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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes in NOD mice represents the end stage of a genetically-programmed autoimmune process mediated by T lymphocytes and directed against insulin-producing beta cells. We have shown in a previous study that the course of the disease is significantly inhibited in NOD mice which have been made tolerant at birth to foreign histocompatibility antigens. This early T cell manipulation results in a significant delay of disease onset, reduced overall incidence and less severe alterations of islet cells. In order to characterize better the nature of the foreign tolerogenic determinants responsible for this protection, we have now examined separately the contribution of MHC and non-MHC antigens. Two lines of congenic mice were used as donors of tolerogenic cells, NOD.H-2b, which differ from NOD by the MHC-encoded antigens only, and B10.H-2g7, which differ by all the minor histocompatibility antigens encoded by the B10 background, but which share with NOD mice the same MHC haplotype. Our results show that NOD recipients of F1 semi-compatible cells become specifically tolerant to the set of alloantigens to which they were neonatally exposed. Unresponsiveness, assessed by lack of CTL generation, is profound and specific. Yet, despite the fact that distinct sets of alloreactive T cell precursors are silenced, mice made tolerant indifferently to major or minor histocompatibility antigens are significantly protected against overt diabetes. These results could mean that each set of MHC and non-MHC encoded determinants can independently cross-tolerize a sufficient proportion of the autoreactive repertoire to slow the natural course of the disease. Alternatively, neonatally-acquired tolerance might induce polyclonal activation of the immune system resulting in the suppression or the immunodeviation of potentially harmful, autoreactive T cell clones.
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PMID:Acquired allo-tolerance to major or minor histocompatibility antigens indifferently contributes to preventing diabetes development in non-obese diabetic (NOD) mice. 141 96

We recently reported that reconstitution of lethally irradiated B10 mouse recipients with 40 x 10(6) untreated WF rat bone marrow cells resulted in stable fully xenogeneic chimerism (WF rat----B10 mouse). In these animals, the tolerance induced for skin xenografts was highly MHC specific in that donor-specific WF rat skin grafts were significantly prolonged while MHC-disparate third-party xenografts were rapidly rejected (median survival time [MST] = 9 days). We have now examined whether islet cell xenografts placed under the renal capsule of chimeras rendered diabetic with streptozotocin would be accepted and remain functional to maintain euglycemia. Animals were prepared, typed for chimerism at 6 weeks, and diabetes induced with streptozotocin. Donor-specific WF (Rt1Au) islet cell xenografts were significantly prolonged (MST greater than 180 days) in WF----B10 chimeras, while MHC-disparate third-party F344 rat (Rt1A1) grafts were rejected with a time course similar to unmanipulated B10 mice (MST = 8 days). The transplanted donor-specific islet cells were functional to maintain euglycemia, since removal of the grafts at from 100 to 180 days in selected individual chimeras uniformly resulted in return of the diabetic state. These data suggest that donor-specific islet cell xenografts are accepted and remain functional in mice rendered tolerant to rat xenoantigens following bone marrow transplantation.
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PMID:Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (WF rat----B10 mouse). 173 20

An experimental autoimmune diabetes in mice characterized by delayed-onset hyperglycemia with lymphocytic infiltrations of the pancreatic islets can be induced by multiple administrations of low doses of streptozocin (STZ). We report on the influence of the MHC (H-2 complex) on this autoimmune diabetes by comparing the susceptibilities of various congenic and recombinant strains with a B10 background. In congenic strains, C57BL/10 (H-2b) and B10.BR (H-2k) mice showed a high incidence of diabetes, whereas B10.D2 (H-2d) and B10.S (H-2s) mice showed a low incidence. Therefore, we suggest that the H-2 complex influences diabetes susceptibility and that both b and k are high-susceptibility alleles, whereas d and s are low-susceptibility alleles. In recombinant strains, those with the same haplotypes on the K, E, S, and D subregions of the H-2 complex showed undefined (high and low) susceptibilities, indicating that the diabetes-susceptibility genes are located outside these loci. Strains possessing I-Ab or I-Ak gene products (C57BL/10, B10.BR, B10.TL, B10.A, and B10.A(2R] showed high incidences, whereas strains possessing I-Ad or I-As (B10.D2, B10.S, B10.S(7R), B10.S(9R), and B10.GD) showed low incidences. In addition, administration of anti-I-A monoclonal antibody prevented the manifestation of diabetes in STZ-administered mice. Passive transfer of STZ-administered T lymphocytes to mice given minute doses of STZ induced significant hyperglycemia. This successful transfer was only observed in H-2-compatible mice. Thus, we conclude that one gene coding for susceptibility to this experimental diabetes was located in the I-A subregion within the H-2 complex.
Diabetes 1990 Oct
PMID:Genetic control by I-A subregion in H-2 complex of incidence of streptozocin-induced autoimmune diabetes in mice. 214 88

The Class I gene, H-2Kb, was linked to the rat insulin promoter and the construct inoculated into fertilized mouse eggs to produce lines of transgenic mice. Mice which expressed the Class I molecule in the beta cells of the pancreas developed diabetes and progressive loss of their pancreatic beta cells. This occurred whether the transgene product was syngeneic or allogeneic with respect to its host. No lymphocytic infiltration was ever seen in transgene expressing mice, even in those deliberately immunized with H-2Kb-bearing cells. When the transgene product was allogeneic, spleen cells from the transgenic mice stimulated in vitro with irradiated B10.A(5R) cells (KbDd), could kill H-2d targets in vitro, but not targets bearing H-2Kb. Responsiveness of spleen cells to H-2Kb targets returned with advancing age, as the severity of diabetes increased. The results indicate that diabetes in this model occurs independently of the immune system, and point to an extra-thymic mechanism of tolerance induction dependent on the continuous presence of antigen.
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PMID:Tolerance and diabetes in transgenic mice over-expressing class I histocompatibility molecules in pancreatic beta cells. 218 64

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Care 1990 Jun
PMID:Lessons learned from molecular biology of insulin-gene mutations. 219 46

B10.BR, DBA/2, and BALB/c by J mice were infected with Trypanosoma brucei rhodesiense (Lou Tat clone 1). Subsequent infection with the D variant of encephalomyocarditis virus (EMC-D) resulted in no diabetes or encephalitis, even in the susceptible DBA/2 and BALB/c by J strains. Low levels of circulating interferon (IFN) were detected in trypanosome-infected mice at the time of EMC-D infection. All strains were severely immunosuppressed as a result of trypanosome infection, as evidenced by decreased virus-specific neutralizing antibody titers, compared to virus-infected controls. We attempted to simulate some aspects of T.b. rhodesiense infection in B10.BR mice by pretreating mice with cyclophosphamide and IFN prior to EMC-D infection. Immunosuppression by cyclophosphamide greatly enhanced the pathogenesis of EMC-D, while IFN protected against the diabetogenic effect of this virus. Our results indicate that: (i) T.b. rhodesiense infection inhibited EMC-D-induced diabetes, (ii) this inhibition was not due solely to the immunosuppression generated by the trypanosome infection, and (iii) IFN generated by the trypanosome infection could play some protective role in the inhibition of EMC-D-induced diabetes by trypanosome infection.
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PMID:Trypanosoma brucei rhodesiense infection in mice prevents virus-induced diabetes: possible role of interferon and immunological mechanisms. 243 62

T cell autoreactivity to insulin in type I diabetic and related non-diabetic individuals was analyzed. Peripheral T lymphocytes from both insulin-treated diabetic and untreated non-diabetic members of four families were found to proliferate in vitro in response to human insulin. T cell autoreactivity to insulin therefore does not appear to be diagnostic of the onset of type I diabetes. Highest T cell responses to human insulin were usually detected in insulin-dependent type I diabetes patients treated with a mixture of beef and pork insulin than with self insulin, the greater the dose of animal insulin the higher the T cell response. The T cell repertoires for self insulin appear to be similar in diabetics and non-diabetics based on their patterns of T cell reactivity to beef insulin, port insulin, human insulin, and various peptide of human insulin. The autoreactive T cells analyzed recognize two conformational epitopes of human insulin formed by interactions between A chain and B chain residues. One epitope is associated with the A chain loop and is present in the A1-A14/B1-B16 peptide, and the other epitope consists mainly of B chain residues located in the A16-A21/B10-B25 peptide. These two epitopes are present in amphipathic alpha-helical regions of insulin. HLA-DR (DR3, DR4, and DR5) and HLA-DQ (DQw2/DQw3) Ag can restrict these T cell responses to human insulin epitopes. The ability to detect insulin-specific autoreactive T cells in healthy non-diabetic individuals supports the hypothesis that autoreactive lymphocytes do not necessarily elicit autoimmune disease if present in an environment in which their activity is immunoregulated.
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PMID:T cell autoreactivity to insulin in diabetic and related non-diabetic individuals. 245 92

Coxsackie B viruses are known etiological agents of pancreatic diseases, including diabetes. The pathogenesis of these infections is influenced by both host and viral factors. In this report, we examined whether the outcome of Coxsackie B4 virus infection is dependent on the genes within the major histocompatibility complex (MHC). We generated a pancreatic variant, CB4-V and established an animal model system of pancreatitis with concurrent hypoglycemia in mice. Infection of various B10 H-2 congenic strains of mice revealed that the development of hypoglycemia with accompanying pancreatitis was independent of the MHC haplotype. However, the severity of the disease as monitored by the extent and duration of hypoglycemia and by mortality rate was found to be associated with the H-2 haplotype, specifically the H-2Kq locus. Pancreatic damage induced by CB4-V appeared to be both immune-mediated and viral-mediated. Histological examination of pancreatic tissue from infected B10 H-2 congenic mice revealed an association between acute destruction of the exocrine pancreas and lymphocytic infiltration. This infiltration may correlate with immune-mediated destruction of the infected pancreatic tissue. Since preferential replication of CB4-V was not observed in the most susceptible B10 mouse strain, direct viral destruction may not be the major mechanism of pancreatic injury.
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PMID:Severity of disease induced by a pancreatropic Coxsackie B4 virus correlates with the H-2Kq locus of the major histocompatibility complex. 256 Feb 95

In vitro manipulation of pancreatic islets to decrease islet immunogenicity before transplantation has largely been directed at eliminating the major histocompatibility complex (MHC) class II-positive passenger leukocytes from the islets. The mixed islet-lymphocyte coculture (MILC) system was used to quantitate the efficacy of immunodepletion of MHC class II-positive cells from pancreatic islets in terms of reducing immunogenicity. With these experiments we compared the in vitro immunogenicity of MHC class II-depleted islets with untreated islets. B10.BR (H-2k) islets were treated with anti-Iak alloserum followed by complement. This treatment successfully eliminated MHC class II-positive cells from the islets, as demonstrated by indirect immunofluorescence techniques. Depleted islets generated slightly lower amounts of allospecific cytotoxic T-lymphocyte (CTL) activity when exposed to C57BL/6 (H-2b) splenocytes in the MILC than untreated control islets. Although the amount of CTL generated by the depleted islets was slightly less than that generated by untreated islets, there was significant stimulation of CTL by the MHC class II-depleted islets. Therefore, the presence or absence of MHC class II cells within the islet is unlikely to be the decisive factor contributing to islet immunogenicity.
Diabetes 1989 Jan
PMID:Effect of immunodepletion of MHC class II-positive cells from pancreatic islets on generation of cytotoxic T-lymphocytes in mixed islet-lymphocyte coculture. 264 41

Reciprocal allogeneic bone marrow transplantations were carried out between diabetes-susceptible nonobese diabetic (NOD) and diabetes-nonsusceptible C57BL/6 or B10.BR/cd mice to examine the role of the immune system and host environment in the development of autoimmune diabetes. Serotyping of lethally irradiated hosts reconstituted with allogeneic bone marrow showed the hematopoietically derived cells to be of donor origin. Our results showed that lethally irradiated NOD mice reconstituted with a B10.BR/cd hematopoietic cell system remained totally free of insulitis, failed to develop diabetes, and thrived to old age. In contrast, lethally irradiated C57BL/6 or B10.BR/cd mice reconstituted with an NOD hematopoietic cell system all developed insulitis, but only approximately 10% progressed to overt diabetes. Direct adoptive transfer of insulitis and diabetes by mature T-lymphocytes apparently was not required; analogous results were obtained when diabetes-nonsusceptible hosts were reconstituted with NOD hematopoietic cells containing T-lymphocytes or devoid of Thy-1+ cells. The difference in frequency for the development of insulitis versus insulitis plus overt diabetes in C57BL/6 and B10.BR/cd mice suggests that the hematopoietically derived immune cells from NOD mice were sufficient to induce anti-islet reactivity but may require the diabetogenic host environment to develop the frequency and severity of diabetes observed in NOD mice.
Diabetes 1989 Jul
PMID:Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes. 266 Dec 86


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