Age related changes in pancreatic beta cells: A putativeextra-cerebral site of Alzheimer’s pathology

Frequent concomitant manifestation of type 2 diabetesmellitus (T2DM) and Alzheimer’s disease (AD) hasbeen recently demonstrated by epidemiological studies.This might be due to functional similarities between β-cells and neurons, such as secretion on demand ofhighly specific molecules in a tightly controlled fashion.An additional similarity represents the age-relatedalteration of hyperphosphorylated tau in AD patients.Similarly, alterations have been identified in β-cells of T2DM patients. The islet amyloid polypeptide has beenassociated with β-cell apoptosis. As a consequence ofincreasing age, the accumulation of highly modified proteins together with decreased regenerative potentialmight lead to increasing rates of apoptosis. Moreover, reduction of β-cell replication capabilities results in reduction of β-cell mass in mammals, simultaneously withimpaired glucose tolerance. The new challenge is tolearn much more about age-related protein modifications. This can lead to new treatment strategies forreducing the incidence of T2DM and AD.     

Enterovirus and type 1 diabetes: What is the matter?

A complex interaction of genetic and environmental factors can trigger the immune-mediated mechanism responsible for type 1 diabetes mellitus(T1DM) establishment. Environmental factors may initiate and possibly sustain, accelerate, or retard damage to β-cells. The role of environmental factors in this process has been exhaustive studied and viruses are among the most probable ones, especially enteroviruses. Improvements in enterovirus detection methods and randomized studies with patient follow-up have confirmed the importance of human enterovirus in the pathogenesis of T1 DM. The genetic risk of T1 DM and particular innate and acquired immune responses to enterovirus infection contribute to a tolerance to T1DM-related autoantigens. However, the frequency, mechanisms, and pathways of virally induced autoimmunity and β-cell destruction in T1 DM remain to be determined. It is difficult to investigate the role of enterovirus infection in T1 DM because of several concomitant mechanisms by which the virus damages pancreatic β-cells, which, consequently, may lead to T1 DM establishment. Advances in molecular and genomic studies may facilitate the identification of pathways at earlier stages of autoimmunity when preventive and therapeutic approaches may be more effective.     

Positive evidence for vitamin A role in prevention of type 1 diabetes

Type 1 diabetes mellitus(T1DM) as one of the most well-known autoimmune disease, results from the destruction of β-cells in pancreas by autoimmune process. T1 DM is fatal without insulin treatment. The expansion of alternative treatment to insulin is a dream to be fulfilled. Currently autoimmunity is considered as main factor in development of T1 DM. So manipulation of the immune system can be considered as alternative treatment to insulin. For the past decades, vitamin A has been implicated as an essential dietary micronutrient in regulator of immune function. Despite major advantage in the knowledge of vitamin A biology, patients who present T1 DM are at risk for deficiency in vitamin A and carotenoids. Applying such evidences, vitamin A treatment may be the key approach in preventing T1 DM.     

New therapeutic approaches for type 1 diabetes: Disease-modifying therapies

It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.     

Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.     

不同胃肠道重建方式对2型糖尿病患者术后胰岛功能的影响

目的探讨不同胃肠道重建方式对2型糖尿病患者术后胰岛功能的影响。方法对23例胃癌合并2型糖尿病患者的临床资料进行回顾性分析．并按消化道重建方式的不同分为BillrothⅠ式组（13例）和胃肠旁路组（10例。其中毕Ⅱ式吻合4例,Roux—en—Y吻合6例）。行口服糖耐量试验（OGTr）．采用电化学发光法检测血清胰岛素水平．采用葡萄糖氧化酶法测定血糖．采用稳态模式评估法评价胰岛素抵抗指数和胰岛素分泌指数。结果胃肠旁路术组和BillorthⅠ式组术后糖尿病好转率分别为90％（9／10）和23％（3／13）,差异有统计学意义（P〈0．01）。与术前相比,胃肠旁路组术后糖化血红蛋白A1c和糖化血红蛋白HbAl显著降低（P〈0．01）．而BillrothⅠ式组则无明显改善（P〉0．05）。OGTF结果显示,胃肠旁路组空腹血糖及及糖负荷后各个时间点的血糖水平均显著低于BillrothⅠ式组：在糖负荷后30min和60min．胃肠旁路术组胰岛素水平和胰岛素释放指数明显高于BillrothⅠ式组（均P〈0．05）。胃肠旁路组的胰岛素分泌指数和早期胰岛素分泌反应同样明显高于BillrothⅠ式组。结论采用胃肠旁路术进行胃切除术后消化道重建．可有效控制2型糖尿病并明显改善术后胰岛功能。     

Effects of All-Trans Retinoid Acid and Exendin-4 on Islet Transplantation in NOD Mice

Type 1 diabetes usually develops due to autoimmune destruction of β-cells in the pancreas. It has been shown that all-trans retinoid acid (ATRA), a potent derivative of vitamin A, hinders the development of autoimmune diabetes by inducing immune tolerance status. In addition, exendin-4, a glucagon-like peptide-1 receptor agonist, stimulates growth and differentiation of β-cells and exerts anti-apoptotic effect on β-cells. Thus, we hypothesized that the ATRA and exendin-4 therapy may improve the outcome of islet transplantation in non-obese diabetic (NOD) mice. After the onset of diabetes, each NOD mouse was transplanted with 300 or 600 islets isolated from NOD/severe combined immunodeficient (SCID) mice with or without treatment of ATRA (0.5 mg intraperitoneally every other day) and/or exendin-4 (3 μg/kg subcutaneously twice daily) for 6 weeks. After 300 or 600 NOD/SCID islet transplantation without any other treatment, all NOD recipients remained diabetic. However, the lowest blood glucose level in mice transplanted with 600 but not 300 islets was significantly lower than those without islet transplantation (P < .05), although their survival time was comparable. Among recipients treated with ATRA, exendin-4, ATRA and exendin-4, and without treatment, their lowest blood glucose levels and survival time were not different. However, one recipient treated with ATRA survived for 223 days with intermittent hyperglycemia and the other who was treated with ATRA and exendin-4 achieved normoglycemia. In conclusion, islet transplantation lowered blood glucose levels in diabetic NOD mice. With a few exceptions, treatment with ATRA and exendin-4 alone or in combination in islet recipients could not reverse diabetes or prolong survival.     

Treatment of insulin-dependent diabetes by hematopoietic stem cell transplantation

Type 1 diabetes (T1D) is an autoimmune disease resulting from the demolition of β-cells that are responsible for producing insulin in the pancreas. Treatment with insulin (lifelong applying) and islet transplantation (in rare cases and severe diseases), are standards of care for T1D. Pancreas or islet transplantation have some limitations, such as lack of sufficient donors and longtime immune suppression for preventing allograft rejection. Recent studies demonstrate that autologous hematopoietic stem cells (HSC) can regenerate immune tolerance against auto-antigens. Taking advantage of this feature, autologous HSC transplantation (auto-HSCT) is likely the only treatment for T1D that is associated with lasting and complete remission. None of the other evaluated immunotherapies worldwide had the clinical efficacy of auto-HSCT. Therapy with auto-HSCT is insulin-independent rather than reducing insulin needs or delaying loss of insulin production. This review provided the latest findings in auto-HSCT for treatment of T1D.     

Disruption of Transplant Tolerance by an “Incognito” Form of CD8 T Cell–Dependent Memory

Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross‐react to donor MHC antigens. Such preexisting “heterologous” memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor‐derived non‐MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8⁺ T cell–dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or “incognito,” form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.     

IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice

Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic β-cells. Both T-cell–mediated adaptive responses as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor–associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in Toll-like receptor pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M–deficient (IRAK-M^−/−) nonobese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis, and increased serum anti-insulin autoantibodies. Mechanistic studies showed that the enhanced activation and antigen-presenting function of IRAK-M^−/− antigen-presenting cells from IRAK-M^−/− mice were responsible for the rapid progression of disease. Moreover, IRAK-M^−/− dendritic cells induced enhanced activation of diabetogenic T cells in vitro and the rapid onset of T1DM in vivo in immunodeficient NOD mice when cotransferred with diabetogenic T cells. This study illustrates how the modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.     

Advances in transplantation immunology

Although there have been dramatic advances in clinical organ transplantation over the past 20 years, rejection, both acute and chronic, and the complications of immunosuppression remain major problems. Nevertheless as our understanding of the immune response to a vascularized organ allograft develops, so too will our ability to develop more specific immunosuppression. In any strategy for more specific immunosuppression compatibility for the major histocompatibility complex of antigens (HLA in man) is likely to be important. Monoclonal antibodies to T cell subpopulations, or even to T cells specifically activated by the graft, provide methods of suppressing the immune response at a more specific level. The recognition that stable grafts are maintained, at least in experimental rodent models, by T suppressor cells may allow development of precise methods of inducing the generation of such cells in clinical practice. The induction of tolerance in the adult animal can be achieved in a number of ways, the most promising of which for clinical application, is antigen pretreatment. If tolerance could be achieved in clinical practice within the not too distant future, then this would represent the attainment of the ultimate goal of transplantation.     

New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy

Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic β-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting.     

Central role for interleukin-2 in type 1 diabetes

Type 1 diabetes presents clinically with overt hyperglycemia resulting from progressive immune-mediated destruction of pancreatic β-cells and associated metabolic dysfunction. Combined genetic and immunological studies now highlight deficiencies in both the interleukin-2 (IL-2) receptor and its downstream signaling pathway as a central defect in the pathogenesis of type 1 diabetes. Prior intervention studies in animal models indicate that augmenting IL-2 signaling can prevent and reverse disease, with protection conferred primarily by restoration of regulatory T-cell (Treg) function. In this article, we will focus on studies of type 1 diabetes noting deficient IL-2 signaling and build what we believe forms the molecular framework for their contribution to the disease. This activity results in the identification of a series of potentially novel therapeutic targets that could restore proper immune regulation in type 1 diabetes by augmenting the IL-2 pathway.     

Oral administration of glomerular basement membrane prevents the development of experimental autoimmune glomerulonephritis in the WKY rat

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of collagenase-solubilized rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The inhibitory effect of orally administered antigens has been reported in various animal models of autoimmunity but not in EAG in the rat. The effects of feeding rat GBM by gavage, at total doses of 0.5, 2.5, or 5 mg, before immunization were examined. A dose-dependent effect was observed on the development of EAG. A dose of 0.5 mg of GBM had no effect on disease, 2.5 mg resulted in a moderate reduction in the severity of nephritis but no change in anti-GBM antibody production, and 5 mg resulted in a marked reduction in circulating and deposited anti-GBM antibodies, albuminuria, deposits of fibrin in the glomeruli, severity of glomerular abnormalities, and numbers of infiltrating T cells and macrophages. Animals that were fed 5 mg of GBM showed a significant reduction in IgG2a but not IgG1, anti-GBM antibody levels, suggesting downregulation of Th1 responses. There was also a dose-dependent reduction in the proliferative responses of splenic T cells from treated animals to GBM antigen in vitro. These results clearly demonstrate that mucosal tolerance can be induced by oral administration of GBM antigen and that this approach is effective in preventing EAG.     

Tolerance induction in clinical transplantation

Introduction of modern immunosuppressive agents has led to great success of allotransplantation in humans, and survival rates for all solid organs have been dramatically improved. However, a constant proportion of organs is lost every year due to chronic allograft rejection and immunosuppressive drug toxicity. This has led to a situation where, despite the of donor organ shortage, about one third of the patients on the kidney transplant waiting list are listed for a retransplant. The induction of donor-specific tolerance has the potential of at least partially resolving this problem, since it might prevent chronic rejection and drug toxicity at the same time. For a variety of protocols, successful tolerance induction has been demonstrated in rodent models. However, translation of such protocols to large animal models and on clinical trials has turned out to be very difficult. This review briefly describes mechanisms and barriers to transplantation tolerance, and then focuses on pre-clinical and clinical studies in non-human primates and humans. We have divided the strategies into two groups, based on the principle mechanisms of tolerance induction: the first group are protocols not using hematopoietic stem cell transplantation (HCT) as part of there regimen. They rely mainly on intensive T cell depletion (either by total body irradiation, total lymphoid irradiation or treatment with T cell-depleting agents such as anti-thymocyte globulin, anti-CD52 antibody or CD3 immunotoxin), which have been combined with costimulatory blockade, signaling blockade or donor antigen infusion. The second group are HCT-based protocols combining HCT with T cell-depleting agents and cytoreductive treatment. So far, only two protocols (one with total lymphoid irradiation and anti-thymocyte globulin, but no HCT; one with HCT, cyclophosphamide, anti-thymocyte globulin and thymic irradiation) have been translated into successful human studies. We summarize and discuss the results of these trials and suggest goals for further studies for the development tolerance protocols applicable for a broad population of allograft recipients.     

Effects of exercise on brain functions in diabetic animal models

Human life span has dramatically increased over several decades,and the quality of life has been considered to be equally important.However,diabetes mellitus(DM) characterized by problems related to insulin secretion and recognition has become a serious health problem in recent years that threatens human health by causing decline in brain functions and finally leading to neurodegenerative diseases.Exercise is recognized as an effective therapy for DM without medication administration.Exercise studiesusing experimental animals are a suitable option to overcome this drawback,and animal studies have improved continuously according to the needs of the experimenters.Since brain health is the most significant factor in human life,it is very important to assess brain functions according to the different exercise conditions using experimental animal models.Generally,there are two types of DM; insulin-dependent type 1 DM and an insulin-independent type 2 DM(T2DM); however,the author will mostly discuss brain functions in T2 DM animal models in this review.Additionally,many physiopathologic alterations are caused in the brain by DM such as increased adiposity,inflammation,hormonal dysregulation,uncontrolled hyperphagia,insulin and leptin resistance,and dysregulation of neurotransmitters and declined neurogenesis in the hippocampus and we describe how exercise corrects these alterations in animal models.The results of changes in the brain environment differ according to voluntary,involuntary running exercises and resistance exercise,and gender in the animal studies.These factors have been mentioned in this review,and this review will be a good reference for studying how exercise can be used with therapy for treating DM.     

CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues

Background  CTLA-4 (cytotoxic T lymphocyte–associated antigen 4) is a modulatory receptor on T cells involved in downregulating T cell activation. In animal models, CTLA-4 blockade abrogates tolerance to “self” antigens, resulting in the augmentation of antitumor immunity and induction of autoimmunity. CTLA-4 blockade by means of monoclonal antibodies (ipilimumab and tremelimumab) has been evaluated in multiple clinical trials in patients with metastatic cancer, mainly those with melanoma and renal cell cancer. Methods  We examine available literature and ongoing clinical trials with ipilimumab and tremelimumab and review our own experience with patients treated with CTLA-4 blockade, with an emphasis on issues of direct relevance to surgical oncologists. Results  CTLA-4 blockade can cause durable tumor regression in patients with metastatic melanoma and other solid tumors. Grade III/IV autoimmune toxicity has been frequently encountered in clinical trials and includes enterocolitis, dermatitis, hypophysitis, uveitis, and hepatitis. Enterocolitis is the most common immune-related adverse event and may cause severe diarrhea requiring intravenous hydration, high-dose corticosteroids, and blockade of tumor necrosis factor alpha with infliximab. Most patients respond to medical treatment, but up to 12% with grade III/IV enterocolitis develop perforation or bleeding that requires colectomy. Conclusions  As more patients are enrolled onto clinical trials involving ipilimumab and tremelimumab, an increasing number of surgeons may be involved in the care of these patients who develop treatment-related complications. In this report, we review the rationale for CTLA-4 blockade and review selected clinical studies published so far with ipilimumab and tremelimumab. We offer guidelines on the management of patients who develop enterocolitis.     

Where do T cells stand in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of cartilage and bone. The destructive lesions result from both immune responses and non-antigen-specific inflammatory processes. Little is known about the primary cause of RA. Although the primacy of T-cell-related events early in the disease remains debated, strong evidence indicates that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. We will discuss evolving concepts about T-cell involvement in RA and the roles for various T cell subsets in the development of joint abnormalities. The hypothesis that RA is a T-cell driven disease was put forward when studies of RA synovium showed numerous T cells carrying activation markers. These T cells were found to participate in the complex network of cell- and mediator-driven events leading to joint destruction. Conceivably, these T cells may be stimulated by an autoantigen (whether specific to the joints or ubiquitous), a highly conserved foreign protein cross-reacting with its human homolog, or a neo-antigen expressed as a result of posttranslational events. For many years, animal models have provided valuable evidence supporting a role for T cells in RA. We will review three murine models of arthritis caused by different mechanisms. In collagen-induced arthritis, the immune response to a joint antigen is mediated by pathogenic Th1 cells that elicit severe inflammatory synovitis. Spontaneous arthritis in K/BxN T-cell-receptor transgenic mice is related to an adaptive immune response against a ubiquitous protein whose end-stage effector mechanisms are heavily dependent on the innate immune system. In the SKG model of autoimmune inflammatory arthritis, a point mutation in the gene encoding a key signal-transduction molecule in T cells causes defective T cell selection in the thymus, which releases polyclonal autoreactive T cells. Studies in these and other animal models have established that a variety of T-cell subsets whose roles vary with cell location and disease stage can contribute to synovitis. Finally, in addition to direct autoimmune attack by effector T cells, arthritis may result from defective homeostatic control of immunity by regulatory T cells.     

Donor bone marrow transplantation: chimerism and tolerance

Infusion of donor bone marrow (DBM)-derived cells continue to be tested in clinical protocols intended to induce specific immunologic tolerance. Central clonal deletion of donor-specific alloreactive cells associated with mixed chimerism reliably produced long-term graft tolerance. In this setting, depletion of recipient T cells by antilymphocyte antibodies and subsequent repopulation by donor hematopoietic cells after donor bone marrow infusion (DBMI) are prerequisites for tolerance induction. Major advances have been made in animal models and in pilot clinical trials and the key questions with the future perspectives are presented in this article.