Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major histocompatibility complex Class II alleles, HLA-DQ, and the related HLA-DR, are the chief genetic elements of human type 1 diabetes. These genes code for polymorphic heterodimeric proteins, whose chief function is to trap peptide antigens in the endosome and present them on the surface of antigen-presenting cells (dendritic cells, B lymphocytes, monocytes/macrophages) to CD4(+) T helper cells. A systematic investigation of the molecular properties of HLA-DQ alleles linked to susceptibility or resistance to type 1 diabetes has shown that these properties segregate along lines of susceptibility or resistance. A correlation of these features with the function of each particular segment of the HLA-DQ molecule yields interesting insights into the possible pathways leading to type 1 diabetes. There remain, however, areas to be clarified, including mechanisms by which dominant protection is conferred by certain alleles, the interplay between HLA-DQ and the related locus HLA-DR, that also shows autoantigen-specific reactivity, and the cross-Class help delivered to CD8(+) T cells, the final effectors in pancreatic beta-cell destruction. Clarification of these issues may lead to ways to prevent diabetes in predisposed individuals already exhibiting the genetic and immunological characteristics, and perhaps a cure in those with the disease, by means of transplantation, and measures for prevention of disease recurrence.
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PMID:Molecular properties of HLA-DQ alleles conferring susceptibility to or protection from insulin-dependent diabetes mellitus: keys to the fate of islet beta-cells. 1211 75

Pancreatic islet xenotransplantation has been advocated as a way of overcoming the shortage of human donor tissue for the treatment of type 1 diabetes. However, the potent immune response against xenografts is a major barrier to their use. We show that a short course of the anti-CD45RB antibody, MB23G2, prolongs survival of fetal pig pancreas grafts in mice. To investigate this effect further we used an i.p. xenograft model in which both donor pig cells and host inflammatory cells can be expediently recovered and analyzed. Graft prolongation was associated with reduced T cell and macrophage infiltration, and reduced production of both T(h)1 and T(h)2 cytokines at the graft site. Graft survival was further increased and T cell infiltration further reduced by combining anti-CD45RB antibody with co-stimulation blockade. The primary effect of anti-CD45RB antibody may be on CD4 T cells, in keeping with the marked reduction in T cell cytokine production in both spleen and graft sites. This concurs with previous studies in allogeneic models that indicate that this antibody perturbs T cell responses by modifying signaling via the TCR. In addition, anti-CD45RB treatment led to reduced expression of LFA-1 and CD62 ligand (CD62L) on CD4 T cells, independent of antigenic challenge. LFA-1 may enhance co-stimulation, and both LFA-1 and CD62L are involved in T cell trafficking. Their reduced expression provides an explanation why the T cell pool is reduced in lymph nodes. We conclude that modulation of inflammation against xenografts by anti-CD45RB antibody is due to effects on both T cell priming and trafficking.
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PMID:Anti-CD45RB antibody deters xenograft rejection by modulating T cell priming and homing. 1214 32

Spontaneous type 1 diabetes in BB rats is dependent on the RT1(u) MHC haplotype and homozygosity for an allele at the Lyp locus, which is responsible for a peripheral T-lymphopenia. Genetic studies have shown that there are other, as yet unidentified, genetic loci contributing to diabetes susceptibility in this strain. BB rats carrying wild-type Lyp alleles are not lymphopenic and are resistant to spontaneous diabetes (DR). Here we show that thymectomy and exposure to one sublethal dose of gamma-irradiation (TX-R) at 4 weeks of age result in the rapid development of insulitis followed by diabetes in 100% of DR rats. Administration of CD4(+)45RC(-) T-cells from unmanipulated, syngeneic donors immediately after irradiation prevents the disease. Splenic T-cells from TX-R-induced diabetic animals adoptively transfer type 1 diabetes to T-deficient recipients. ACI, WF, WAG, BN, LEW, PVG, and PVG.RT1(u) strains are resistant to TX-R-induced insulitis/diabetes. Genetic analyses revealed linkage between regions on chromosomes 1, 3, 4, 6, 9, and 16, and TX-R-induced type 1 diabetes in a cohort of nonlymphopenic F(2) (Wistar Furth x BBDP) animals. This novel model of TX-R-induced diabetes in nonlymphopenic BB rats can be used to identify environmental and cellular factors that are responsible for the initiation of antipancreatic autoimmunity.
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PMID:Thymectomy and radiation-induced type 1 diabetes in nonlymphopenic BB rats. 1235 36

Insulin has been used to modify T-cell autoimmunity in experimental models of type 1 diabetes. In a large clinical trial, the effect of insulin to prevent type 1 diabetes is currently investigated. We here show that insulin can adversely trigger autoimmune diabetes in two mouse models of type 1 diabetes, using intramuscular DNA vaccination for antigen administration. In female nonobese diabetic (NOD) mice, diabetes development was enhanced after preproinsulin (ppIns) DNA treatment, and natural diabetes resistance in male NOD mice was diminished by ppIns DNA vaccination. In contrast, GAD65 DNA conferred partial diabetes protection, and empty DNA plasmid was without effect. In RIP-B7.1 C57BL/6 mice (expressing the T-cell costimulatory molecule B7.1 in pancreatic beta-cells), autoimmune diabetes occurred in 70% of animals after ppIns vaccination, whereas diabetes did not develop spontaneously in RIP-B7.1 mice or after GAD65 or control DNA treatment. Diabetes was characterized by diffuse CD4(+)CD8(+) T-cell infiltration of pancreatic islets and severe insulin deficiency, and ppIns, proinsulin, and insulin DNA were equally effective for disease induction. Our work provides a new model of experimental autoimmune diabetes suitable to study mechanisms and outcomes of insulin-specific T-cell reactivity. In antigen-based prevention of type 1 diabetes, diabetes acceleration should be considered as a potential adverse result.
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PMID:Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice. 1240 15

Phogrin (IA-2beta), a major autoantigen in type 1 diabetes in man is recognized by peripheral T cells in the nonobese diabetic (NOD) mouse. CD4(+) T-cell clones derived from immunized NOD animals elicit islet destruction in a disease transfer model. Spontaneous proliferative responses to the protein and derived peptide epitopes were detected in peripheral lymph node cells (LNC) of unprimed NOD mice but not BALB/c controls as early as 4 weeks of age at a time point when insulitis in NOD animals is minimal. Responses to irradiated NOD islet cells but not irradiated NOD spleen cells were observed for both male and female NOD animals. Insulin, phogrin and phogrin-peptide 7 (aa 755-777) but not phogrin-peptide 2 (aa 640-659) or tetanus toxin peptide were recognized as antigens. Islet cell-reactive and phogrin peptide 7-specific CD4(+) T-cell lines were generated from splenocytes of unprimed 4-week-old NOD females and shown to secrete Th1-type cytokines. The results show that the phogrin molecule is targeted early in the course of disease in NOD animals at a time when circulating autoantibodies are absent and insulitis is minimal.
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PMID:Spontaneous peripheral T-cell responses to the IA-2beta (phogrin) autoantigen in young nonobese diabetic mice. 1241 81

Psoriasis is characterized by a dermal and epidermal infiltrate comprised predominantly of CD4(+) and CD8(+) T cells, respectively. These cells behave in an antigen-dependent manner, which suggests that psoriasis may be a T-cell-mediated autoimmune disease. Psoriasis shares certain immunological features with recognized autoimmune conditions such as type I diabetes mellitus and multiple sclerosis, in both of which a pathogenic role is postulated for natural killer (NK) cells and natural killer-like T (NK-T) cells. However, there are few studies assessing the role of NK and NK-T cells in psoriasis. We sought to determine whether NK and NK-T cells are present in psoriasis. Skin biopsies were taken from the active edge of a psoriasis plaque and from uninvolved skin at least 5 cm away from involved skin of ten patients with chronic plaque psoriasis. Skin from four normal subjects was used as controls. Using an immunoperoxidase technique, cryostat sections were stained using antibodies to T-cell markers CD2, CD3, CD4 and CD8; cutaneous leucocyte associated antigen; NK cell markers CD16, CD56, CD57, CD94 and CD158a; and the NK-T cell marker CD161. There were significantly more cells expressing T cell markers, NK cell markers CD16, CD57, CD94 and CD158a and NK-T cell marker CD161 in involved skin than in uninvolved or normal skin ( P<0.01). There was no difference in the number of cells expressing CD56. Cells expressing NK markers were found most commonly in the papillary dermis immediately subjacent to the dermoepidermal junction. Cells expressing CD57 were found in significantly higher numbers in the epidermis and reticular dermis of involved skin. This study demonstrates that cells expressing NK markers and NK-T cell markers are present in plaques of psoriasis. The exact roles of NK and NK-T cells in psoriasis are unclear, although they may modulate autoimmune inflammation and act as a source of Th(1) cytokines important in the psoriatic process.
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PMID:Natural killer and natural killer-T cells in psoriasis. 1242 Jan 5

We used NOD mice to investigate the effects of injecting transduced lymphocytes on insulitis, nonfasting blood glucose levels, and immune responses. Syngeneic splenocytes were transduced with retroviral particles carrying a cDNA construct encoding the beta cell antigen glutamic acid decarboxylase (GAD65), a secreted form of GAD65 (SGAD55), or secreted alkaline phosphatase (SEAP) as a control antigen. Different multiplicities of infection (m.o.i.) were used with different constructs. Four-week-old NOD mice received intravenous injection of CD4(+) cells isolated from transduced splenocytes, and insulitis and blood glucose levels were determined at 10 weeks of age. No significant effects were observed with lymphocytes transduced with gad65 and sgad55 constructs at low m.o.i. By contrast, at high m.o.i., lymphocytes transduced with the sgad55 and seap constructs caused a decrease in insulitis and blood glucose levels and in insulitis alone, respectively. ELISA of anti-GAD antibody isotypes indicated that GAD-transduced lymphocytes induced similar Th2-like responses at all m.o.i. These results suggest that retroviral particles carrying sgad55 can be used for engineering cell vaccines for type 1 diabetes and provide further evidence that Th2-like responses induced by immunization may not always be a primary cause of diabetes suppression in NOD mice.
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PMID:Decreased insulitis and blood glucose levels after injection of GAD-transduced lymphocytes into NOD mice. 1249 66

B lymphocytes partially contribute to autoimmune type 1 diabetes (T1D) as a subset of APC with a preferential ability to trigger pathogenic CD4 T cells. We hypothesized that this resulted from the unique ability of B lymphocytes to take up pancreatic beta cell proteins through Ig mediated capture. T1D was significantly delayed, but not prevented, in a NOD stock in which the B lymphocyte Ig repertoire was strongly restricted because of the allelic exclusion induced by transgenic Ig molecules specific for the disease irrelevant hen egg lysozyme (HEL) protein (NOD.IgHEL mice). However, introducing the Ig(mu)null mutation to eliminate the small residual numbers of non-transgenic B lymphocytes in the NOD.IgHEL stock strongly suppressed T1D to the same low levels that characterize B lymphocyte deficient NOD.Ig(mu)null mice. In contrast to standard NOD mice, both the NOD.IgHEL.Ig(mu)null and NOD.Ig(mu)null stocks were unable to generate T cell responses against the candidate diabetes autoantigen, glutamic acid decarboxylase. These results indicate that Ig-mediated capture of beta cell autoantigens accounts for why B lymphocytes have a greater capacity than other APC subtypes to trigger diabetogenic T cells. Hence, defects in B lymphocyte, as well as T lymphocyte, tolerance induction mechanisms may contribute to T1D in NOD mice.
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PMID:The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen-specific immunoglobulin receptors. 1251 57

Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 costimulatory molecules, low IL-12 and enhanced IL-10 secretion. We have found that a short treatment with 1,25(OH)(2)D(3) induces tolerance to fully mismatched mouse islet allografts that is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. This effect is enhanced by co-administration of mycophenolate mofetil (MMF), a selective inhibitor of T and B cell proliferation that has also effects similar to 1,25(OH)(2)D(3) on DCs. Graft acceptance is associated with an increased percentage of CD4(+)CD25(+) regulatory cells in the spleen and in the draining lymph node that can protect 100% of syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells, able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells, are also induced by treatment of adult nonobese diabetic (NOD) mice with 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-698). This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non-hypercalcemic doses. The enhancement of CD4(+)CD25(+) regulatory T cells, able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with VDR ligands, suggests possible clinical applications of this approach.
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PMID:Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. 1252 May 19

Given the importance of the NOD mouse as a model of type 1 diabetes, there is a surprising lack of published information on the overall composition of the thymic and peripheral T-cell compartments. In this study, we revisited some earlier reports of T-cell abnormalities in this strain and examined a number of additional parameters to provide a global view of T-cells in prediabetic NOD mice. In some cases, we concur with past conclusions, but in other important areas, we find that NOD mice closely resemble nonautoimmune strains. Specifically, and contrary to published reports, the thymocyte subset distribution, the rate and composition of thymic export, and the composition of the peripheral T-cell pool, including the proportion of CD25(+)CD4(+) T-cells, are essentially normal in prediabetic NOD mice. These factors are therefore unlikely to be involved in the loss of tolerance that leads to autoimmunity within this strain.
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PMID:T-cell compartments of prediabetic NOD mice. 1254 Jun 4


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