基因全部为纯合子，基因型一致，因某些位点不同程度地参与糖的代谢过程，可能导致糖尿病的发生。     

An oceanic cold reversal during the last deglaciation

A detailed deuterium excess profile measured along the Dome C EPICA (European Project for Ice Coring in Antarctica) core reveals the timing and strength of the sea surface temperature changes at the source regions for Dome C precipitation. We infer that an Oceanic Cold Reversal took place in the southern Indian Ocean, 800 years after the Antarctic Cold Reversal. The temperature gradient between the oceanic moisture source and Antarctica is similar to the Dome C sodium profile during the deglaciation, illustrating the strong link between this gradient and the strength of the atmospheric circulation.     

Interleukin-22 drives endogenous thymic regeneration in mice

Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection, or immunodepletion. However, the mechanisms governing this regeneration remain poorly understood. We detail such a mechanism, centered on interleukin-22 (IL-22) and triggered by the depletion of CD4(+)CD8(+) double-positive thymocytes. Intrathymic levels of IL-22 were increased after thymic insult, and thymic recovery was impaired in IL-22-deficient mice. IL-22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was up-regulated by radio-resistant RORγ(t)(+)CCR6(+)NKp46(-) lymphoid tissue inducer cells after thymic injury in an IL-23-dependent manner. Administration of IL-22 enhanced thymic recovery after total body irradiation. These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.     

Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta

Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.     

Anti-HIV and anti-anti-MHC antibodies in alloimmune and autoimmune mice

Alloimmune mice (mice that have been exposed to cells from another murine strain) were shown to make antibodies against gp120 and p24 of human immunodeficiency virus (HIV), and mice of the autoimmune strains MRL-lpr/lpr and MRL-(+)/+ made antibodies against gp120. This is surprising because the mice were not exposed to HIV. Furthermore, anti-anti-MHC antibodies (molecules that have shapes similar to those of major histocompatibility complex molecules) were detected in both alloimmune sera and MRL mice. These results are discussed in the context of a possible role for allogeneic stimuli in the pathogenesis of acquired immunodeficiency syndrome, as suggested by an idiotypic network model.     

A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes

Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Asp(beta57) leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.     

Neurons: secretory activity during limb regeneration and induction in the newt

Material staining with aldehyde fuchsin appeared in sensory ganglion cells supplying a regenerating limb or nerve-induced blastema and in regenerating nerve fibers within the blastema. With the electron microscope, large (1000 to 2500 angstroms), dense granules were observed in the perikarya and within end bulbs of peripheral nerves. Secretory materials may be elaborated and transported by neurons during limb regeneration and induction in the newt.     

小立碗藓原生质体再生过程中蛋白质相互作用网络分析

[目的]探明蛋白质间的相互作用对于阐明细胞生命活动的分子机制具有重要意义.[方法]应用Cytoscape平台中MiMI插件,进行磷酸化修饰蛋白质之间的相互作用(protein-protein interaction,PPI)网络分析.采用基于DAVID分析系统对PPI网络中的蛋白质进行Gene Ontology (GO)富集分析.[结果]有5个磷酸化蛋白质(ATX1、AGL21、KNAT2、EOL2和VIP4)与其他33个蛋白质存在相互作用关系.这些PPI网络中的蛋白质主要参与分生组织的分生状态的维持,干细胞的发育以及基因的表达调控等生物过程.[结论]小立碗藓原生质体的再生机制可能与种子植物的胚后发育相似.     

Self-organizing and stochastic behaviors during the regeneration of hair stem cells

Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs.     

四氧嘧啶与链脲佐菌素诱导小鼠糖尿病模型的效果比较

用相同总剂量的四氧嘧啶1次给药和2次给药及较大剂量链脲佐菌素1次给药3种方法诱导小白鼠糖尿病模型,多次测定血糖,体重等糖尿病相关指标,以确定糖尿病模型建立的最佳方法。结果表明,四氧嘧啶建模率为91．94％,高于链脲佐菌素建模率(66．7％)(P<0．05);四氧嘧啶建模组的死亡率为15％及体重下降率为 18．1％,均高于链脲佐菌素建模组(死亡率3．3％,体重下降率12．0％)(P<0．05);四氧嘧啶连续2次小剂量给药的建模效果优于1次性大剂量给药。两种药物比较,虽然四氧嘧啶的建模率高于链脲佐菌素,但其对建模小鼠的损害亦明显大于链脲佐菌素,建模时连续小剂量给药,并于4．5～5 h后灌胃质量分数50％葡萄糖,可以降低死亡率, 提高建模率。     

Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice

A polygenic basis for susceptibility to insulin-dependent diabetes in nonobese diabetic (NOD) mice has been established by outcross to a related inbred strain, nonobese normal (NON). Analysis of first and second backcross progeny has shown that at least three recessive genes are required for development of overt diabetes. One, Idd-1s, is tightly linked to the H-2K locus on chromosome 17; another, Idd-2s, is localized proximal to the Thy-1/Alp-1 cluster on chromosome 9. Segregation of a third, Idd-3s, could be shown in a second backcross. Neither Idd-1s nor Idd-2s could individually be identified as the locus controlling insulitis; leukocytic infiltrates in pancreas were common in most asymptomatic BC1 mice. Both F1 and BC1 mice exhibited the unusually high percentage of splenic T lymphocytes characteristic of NOD, suggesting dominant inheritance of this trait. The polygenic control of diabetogenesis in NOD mice, in which a recessive gene linked to the major histocompatibility complex is but one of several controlling loci, suggests that similar polygenic interactions underlie this type of diabetes in humans.     

Prevention of type I diabetes in nonobese diabetic mice by virus infection

The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease.     

南京市八卦洲乡发展芦蒿的调查

八卦洲乡自1992年以来利用洲上的野生芦蒿进行人工规模栽培，农户收入不断提高。1995年户均增收1337元，1996年达2075元，1997年至4月户均增收为2540元，芦蒿上市量达4000t。芦蒿成了农户主要的农业收入之一，芦蒿的上市丰富了市场供应，产生了巨大的经济效益和社会效益，为我国挖掘、利用野生蔬菜资源进行规模生产提供了典型范例。乡政府在芦蒿的规模生产上起了主导作用，但离产业化的目标还有差距。     

Hereditary autoimmune thyroiditis in the fowl

In the Cornell C strain of White Leghorn chickens, thyroiditis appeared spontaneously. It was characterized by phenotypic changes due to a decrease of thyroxine, histological damage to the thyroid gland, and the presence in the seruim of antibodies to thyroglobulin. Susceptibility to the disease is genetically inherited. Hormonal bursectomy (androgen given to the embryo) suppresses the development of thyroiditis.