Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here, we report on the detection of a novel point mutation of the CTLA4 gene at nucleotide position 159 (C-->G) leading to amino acid substitution at position 53 (I-->M), as well as its association with type 1 diabetes in two ethnically distinct populations. Subjects included 182 unrelated type 1 diabetes children and 201 control subjects from Ghana, West Africa. The Chinese study population consisted of 350 type 1 diabetic children and 420 healthy control subjects from central China. Polymerase chain reaction-single-strand conformation polymorphism and sequence analysis were used to screen for polymorphisms in the CTLA4 gene. CTLA4 49 (A-->G) mutation conferred a risk of type 1 diabetes in the Chinese children (odds ratio 1.78, 95% CI 1.58-2.0), but not in the West African children (1.17, 0.84-1.64). On the other hand, the novel CTLA4 159 (C-->G) mutation conferred a risk of type 1 diabetes in the West African children (2.1, 1.54-2.86), but not in the Chinese type 1 diabetic children. The novel CTLA4 gene polymorphism at nucleotide position 159 significantly associated with type 1 diabetes in West Africans, but not in Chinese. On the other hand, the CTLA4 gene polymorphism at nucleotide position 49 significantly associated with type 1 diabetes in Chinese, but not in West Africans.
Diabetes 2001 Sep
PMID:Association of a novel point mutation (C159G) of the CTLA4 gene with type 1 diabetes in West Africans but not in Chinese. 1152 87

The need for permanent, nonspecific, and potentially harmful immunosuppression remains a major obstacle for islet transplantation. The response of a type 1 diabetic recipient to an islet graft includes a specific allogenic immune response and the recurrence of autoimmunity. Free or encapsulated in an immunoisolation device, islet cells are exposed to immune aggression, initiated by donor antigen-presenting cells or by indirect, host antigen-presenting cell-mediated antigen presentation. CTLA4-Ig is a genetically engineered fusion protein of human CTLA4 and the IgG 1 Fc region. It prevents T-cell activation by binding to human B7, which costimulates T cells through CD28. Interesting data were reported in experimental islet transplantation, suggesting that CTLA4-Ig may be slightly but significantly beneficial to islet allograft survival, although studies in autoimmune diabetes are scarce. The main limitations include transient and low levels of expression when CTLA4-Ig is delivered locally, a predominant effect on the direct recognition pathway, and the lack of effect on memory cells. Clinical trials in islet transplantation could be discussed in nonuremic patients, with steroid-free and anticalcineurin-free regimens, in combination with another costimulation blocker, rapamycin, and an anti-interleukin 2 receptor antibody, and with a strategy directed against the recurrence of autoimmunity.
 ...
PMID:Immunomodulation with CTLA4-Ig in islet transplantation. 1181 61

Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti-IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti-IL-2R regimen (n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-gamma enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model.
Diabetes 2002 Feb
PMID:Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. 1181 31

Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.
 ...
PMID:Impact of genetic and non-genetic factors in type 1 diabetes. 1211 72

Collagen Induced Arthritis (CIA) is a widely studied animal model to develop and test novel therapeutic approaches for treating Rheumatoid Arthritis (RA) in humans. Soluble Cytotoxic T-Lymphocyte Antigen 4 (CTLA4-Ig), which binds B7 molecule on antigen presenting cells and blocks CD28 mediated T-lymphocyte activation, has been shown to ameliorate experimental autoimmune diseases such as lupus, diabetes and CIA. Objective of our research was to investigate in vivo the effectiveness of blocking the B7/CD28 T-lymphocyte co-stimulatory pathway, utilizing a gene transfer technology, as a therapeutic strategy against CIA. Replication-deficient adenoviruses encoding a chimeric CTLA4-Ig fusion protein, or beta-galactosidase as control, have been injected intravenously once at arthritis onset. Disease activity has been monitored by the assessment of clinical score, paw thickness and type II collagen (CII) specific cellular and humoral immune responses for 21 days. The adenovirally delivered CTLA4-Ig fusion protein at a dose of 2x10^8 pfu suppressed established CIA, whereas the control beta-galactosidase did not significantly affect the disease course. CII-specific lymphocyte proliferation, IFNgamma production and anti-CII antibodies were significantly reduced by CTLA4-Ig treatment. Our results demonstrate that blockade of the B7/CD28 co-stimulatory pathway by adenovirus-mediated CTLA4-Ig gene transfer is effective in treating established CIA suggesting its potential in treating RA.
 ...
PMID:[Recombinant adenovirus-mediated gene transfer suppresses experimental arthritis] 1246 78

Our goal is to develop effective islet xenografts for treating human diabetes. We have studied microencapsulated neonatal porcine islet cell clusters (ICCs) transplanted intraperitoneally in spontaneously diabetic NOD mice, where they function to maintain normoglycemia in the autoimmune host. Nonencapsulated neonatal porcine ICCs functioned for 4.5 +/- 0.5 days before being rejected; encapsulation prolonged graft function to 17 +/- 2 days. CTLA4-Ig treatment did not enhance the survival of nonencapsulated ICCs. However, CTLA4-Ig treatment significantly extended the function of encapsulated ICCs to 73 +/- 5 days. Histological analyses demonstrated a profuse pericapsular cellular reaction associated with rejection of encapsulated islet xenografts in untreated mice, while this reaction was significantly reduced in CTLA4-Ig-treated mice. To study mechanisms of xenograft rejection in this model, we analyzed proliferative responses to neonatal porcine ICCs and cytokines present in the peritoneal cavities of transplanted mice. Spleen cells from both CTLA4-Ig-treated and untreated rejecting NODs exhibited vigorous proliferation in the absence of antigenic stimulation, suggesting prior activation in vivo, while splenocytes from CTLA4-Ig-treated NODs with functioning grafts had low proliferative levels, equal to controls. Islet-specific proliferation was not detected in islet-rejecting mice, perhaps due to their high background levels. With the exception of elevated IL-6 levels, empty capsules did not provoke a significant peritoneal cytokine response compared with sham surgery or untransplanted control mice. However, IL-5, IL-12, TGF-beta, and IL-1beta were significantly elevated in NODs receiving encapsulated neonatal porcine ICCs compared with untransplanted controls. There were no significant differences between peritoneal cytokine concentrations in CTLA4-Ig-treated mice with long-term functioning grafts compared to mice that rejected grafts at earlier time points. We conclude that the combination of donor islet microencapsulation and brief treatment of the recipient with co-stimulatory blockade delays sensitization of the host, possibly by altering mechanism(s) for recruitment and/or activation of host effector cells.
 ...
PMID:Proliferative and cytokine responses in CTLA4-Ig-treated diabetic NOD mice transplanted with microencapsulated neonatal porcine ICCs. 1251 96

CD4+CD25+ T cells regulate a variety of autoimmune and alloimmune responses including the development of autoimmune diabetes in non-obese diabetic (NOD) mice. We have examined the role of CD28/CTLA4/B7 interactions in the expansion and survival of CD4+CD25+ regulatory T cells (T(reg)) in this setting. CD28/ B7 interactions are essential in the development of T(reg) in the thymus and for their survival in the periphery. The CD28-mediated homeostasis of these cells is independent of Il2, OX40, CD40L, and survival factor Bcl-XI. In addition, analysis of T(reg) from CTLA4-deficient mice suggests that CTLA4 expression is not required for their development or function. However, non-activating anti-CTLA4 antibodies blocked the suppressor activity of regulatory cells in vitro. Thus, clinical application of co-stimulatory blockade using agents such as CTLA4Ig in the treatment of autoimmune disease may result in complicated outcomes.
 ...
PMID:The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. 1460 12

Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance. Until recently, only three susceptibility genes had been reproducibly identified, namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new putative susceptibility genes have been isolated from both human and animal models of the disease. We present eight genes implicated in type 1 diabetes etiology and discuss them in relation to the pathogenesis of the disease: VDR, IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.
 ...
PMID:New autoimmune genes and the pathogenesis of type 1 diabetes. 1503 74

Type I diabetes is the result of a selective destruction of insulin-producing beta cells in pancreatic islets by autoreactive T cells. Depletion of autoreactive T cells through apoptosis may be a potential strategy for the prevention of autoimmune diabetes. Simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by a CTLA4-Fas ligand (FasL) fusion protein has been reported to lead to enhanced in vitro apoptosis of peripheral lymphocytes. To test the feasibility of CTLA4-FasL-based gene therapy to prevent autoimmune diabetes, we developed a recombinant adenovirus containing the human CTLA4-FasL gene (AdCTLA4-FasL). A single injection of 2 x 10(8) plaque-forming units of AdCTLA4-FasL via the tail vein of mice greatly reduced the incidence of autoimmune diabetes (13%, n=15) induced by multiple low-dose streptozotocin. AdCTLA4-FasL administration abrogated pancreatic insulitis, significantly increased apoptosis of pancreatic T-lymphocytes, and altered splenocyte response to mitogenic and antigenic stimulation. These results indicate the therapeutic potential of simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by adenovirus-mediated CTLA4-FasL gene transfer in the prevention of autoimmune diabetes.
 ...
PMID:Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin. 1504 21

Type 1 diabetes (T1D) is a complex autoimmune disease. Several genetic loci have been implicated in the susceptibility to this illness. Evaluated was the role of the CTLA4 exon 1 A49G polymorphism and its role as a risk factor for T1D in our population. DNA from 190 patients with T1D and their families and 96 control individuals were genotyped for CTLA4 exon 1 polymorphism and human leukocyte antigen (HLA)-DQB1*0201 and *0302 haplotypes by polymerase chain reaction (PCR) amplification-restriction enzyme analysis and PCR amplification that used sequence-specific primers, respectively. Patients were nonobese and <26 years old. The CTLA4 G allele was found to be more frequently present in patients with T1D (32.4%) as compared with its frequency in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). chi(2) analysis and family-based association studies were performed and suggested the association of CTLA4 exon 1 G polymorphism with T1D (p = 0.0229). Furthermore, in HLA-DQB1*0201-positive patients with T1D, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. This study suggests that CTLA4 is a candidate susceptibility gene for T1D.
 ...
PMID:Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene. 1530 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>