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E Colle

Publications and source records attributed to E Colle.

At least 37 records · Page 2Linked to original sources
PubMed1989

Interferon-gamma induces transcription and differential expression of MHC genes in rat insulinoma cell line RINm5F.

We have reported that enhanced levels of class I major histocompatibility complex (MHC) antigen are expressed throughout the islets of prediabetic and newly diabetic BB rats and that the endocrine cells of the islet remained class II negative. In this study we investigated the molecular biology of lymphokine-induced expression of the class I and II MHC genes in subclones of the rat insulinoma cell line RINm5F. Treatment of a particular subclone of RINm5F cells (which are normally class II negative, class I low expressors) with crude lymphokine preparation or various doses of recombinant interferon-gamma resulted in enhancement of MHC class I antigen expression but no detectable induction of class II antigen expression. This enhancement of class I antigen expression was a dose-dependent phenomenon and was preceded by a dose-dependent increase in class I-specific RNA. Both class I and II genes were induced at the transcriptional level, as determined by Northern blotting and in vitro nuclear transcription assays, but exhibited strikingly different induction kinetics. Supernatants from concanavalin A-stimulated splenocytes had a similar class I-restricted inductive effect on MHC gene expression. This subclone of RINm5F cells, which exhibits a class I lymphokine response-positive, class II response-negative phenotype, 1) mimics the behavior of beta-cells in the prediabetic and newly diabetic pancreas and 2) represents a valuable system for probing the similarities and differences in the lymphokine-mediated induction pathways for class I and II MHC genes.

Adenoma, Islet Cell↗
PubMed1989

Case-control study of IDDM.

Insulin-dependent diabetes mellitus (IDDM) may be caused by a combination of genetic predisposition and environmental insults. However, there are few solid leads concerning human diabetogenic environmental agents. A case-control study was carried out to investigate the possible relationships between IDDM and various biological, chemical, and psychological factors. All 161 cases of IDDM among children aged 0-17 yr occurring in Montreal from 1983 to 1986 were included. The parent of each newly diagnosed diabetic subject was asked to provide the names of two of the child's friends or neighbors who would be age and sex matched to serve as controls. For those unable to do so, matched controls were selected from a hospital emergency room. Parents of cases and controls were interviewed concerning many factors. There was little or no difference between cases and controls with regard to parental smoking habits, exposure to pets, and consumption of meat products high in nitrosamines. In univariate analyses, there was some indication of elevated risk for children who had not been breast-fed, who attended day care or nursery before age 5 yr, who lived in a crowded household at age 3 yr, or who had a history of asthma or eczema, although in multivariate analyses the only variables that had any effect were crowding and day-care attendance. In univariate and multivariate analyses, there was high risk of IDDM among children who had experienced selected stressful life events during the 12 mo preceding onset of IDDM or who had exhibited symptoms of social or psychological dysfunction during that time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Susceptibility and resistance genes to insulin-dependent diabetes mellitus in the BB rat.

Insulin-dependent diabetes mellitus (IDDM, type I) is an autoimmune disorder exhibiting a strong association with particular haplotypes of the major histocompatibility complex (MHC). We have previously shown that the u haplotype of the rat MHC (RT1) is absolutely required for expression of IDDM in the BB rat model of the disease. To define the precise regions of the RT1 contributing to disease occurrence and to address the mechanism by which the associated haplotype participates in disease pathogenesis, we have transferred recombinant haplotypes bearing the IDDM-associated MHC in defined regions onto the BB rat genetic background. In this report, we present data from two breeding studies utilizing the r8 haplotype (RT1AaBuDuEuCu) that demonstrate that (1) the RT1A locus is not involved in the disease association, (2) the MHC genes determining disease susceptibility are not unique to the BB rat, and (3) IDDM resistance genes are found outside the MHC. We also present evidence that the immunoregulatory defect characteristic of BB rats enhances the incidence of IDDM although it is not absolutely required for disease expression. We were able to track the transmission of the recombinant haplotypes in diabetic progeny using a combination of monospecific alloantisera and restriction fragment length polymorphism analysis using locus-specific MHC gene probes.

Animals↗
PubMed1989

Immunologic and genetic studies of diabetes in the BB rat.

The spontaneous development of diabetes in the Bio-Breeding (BB) rat is an excellent model of human insulin-dependent diabetes mellitus (IDDM). Disease expression is dependent on several genetically determined abnormalities, including specific major histocompatibility complex (MHC) genes. At least one MHC class II locus of the U haplotype is a necessary, but not sufficient, condition for disease expression. The immune system of BB rats is markedly abnormal. There is a striking reduction in the number and function of mature cytotoxic/suppressor T cells, a poor proliferative response to mitogens and in mixed lymphocyte culture, poor interleukin-2 production, and a reduced ability to reject skin allografts. While these immune system abnormalities are closely related to the development of diabetes, the immune recognition and effector mechanisms resulting in islet cell destruction are still poorly understood. The hypothesis that MHC class II induction on pancreatic beta cells serves to target these lymphokines, natural killer (NK) cells, macrophages, etc.) have been implicated in islet cell killing. The incidence of IDDM is reduced by immunosuppressive therapy in both rats and humans, further supporting the role of immune mechanisms in this disease.

Animals↗
PubMed1989

The effect of islet-activating protein (IAP) of pertussis toxin on the spontaneous diabetic syndrome in the rat.

The administration of the Islet-Activating Protein (IAP) of pertussis toxin results in an increased insulin response to oral glucose in a dose- dependent manner. This response can be detected for up to 12 days after a single injection. In addition, IAP increases the number of peripheral blood leucocytes and lymphocytes. Inbred strains of rats differ in the magnitude of the leucocyte but not the insulin responses to IAP. Multiple injections of 1,000 ng of IAP to diabetes-prone BB rats at 50, 64 and 78 days of age caused an increased release in response to glucose challenge and a slight increase in peripheral blood leucocytes when compared to animals receiving saline injections. The prevalence of insulin-dependent diabetes in BB rats was increased in the IAP group as compared to controls. Histolgic examination of the pancreas at the time of detection of diabetes revealed a widespread intense insulitis. We speculate that the increased expression of disease observed in the BB rats receiving IAP may be secondary to the chronic increase in insulin release and/or to an effect on the cells of the immune system.

Animals↗
PubMed1988

Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line in vitro following exposure to gamma interferon.

A study of Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line (RINm5F) was performed using monoclonal antibodies and immunoperoxidase techniques. RINm5F cells were incubated with different concentrations of gamma interferon. RINm5F cells exhibit low levels of Class I molecules and are normally devoid of Class II gene products. Upon exposure to gamma interferon, RINm5F cells showed a dramatic increase in Class I expression. This expression was homogenous and could be detected on all cells after 18 h of incubation with as little as 1 unit/ml of interferon. In contrast, de novo Class II expression was not homogeneous and required 36 h of incubation with 10 units/ml of interferon. The number of RINm5F cells expressing Class II antigens was dose- and time-dependent. Interferon treatment did not affect the morphology of RINm5F cells as determined by ultrastructural analysis. Withdrawal of interferon from the culture medium for as long as 78 h diminished but did not abolish the expression of Class I and Class II molecules already induced. The ability of interferon to enhance expression of Class I gene products and induce de novo expression of Class II molecules on B-cell-derived RINm5F cells supports the hypothesis that aberrant expression of major histocompatibility complex gene products on pancreatic B cells may be an important factor in triggering the immune response in Type 1 (insulin dependent) diabetes mellitus.

Adenoma, Islet Cell↗
PubMed1988

Autoimmunity-prone BB rats lack functional cytotoxic T cells.

BB rats are prone to develop an autoimmune form of insulin-dependent diabetes mellitus (IDDM) and thyroiditis. Development of autoimmunity is thymus dependent. Previous studies have shown that BB rats lack a population of T cells bearing the RT6 antigen and have very low numbers of suppressor/cytotoxic T cells. In this study, we confirm that BB rats have decreased numbers of phenotypic T suppressor/cytotoxic (Ts/c) cells (OX19+, OX8+ cells) in their lymphoid organs. Moreover, we find that the phenotypic Ts/c cells of BB rats lack apparent cytotoxic activity. These T cells fail to kill allogeneic target cells in a cell-mediated lympholysis assay and fail to generate lectin-dependent cytotoxicity. The addition of interleukin 2, gamma-interferon, and other lymphokines to cultures of BB T cells does not induce functional cytotoxic T lymphocytes. We find that the activated T cells of newly diabetic rats are incapable of killing major-histocompatibility-complex-matched islet cells, despite the ability of these cells to cause IDDM in passive transfer experiments. We conclude that autoimmune disease occurs in BB rats in the absence of functional cytotoxic T cells.

Animals↗
PubMed1988

Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex.

This study was designed to map the diabetes susceptibility gene(s) associated with the rat major histocompatibility complex (MHC) RT1. We have crossed spontaneously diabetic male rats bearing the recombinant RT1r8 haplotype with female rats of the AC1.1r4 congenic strain. Three diabetic rats were determined to be homozygous for the r4 haplotype by serotyping. The absence of recombination within the MHC was confirmed by inspection of restriction-fragment-length patterns of the diabetic animals and the parental strains. In conjunction with previous breeding studies, this study maps the diabetes susceptibility gene to the right of the RT1-A locus and to the left of the RT1-C locus. A low incidence of diabetes in the F2 (4.5%) emphasizes the multifactorial nature of the susceptibility. The presence of depressed responsiveness of peripheral blood lymphocytes to concanavalin A stimulation increases the prevalence of the overt disease. An unusual feature of the diabetic syndrome in this study is the sparse or absent pancreatic lymphocytic inflammatory response, with true insulitis being a rare finding.

Animals↗
PubMed1988

Two-color flow cytometry analysis of activated T-lymphocyte subsets in type I diabetes mellitus.

We addressed the question of whether newly diagnosed type I (insulin-dependent) diabetes mellitus patients showed an increased number of DR (la+) T-lymphocytes compared with nondiabetic siblings and normal control subjects. Two-color flow cytometry measurements of peripheral-blood lymphocytes showed a slight but statistically significant increase in DR+ T-lymphocytes in diabetic subjects as well as the nondiabetic sibling control compared with the normal control subjects. This difference was not present in long-term-diabetic subjects. Thus, in addition to minor changes in this lymphocyte subset in peripheral blood, the sibling data demonstrate a lack of specificity for the disease; therefore, these measurements are probably of limited diagnostic usefulness.

Adolescent↗
PubMed1988

Incidence of IDDM in Montreal by ethnic group and by social class and comparisons with ethnic groups living elsewhere.

We examined the incidence of insulin-dependent diabetes mellitus (IDDM) among children aged 0-14 yr in Montreal by social class and by ethnic group from 1971 to 1985. There was a slightly higher risk in wealthier as opposed to poorer classes. This income gradient was more marked in younger than in older children. Children of French extraction had about two-thirds the risk of IDDM of children of other origins, mainly British and other European. This mimics the patterns of risk in Europe, where France is reported to have lower rates than does Britain and Scandinavia. The absolute levels of risks among French Canadian and Jewish Canadian children were about double those reported from France and Israel, respectively. These various results are compatible with the hypothesis that both genetic and environmental factors influence IDDM risk.

Adolescent↗
PubMed1988

Epitope specificity of spontaneous and induced thyroglobulin autoantibodies in the rat.

We have investigated the epitope specificities of rat thyroglobulin (Tg) autoantibodies arising either spontaneously in BB hybrid and BB rats or following induction in normal rats with thyroglobulin and adjuvant. Using a panel of thyroglobulins from different animal species it was possible to identify three different patterns of reactivity. These were: 1) recognition of all species of thyroglobulin; (2) recognition restricted to rat and mouse thyroglobulins and 3) recognition biased towards dog, rat and mouse thyroglobulins. Furthermore, using human thyroglobulin manifesting different levels of iodination, it was possible to show that sera with recognition pattern 1 recognized the iodination site of thyroglobulin and that this was inhibitable by thyroxine. Taken together these data provide evidence of restricted epitope recognition by Tg autoantibodies in the rat.

Animals↗
PubMed1988

IDDM in BB rats. Enhanced MHC class I heavy-chain gene expression in pancreatic islets.

Modulation in major histocompatibility complex (MHC) gene expression correlates with the inflammatory reactions that occur during graft rejection and autoimmune disease. We analyzed the expression of class I and II MHC genes in the pancreatic islets of prediabetic and newly diabetic BB rats by immunohistochemistry of tissue sections and Northern blotting of RNA extracted from isolated islets. We show that enhanced levels of MHC class I heavy-chain RNA are present in pancreatic islets before overt inflammation and the onset of insulin-dependent diabetes mellitus (IDDM) in the spontaneously diabetic BB rat. Immunohistochemical analysis revealed enhanced class I antigen expression throughout the pancreatic islets of newly diabetic animals but no induction of class II antigen on endocrine cells within the islet. Varying degrees of inflammatory infiltrate were observed in the sections exhibiting enhanced class I antigen expression or in nearby serial sections. Southern blot analysis revealed no restriction-fragment-length polymorphism or amplification of the endogenous class I heavy-chain genes compared with those of seroidentical disease-resistant Wistar-Furth rats. I-A alpha and I-E alpha hybridizing RNA appeared de novo before overt diabetes, although concomitantly with T-lymphocyte-receptor beta-chain and interferon-gamma gene hybridizing RNA and after MHC class I heavy-chain RNA enhancement was observed. These data indicate the possibility that enhanced class I heavy-chain gene expression plays a role in the progression of IDDM.

Animals↗
PubMed1988

The effect of diet on the spontaneous insulin dependent diabetic syndrome in the rat.

We have fed rats prone to developing spontaneous insulin dependent diabetes mellitus (IDDM) defined diets in which casein was the sole source of protein and the fat content was either menhaden oil, safflower oil, or corn oil. The incidence of IDDM was compared to that in litter mates fed rat chow. Animals receiving the defined diets had a lower frequency of overt IDDM than did animals receiving rat chow. The effect was seen only when the diet was introduced before the animals had reached the age of 30 days. The defined diets did not affect the distribution of peripheral blood T lymphocytes. Rats fed defined diets had decreased intensity of expression of Class I major histocompatibility complex (MHC) products on the endocrine cells of the pancreas compared to animals receiving rat chow.

Animals↗
PubMed1987

Major histocompatibility complex restriction of T-lymphocyte responses to islet cell antigens in IDDM rats.

BBUF rats, derived from BB rats, spontaneously develop a form of insulin-dependent diabetes mellitus (IDDM) associated with infiltration of the islets of Langerhans by lymphocytes (insulitis). BBUF rats bear the RT1u major histocompatibility complex (MHC) haplotype that we have shown to be necessary for the expression of this form of IDDM. A T-lymphocyte line obtained from the pancreas of a diabetic rat (UPCC.5) and three T-lymphocyte hybridomas derived by fusing T-lymphocytes of BBUF rats (MUS1.2, MUS1.13, and MUP3.21) respond to islet cell antigens in an MHC-restricted way. UPCC.5 responds to a combination of islet cell antigens (ICAg) and antigen-presenting cells by proliferation, whereas the T-hybridoma responses are detected on the basis of IL-2 production in a similar assay. This study reveals that an antiserum against mu-haplotype MHC antigens or a monoclonal antibody against the product of the D class II subregion of the rat MHC could inhibit ICAg recognition. A monoclonal antibody against the product of the B class II MHC subregion of the rat was not inhibitory. These results suggest that RT1.D antigens (analogous to human DR and mouse I-E) restrict islet cell recognition in this rat model of spontaneous IDDM.

Animals↗
PubMed1986

The distribution of type I (insulin-dependent) diabetes mellitus by age, sex, secular trend, seasonality, time clusters, and space-time clusters: evidence from Montreal, 1971-1983.

The etiology of insulin-dependent diabetes mellitus remains obscure. In an attempt to clarify some aspects of the epidemiology, including its compatibility with an acute infectious process, the authors undertook in-depth analyses of childhood cases accumulated in a population-based register in Montreal during the period from 1971-1983. Incidence rates increased with age until puberty, at which point they plateaued and decreased. There was no overall difference in incidence between males and females; however, the rate for females peaked approximately two years before the rate for males. While there was some variation over time, there was no evidence of a long-term trend, nor was the yearly variation impressive in magnitude. The findings further indicate that the disease is not characterized by explosive outbreaks. There was slight seasonality, with a 28% higher rate of onset in fall and winter than in spring and summer. There was some evidence of space-time clustering in 1971-1973, but not thereafter. Taken as a whole, these findings do not support the hypothesis that a significant portion of insulin-dependent diabetes is caused by an acute infectious process.

Adolescent↗
PubMed1986

Insulin-dependent diabetes mellitus is associated with genes that map to the right of the class I RT1.A locus of the major histocompatibility complex of the rat.

Previous studies have demonstrated that the presence of at least one u-haplotype of the rat major histocompatibility complex (MHC), RT1, is a necessary but not sufficient condition for the development of overt diabetes mellitus. The present studies were undertaken to determine which portion of the RT1 gene complex is necessary for the occurrence of diabetes. We crossed hooded diabetic rats (RT1.AuBuDu) with PVGr8 rats (RT1.AaBuDu). F1 animals were mated to give 82 F2 animals and backcrossed with the hooded diabetics to produce 41 backcross animals. Diabetes occurred in animals with all three possible RT1.A genotypes. The diabetes was similar to that seen in BB rats and in hybrid strains developed from them. An immunoregulatory defect was marked by decreased percentage of peripheral blood lymphocytes staining with w3/25 monoclonal antibody, by an increased percentage of peripheral blood lymphocytes binding a mouse ascites control protein, and by decreased responsiveness of peripheral blood lymphocytes to stimulation by concanavalin A. We conclude that the u-allele of the class I A-locus gene product is not necessary for susceptibility to the development of diabetes in the rat. Therefore, either genes coding for the class II products of the u-haplotype or genes in linkage disequilibrium with these genes and mapping to the right of the A locus provide the permissive condition. Furthermore, the data suggest, but do not prove, that the u-haplotype derived from a strain remote from the BB rat can confer this susceptibility to the development of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Genetics of the spontaneous diabetic syndrome. Interaction of MHC and non-MHC-associated factors.

The occurrence of the spontaneous insulin-dependent diabetic syndrome in the rat is the result of several genetic susceptibilities. There is a requirement for the u haplotype of the rat major histocompatibility complex (MHC), RT1. More specifically this requirement is for genes mapping to the right of the RT1 A locus, which codes for class I products. Furthermore, u haplotypes from inbred strains other than the BB rat can provide this permissive u haplotype. Diabetes occurs in animals with either one or two u haplotype and the diabetic syndrome is similar in its characteristics. In addition to the requirement for the MHC genes, there are abnormalities of the immune system of the various diabetes-prone strains, which are present in animals that develop overt disease. These abnormalities segregate independently of the RT1 and interaction between the susceptibilities is necessary for the manifestation of the complete clinical syndrome.

Alleles↗