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1.
Proc Natl Acad Sci U S A ; 98(20): 11533-8, 2001 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-11572996

RESUMO

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic beta cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the beta(2) microglobulin (beta(2)M)(a) allele develop diabetes, whereas NOD mice expressing a murine beta(2)M(b) or human allele are protected. The murine beta(2)M(a) allele differs from the beta(2)M(b) allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD beta(2)M(a) isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.


Assuntos
Predisposição Genética para Doença/genética , Camundongos Endogâmicos NOD/imunologia , Microglobulina beta-2/imunologia , Animais , Sequência de Bases , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética
2.
Immunol Cell Biol ; 79(6): 597-601, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11903619

RESUMO

Previous studies have implicated B lymphocytes in the pathogenesis of diabetes in the non-obese diabetic (NOD) mouse. While it is clear that B lymphocytes are necessary, it has not been clear at which stage of disease they play a role; early, late or both. To clarify when B lymphocytes are needed, T lymphocytes were transferred from 5-week-old NOD female mice to age-matched NOD/severe combined immunodeficiency (SCID) recipient mice. NOD/SCID mice, which lack functionally mature T and B lymphocytes, do not normally develop insulitis or insulin-dependent diabetes melitus (IDDM). The NOD/SCID mice that received purified T lymphocytes from 5-week-old NOD mice subsequently developed insulitis and diabetes even though they did not have detectable B lymphocytes. This suggests that while B lymphocytes may be essential for an initial priming event they are not requisite for disease progression in the NOD mouse.


Assuntos
Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/etiologia , Pâncreas/imunologia , Animais , Linfócitos B/patologia , Movimento Celular/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pâncreas/patologia
3.
Immunol Cell Biol ; 76(2): 173-8, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9619488

RESUMO

CD4+ T cells may be assigned a functional status (Th1 or Th2) according to the cytokines they produce including IL-2, IFN-gamma and IL-4. Th1 and Th2 CD4+ T cells deliver different isotype-switching signals to antigen-specific B cells which bias the serum Ig isotypes. The stimulation of Th1 or Th2 responses is influenced by adjuvants and administration of antigen in IFA results in Th1 unresponsiveness as evidenced by: (i) reduced T cell proliferation to antigen; (ii) reduced IFN-gamma production in response to antigen; and (iii) reduced IgG2a isotype antigen-specific antibodies following antigen/CFA challenge. The impact of established human gamma globulin (HGG) specific Th1 unresponsiveness on subsequent immunization with an unrelated antigen, human serum albumin (HSA) in Th1-inducing CFA was then examined. When subsequently challenged with a mixture of HSA and HGG in CFA the HGG-specific Th1 unresponsiveness was infectious and dominant, preventing the induction of a Th1 response to HSA. Reduced T cell proliferation, IFN-gamma production and IgG2a antibody were consequently observed in response to HSA. The HGG-specific Th1 unresponsiveness was not infectious when HGG/CFA and HSA/CFA were administered at separate sites. This demonstrates that antigen-specific Th1 unresponsiveness can be infectious for new, molecularly unrelated antigens and supports studies showing that Th1-mediated autoimmune diseases such as experimental allergic encephalomyelitis (EAE) and diabetes can be ameliorated using antigens molecularly distinct from the disease-inducing immunogen.


Assuntos
Imunização/efeitos adversos , Células Th1/imunologia , Animais , Células Cultivadas , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Imunoglobulina G/sangue , Interferon gama/metabolismo , Interleucina-4/metabolismo , Linfonodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Albumina Sérica/administração & dosagem , Albumina Sérica/imunologia , gama-Globulinas/administração & dosagem , gama-Globulinas/imunologia
4.
Proc Natl Acad Sci U S A ; 95(5): 2441-5, 1998 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-9482904

RESUMO

It has been demonstrated recently that neonatal antigen administration in the mouse can lead to priming for Th2-mediated immune responses. This observation has important implications for the development of vaccination strategies in humans, particularly for individuals who may be predisposed to atopy or asthma. In this paper it is shown that although i.p. administration of antigen (100 microg) in adjuvant to the neonate does indeed prime for Th2-mediated disease in mice [allergic airways disease (AAD)], when the same relatively low dose of antigen is given in soluble form no priming occurs. Further, administration of a larger dose of soluble antigen (1 mg) actually prevents the ability to prime for a Th2 response subsequently and so prevents the induction of AAD. Protection from disease was associated with evidence of functional inactivation of both Th1 and Th2 ovalbumin-specific T cells. In contrast, administration of a very low dose of antigen (10 microg) primed for a Th2 response in a similar fashion to antigen in adjuvant. We suggest that the adjuvant lowers the "effective" dose of antigen administered in the neonate and thereby primes for Th2-type immune responses. These findings demonstrate that neonatal antigen administration can inhibit Th2-mediated diseases, such as AAD, but the dose of antigen may be critical to avoid predisposition to disease.


Assuntos
Antígenos/administração & dosagem , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/prevenção & controle , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Células Th2/imunologia , Animais , Animais Recém-Nascidos , Formação de Anticorpos , Antígenos/farmacologia , Hiper-Reatividade Brônquica/patologia , Células Cultivadas , Imunoglobulina G/sangue , Injeções Intraperitoneais , Interferon gama/biossíntese , Interleucina-4/biossíntese , Interleucina-5/biossíntese , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/farmacologia , Hipersensibilidade Respiratória/patologia
5.
Curr Top Microbiol Immunol ; 206: 51-66, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8608725

RESUMO

Central to the autoimmune pathogenesis of IDDM in NOD mice is the MHC class II region. In all models studied to date, expression of NOD MHC class II genes is essential for disease development suggesting a crucial role for I-ANOD-restricted presentation of autoantigen. Protection has been afforded by transgene incorporation of other non-NOD class II genes and many models have been proposed to account for this effect. It is now clear that protection is not achieved by deletion or permanent silencing of all autoreactive T cell clones. It also appears that expression of these genes is required both intra- and extrathymically. It still remains to be determined what role these genes may have in the various compartments and how the autoreactive cells are held in check in protected NOD transgenic mice. Currently, the most likely explanation is that intrathymic expression of non-NOD class II genes is required for the positive selection of class II-restricted immunoregulatory T cells, while peripheral expression is necessary to bring about the interaction of these cells in a tricellular complex with NOD autoantigen-specific T cells and APCs, so that the response can be deviated to a nonpathogenetic one. Whether this process is active or passive is not known.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Animais , Medula Óssea/imunologia , Diabetes Mellitus Tipo 1/etiologia , Genes MHC da Classe II , Antígenos de Histocompatibilidade Classe II/genética , Camundongos , Camundongos Endogâmicos NOD , Modelos Biológicos , Linfócitos T/imunologia
6.
Proc Natl Acad Sci U S A ; 90(22): 10808-10, 1993 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-7902572

RESUMO

The association of major histocompatibility complex genes with autoimmune diseases is firmly established, but the mechanisms by which these genes confer resistance or susceptibility remain controversial. The controversy extends to the nonobese diabetic (NOD) mouse that develops disease similar to human insulin-dependent diabetes mellitus. The transgenic incorporation of certain class II major histocompatibility complex genes protects NOD mice from diabetes, and clonal deletion or functional silencing of autoreactive T cells has been proposed as the mechanism by which these molecules provide protection. We show that neither thymic deletion nor anergy of autoreactive T cells occurs in NOD mice transgenic for I-Ak. Autoreactive T cells are present, functional, and can transfer diabetes to appropriate NOD-recipient mice.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Ciclofosfamida , Diabetes Mellitus Tipo 1/patologia , Feminino , Imunidade Celular , Imunização Passiva , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD/imunologia , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia
8.
Immunol Cell Biol ; 69 ( Pt 2): 89-93, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1680804

RESUMO

Antigen specific unresponsiveness can be induced in vivo by administration of antibody against CD4, major histocompatibility complex (MHC) Class II or LFA-1 at the time of antigen exposure. Since target cell depletion is not necessary for this effect it was hypothesized that interference with intercellular interaction was responsible. To test this hypothesis, antibody against the ligand for LFA-1, ICAM-1, was administered during primary immunization with human gamma-globulin (HGG) and long-term secondary antibody responses monitored. It was found that HGG specific unresponsiveness resulted from this treatment (less than 10% of normal secondary antibody response). Delayed-type hypersensitivity responses to HGG were also suppressed suggesting unresponsiveness in some T cell subsets. These findings suggest a role for ICAM-1/LFA-1 interaction in determining the long-term outcome of contact with antigen.


Assuntos
Anticorpos Anti-Idiotípicos/biossíntese , Moléculas de Adesão Celular/imunologia , Tolerância Imunológica/imunologia , Animais , Anticorpos Monoclonais , Citometria de Fluxo , Humanos , Hipersensibilidade Tardia/imunologia , Imunização , Imunoglobulina G/imunologia , Molécula 1 de Adesão Intercelular , Camundongos , Camundongos Endogâmicos CBA , Ovalbumina/imunologia , Subpopulações de Linfócitos T/imunologia
9.
Nature ; 345(6277): 724-6, 1990 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-1972779

RESUMO

The non-obese diabetic (NOD) mouse develops insulin-dependent diabetes mellitus (IDDM) with mononuclear cell infiltration of the islets of Langerhans and selective destruction of the insulin-producing beta-cells, as in humans. Most infiltrating cells are T lymphocytes, and most of these carry the CD4 antigen. Adoptive transfer of T cells from diabetic NOD mice into irradiated NOD or athymic nude NOD mice induces diabetes. Susceptibility to IDDM in NOD mice is polygenic, with one gene linked to the major histocompatibility complex class II locus, which in NOD mice expresses a unique I-A molecule but no I-E. Speculation exists as to the role of the I-A molecule in the diabetes susceptibility of NOD mice, especially regarding the significance of specific unique residues. To examine the role of the NOD I-A molecule in IDDM pathogenesis, we made NOD/Lt mice transgenic for I-Ak by microinjecting I-Ak alpha- and beta-genes into fertilized NOD/Lt eggs. Insulitis was markedly reduced and diabetes prevented in NOD/Lt mice expressing I-Ak.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Imunofluorescência , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe II/genética , Imunização Passiva , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Transgênicos , Linfócitos T/imunologia , Linfócitos T/patologia , Distribuição Tecidual
10.
Diabetes ; 38(4): 441-7, 1989 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2522407

RESUMO

Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and beta-cell destruction. These findings suggested that CY was not directly beta-cell toxic and that altered beta-cells were not essential for beta-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged beta-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Doenças Autoimunes/induzido quimicamente , Ciclofosfamida/toxicidade , Diabetes Mellitus Experimental/imunologia , Terapia de Imunossupressão , Animais , Glicemia/análise , Relação Dose-Resposta a Droga , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Mutantes , Pancreatopatias/induzido quimicamente , Pancreatopatias/patologia , Estreptozocina
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