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PubMed1999

Immunobiology of DC in NOD mice.

NOD mice spontaneously develop diabetes between 15 and 20 weeks of age, which is preceded by insulitis characterized by the infiltration of lymphocytes. Dendritic cells (DC) are among the first cells to infiltrate the islet and they have been implicated in the pathogenesis of the disease. Our work has been concerned with the detailed characterization of four distinct DC populations in NOD mice: two derived from bone marrow (BM) cells cultured in either granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4) or GM-CSF alone and two from the spleen of Flt3 ligand (Flt3L) -treated mice, isolated on the basis of CD8alpha expression. Phenotypic and functional differences between these DC subsets in NOD mice have been identified. In addition, we obtained a lower yield of NOD BM-derived DC and they expressed higher levels of cell-surface CD40 and IL-12 p40 mRNA than BM-derived DC from the diabetes-resistant strain, B10.BR. We have also investigated the ability of these DC populations to modulate the development and progression of diabetes in NOD mice.

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PubMed1990

Studies on autoimmunity for initiation of beta-cell destruction. VI. Macrophages essential for development of beta-cell-specific cytotoxic effectors and insulitis in NOD mice.

NOD mice were treated with silica (which is selectively toxic to macrophages) from 4 or 20.5 wk of age. Syngeneic neonatal pancreases were transplanted into the renal subcapsular space of the NOD mice at 21 wk of age. Silica treatment was continued until 24 wk of age, and then the mice were killed for examination of islet morphology. Neither the islets in transplanted pancreases nor the host pancreatic islets from the early long-term silica-treated animals revealed insulitis. In contrast, most of the islets in transplanted pancreases from the late short-term silica-treated animals showed severe insulitis and beta-cell necrosis, as did the host islets. A further experiment was performed to compare the effect of late short-term silica treatment with that of anti-L3T4-antibody treatment of the same time and duration. In contrast to the late short-term silica-treated animals, the transplanted pancreases in the anti-L3T4-antibody-treated animals revealed intact islets, although most of the host islets showed insulitis. The control group, which received no treatment but did receive neonatal pancreases, revealed severe insulitis and beta-cell necrosis of both transplanted and host islets. These results suggest that early macrophage depletion can abolish the development of beta-cell-specific immunologic effectors but that late macrophage depletion, after the development of insulitis, does not affect the destruction of beta-cells by preexisting effectors other than macrophages. We conclude that macrophages are essential for the development of beta-cell-specific cytotoxic effectors in the initial phase of insulitis in NOD mice.

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PubMed2006

Altered susceptibility to EAE in congenic NOD mice: Altered processing of the encephalitogenic MOG35-55 peptide by NOR/LtJ mice.

NOD mice (H-2 g7) naturally develop autoimmune diabetes, while the congenic NOR/LtJ mice (H-2 g7) are resistant. To determine if defective immune regulation renders NOD susceptible to autoimmune disease, we compared MOG35-55-induced EAE in NOD mice to that of NOR/LtJ. In two of three immunization protocols, the NOR/LtJ mice developed significantly reduced indices and severity of clinical disease, in spite of an exaggerated autoimmune response to MOG35-55. Characterization of the responding T cell repertoires revealed that V beta 8+ Th cells directed toward the MOG42-55 core epitope were dominant in both strains. Interestingly, CD8+ CTL were absent or significantly reduced in MOG35-55 lymphoblasts from NOR/LtJ mice, which poorly processed the MOG39-47 CTL epitope from MOG35-55. Thus, while particular MHC class II alleles may be associated with increased risk, molecules involved in the processing of key epitopes may be influential in the progression of autoimmune disease.

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PubMed1998

Characterization of the changing lymphocyte populations and cytokine expression in the exocrine tissues of autoimmune NOD mice.

NOD mice develop chronic lymphocytic invasion of the pancreas, submandibular, and lacrimal glands leading to loss of insulin secretion, salivary flow, and tear production. In this study, we have used flow cytometric analyses and RT-PCR to track glandular lymphocyte populations and cytokine expression spanning the initiation of autoimmune infiltration through the development of widespread autoimmune destruction of the salivary and lacrimal glands of NOD mice. Results demonstrate a predominance of CD4+ to CD8+ lymphocytes and a similar predominance of T-cells versus B-cells in both the submandibular and lacrimal gland infiltrates. A temporal increase in memory (CD3+CD45RBlo) T-cells was also detected; however, naive (CD3+CD45RBhi) T-cell populations as well as a CD3+, CD4-/CD8- double negative population were also present. In addition, a skewing of the TCR Vbeta repertoire toward Vbeta6+ and Vbeta8+ lymphocytes was evident in both glandular infiltrates. Analyses of cytokine mRNA expression in the submandibular glands demonstrated an increase between 12 and 16 wk of age of several proinflammatory cytokines including IL-1beta, IL-6, IL-7, IL-10, IFNgamma, TNFalpha, and inducible Nitric Oxide Synthase (iNOS). IL-4 synthesis was notably absent in both tissues. Cytokine mRNA transcripts detected in lacrimal tissue were similar to those seen in the submandibular glands but appeared both earlier and more intensely. These findings depict the progressive development of autoimmune exocrinopathy and can be used as a foundation to explore the similarities and potential differences in the immunopathogenic lesions of several distinct tissues within the same host.

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PubMed1992

High incidence of thyroiditis and anti-thyroid autoantibodies in NOD mice.

NOD mice develop spontaneous insulin-dependent diabetes mellitus (IDDM) associated with infiltration of pancreatic islets with mononuclear cells. Islet infiltration results in autoimmune destruction of insulin-secreting beta-cells. Because in humans and BB rats diabetes is often associated with autoimmune thyroid disease (ATD), the NOD mouse model was examined for evidence of thyroiditis and serum antibodies reactive with mouse thyroid membrane antigens (MTMAs). The incidence of thyroiditis was 77% in mice greater than 180 days old, 67% in mice 61-180 days old, 72% in mice 31-60 days old, 74% in mice 21-30 days old, 78% in mice 11-20 days old, and 90% in mice less than or equal to 10 days old. NOD mice less than or equal to 30 days old had less-severe thyroiditis than animals greater than 180 days old. There was no significant different in severity of thyroiditis between any of the other age-groups tested. The incidence of thyroiditis was not increased in diabetic compared with nondiabetic animals, nor was an association found between thyroiditis and sex. The high incidence of thyroiditis in the less than or equal to 30-day-old age-group indicates that infiltration of lymphocytes into the thyroid can precede initiation of insulitis in this model. Although both thyroiditis and insulitis in NOD mice began early (by the 1st and 2nd mo of life, respectively), no significant association between infiltration of these two organs was noted in individual mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1994

Peptide therapy for diabetes in NOD mice.

NOD mice spontaneously develop autoimmune diabetes that mimics insulin-dependent diabetes mellitus (IDDM) in man. A peptide of the 60 kDa heat shock protein (hsp60), designated p277, can serve as a target for diabetogenic T-cell clones, and diabetes was prevented by using the p277 peptide to turn off anti-p277 immunity early in life. We report that the p277 peptide, administered once, can arrest the autoimmune process even after it is far advanced. Successful therapy was associated with down-regulation of the autoimmune process and regression of islet inflammation. Thus the immune system is responsive to manipulation by a specific signal even in the face of a virulent, full-blown autoimmune process.

Aging↗

PubMed2005

Characterisation of CD8 monoclonal antibody-induced protection from diabetes in NOD mice.

NOD mice can be protected from transferred diabetes for long periods by short-term treatment with CD8 mabs. This protection has previously been shown to be thymus-dependent as thymectomised mice do not show the long-term protection observed in intact mice. In this study we show that the thymus is required only during antibody treatment as its removal thereafter does not affect protection. Recent thymic emigrants (RTEs) are not necessary for long-term tolerance induction and irradiation plays no part as anti-CD8 treatment cannot protect NOD.scid recipients from diabetes development. IL-10 is also shown to play an important role in the anti-CD8 induced protection in intact mice as it is reversed by IL-10R blockade.

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PubMed1996

Genetically programmed development of salivary gland abnormalities in the NOD (nonobese diabetic)-scid mouse in the absence of detectable lymphocytic infiltration: a potential trigger for sialoadenitis of NOD mice.

NOD (nonobese diabetic) mice develop chronic lymphocytic infiltrates of the salivary glands (sialoadenitis) that correlate with a temporal decline in saliva production. To differentiate autoimmune and nonautoimmune components in this decline, we evaluated glandular function in NOD-scid mice. Although saliva volumes and protein concentrations appeared normal, amylase and EGF activities declined 50 and 20%, respectively, in NOD-scid mice between 10 and 25 weeks of age. Salivary protein profiles on SDS-polyacrylamide gels showed a profound decline in two prominent proteins of 32 and 20 kDa, and the emergence of a new 27-kDa protein. All three proteins exhibited amino acid sequence homology to parotid secretory protein (PSP) and reacted with PSP-specific antibody, suggesting an age-dependent alteration in PSP. In addition, there was an induced expression of proline-rich protein in the salivary glands and saliva of NOD and NOD-scid mice that was not detectable in mouse strains lacking autoimmune disease. Submandibular gland histology revealed selective loss of acinar tissue despite an absence of sialoadenitis. These changes in salivary protein composition and histology in the absence of detectable lymphocytic infiltration suggest that glandular defects in the NOD genetic background may contribute to the triggering of the autoimmune response in the salivary glands.

Amino Acid Sequence↗

PubMed1993

Transfer of autoimmune diabetes from diabetic NOD mice to NOD athymic nude mice: the roles of T cell subsets in the pathogenesis.

The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. To analyze of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, we have been doing a series of studies on the induction of insulitis and diabetes in NOD athymic nude mice by means of T cell transfer. To complement our previous study dealing with the induction of insulitis and cyclophosphamide-induced diabetes in recipients that had been reconstituted with each T cell subset derived from the nondiabetic mice, the present study was conducted to observe the transfer of spontaneous diabetes by injecting T cells harvested from diabetic mice. Any possible in vivo increase in the contaminating T cell subset was prevented by injecting the antibody homologous to it. Transfer of untreated or complement-treated splenic lymphocytes of diabetic mice containing both T cell subsets induced spontaneous diabetes 30 to 58 days after the cell transfer as well as insulitis, while spleen cells from nondiabetic mice rarely produced diabetes. On the other hand, transfer of either CD4+ cell-depleted or CD8+ cell-depleted splenic lymphocytes of diabetic mice did not cause diabetes at least up to 60 days after the cell transfer. Also, transfer of only the CD4+ T cell-depleted fraction did not cause insulitis. In contrast, transfer of only the CD8+ T cell-depleted fraction induced insulitis in all the recipients. However, insulitis was less potent in this group of mice than in the diabetic recipients given both subsets: only a low insulitis score was obtained and a number of beta-cells remained alive despite the insulitis in mice given the CD8+ T cell-depleted fraction, whereas islet damage was very severe and insulin-secreting beta-cells were no longer detected in the diabetic mice. Thus, the present results agree with the previous ones concerning transfer of diabetes, with the aid of cyclophosphamide treatment, by T cells of nondiabetic mouse origin. Consideration of our results together with earlier findings led to the conclusion that CD4+ T cells are primarily responsible for insulitis and that CD8+ T cells migrate into islets and are differentiated into mature killer cells against beta-cells with the aid of CD4+ T cells in both spontaneous and cyclophosphamide-induced diabetes.

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PubMed2005

Transfer of diabetes from prediabetic NOD mice to NOD-SCID/SCID mice: association with pancreatic insulin content.

Splenocytes from prediabetic female NOD mice can transfer diabetes to NOD-SCID mice. Whereas the kinetics of disease transfer was shown to be a function of the age of donor splenocytes, information is scarce as to how the stage of autoimmune disease, as evaluated by pancreatic insulin content, is related to the diabetogenic potency of splenic T-cells. We therefore determined individual diabetes transfer times after an i. v. injection of splenocytes from prediabetic NOD mice of different ages into female NOD-SCID mice in relation to the diabetes incidence in NOD donor mice and their pancreatic insulin contents. Three groups (n = 8) of NOD mice aged 5, 11, and 17 weeks (wk) underwent splenectomy and hemipancreatectomy. After that, 10x10 (6) splenocytes either pooled from all donor NOD mice of the different age groups or individually from single donor mice were transferred to groups of four 6-week-old NOD-SCID mice, respectively, in two sets of experiments. Insulin was extracted from the resected hemipancreas, and the insulin content was determined by a RIA. Diabetes in the NOD-SCID cohort occurred after a mean time of 126 days after transfer of pooled splenocytes from 5-week-old NODs, after 68 days (transfer from 11-week-old NODs), and after a mean time of 43 days (transfer from 17-week-old NODs, 5 vs. 11 wk: p < 0.02, 11 vs. 17 wk: p < 0.001). Individual time to diabetes positively correlated with diabetes transfer times in NOD-SCID recipients (p < 0.0001) in the 17-week-old NOD mice, confirming previous diabetes transfer studies in hemi-pancreatectomized NOD mice. Furthermore, individual insulin concentrations in 17-week-old NOD mice also positively correlated to diabetes transfer times in recipient mice (p < 0.0001). No such correlations for these parameters were seen for the 5 and 11-week-old NOD mice (time to diabetes: 11 wk, p = 0.14, 5 wk, p = 0.75; insulin content: 11 wk, p = 0.81, 5 wk, p = 0.14). These data suggest that destructive T-cell activity increases during the course of islet autoimmunity. The immune response seems to be programmed for beta-cell destruction just before diabetes onset. This is the only time that pancreatic insulin content predicts the impending onset of diabetes.

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PubMed2000

Differential expression of renal AGE-receptor genes in NOD mice: possible role in nonobese diabetic renal disease.

BACKGROUND: Nonobese diabetic mice (NOD) are prone to glomerular pathology, which is accelerated with the onset of diabetes. Advanced glycation end product (AGE) interactions with AGE-receptors (AGE-Rs) in kidneys can contribute to glomerular injury and diabetic nephropathy (DN). The significant elevation in kidney AGE deposits noted in prediabetic NOD mice suggested that delayed AGE turnover in this model may contribute to its propensity toward DN. METHODS: To explore whether excess tissue AGE was linked to altered AGE-R status in the kidney, mRNA/protein expression, and of several AGE-Rs [AGE-R1, AGE-R2, AGE-R3, scavenger receptor II (ScR-II), and receptor for AGE (RAGE)], was determined in renal cortex and in mesangial cells (MCs) isolated from ND-, D-NOD, and ILE mice (N = 20 per group). Ligand binding, receptor site number, and affinity were determined in MCs from the same mouse groups. RESULTS: Prediabetic NOD kidney AGE-R1 mRNA and protein level were threefold lower than that of ILE mice (P < 0.01), while AGE-R3 mRNA was enhanced by twofold (P < 0.05) and AGE-R2, RAGE, and ScR-II mRNA remained close to normal (ILE). The onset of diabetes in NOD mice, while enhancing AGE-R1 mRNA expression by approximately twofold, failed to raise it above the normal (ILE) level, despite increases in tissue, and serum AGE. The latter was associated with higher elevation in AGE-R3 (sixfold, P < 0.05), RAGE (twofold, P = NS), and ScR-II mRNA (2. 8-fold, P = NS) above control. MCs from prediabetic NOD mice showed a threefold lower level of AGE-R1 mRNA (P < 0.02 vs. ILE) and AGE-R1-protein, and AGE-binding activity (<40% of control ILE). In contrast, AGE-R3 mRNA was enhanced (twofold), while AGE-R2 showed no change. Cultured ND-NOD MCs displayed only one fourth of the AGE-binding sites/cell present on ILE MCs (1.6 x 10(6) vs. 6.6 x 10(6), P < 0.05), which after the onset of diabetes rose to the normal range (7.0 x 10(6)/cell), but failed to exceed it. CONCLUSIONS: Reduced AGE-R1 gene expression in this strain may contribute to delayed AGE removal from and early AGE deposition in kidney tissues. This may act as a trigger for those AGE-R genes involved in growth-promoting changes, leading to DN in this strain.

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PubMed1994

Renal TGF-beta regulation in spontaneously diabetic NOD mice with correlations in mesangial cells.

Diabetic nephropathy is characterized by excessive glomerular matrix accumulation, basement membrane thickening and sclerosis. Although it is clear that systemic metabolic disturbances precipitate such renal changes, the signals and pathways involved in this process are not fully elucidated. Recent evidence suggests that growth factors/cytokines are intimately involved in the pathogenesis of diabetic nephropathy. Because of its prosclerotic properties, transforming growth factor-beta (TGF-beta) is a prime candidate mediator of diabetic nephrosclerosis. We examined perfused kidney tissues isolated from spontaneously diabetic, non-obese diabetic mice (NOD) for TGF-beta content. By using murine isotype specific TGF-beta probes, we demonstrate that within 5 to 10 days of hyperglycuria renal TGF-beta 2 mRNA and protein content increases. By immunohistochemical analysis, de novo TGF-beta immunoreactivity was detected within both glomeruli and the interstitium. In order to determine the signals involved in promoting kidney TGF-beta content in vivo, TGF-beta regulation was examined in renal mesangial cells in vitro. Murine mesangial cells stimulated with glycosylated protein secrete bioactive TGF-beta and demonstrate a disproportionate increase in the steady state levels of TGF-beta 2 mRNA. These data suggest that a major early renal response in NOD mice to hyperglycemia or to glycosylated proteins is characterized by increases in TGF-beta.

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PubMed1992

Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes.

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the alpha and beta chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing beta cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2b (NOD.H-2b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2b strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2+ T cells and B220+ B cells. In addition, autoantibodies are present in NOD.H-2b mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only approximately 3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis greater than cyclophosphamide-induced diabetes greater than spontaneous diabetes.

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PubMed1993

FAD-linked glycerophosphate dehydrogenase activity in islets, liver, and splenocytes of NOD mice.

The activity of FAD-linked glycerophosphate dehydrogenase (m-GDH), as well as that of glutamate dehydrogenase and both glutamate-oxalacetate and glutamate-pyruvate transaminases, were measured in islet, liver, and splenocyte homogenates from 6- to 7-week-old female nonobese diabetic mice (NOD) and age- and sex-matched control mice. Despite incipient insulitis and euglycemia, the NOD mice displayed both high islet insulin content and elevated insulinemia. The activity of m-GDH, expressed relative to protein content, was not decreased in islets of NOD mice, despite the fact that such a specific activity is lower in splenic lymphocytes than islet cells. In liver homogenates, the activity of m-GDH was even higher in NOD than control mice. It is proposed, therefore, that in this model of insulin-dependent diabetes no primary decrease in islet m-GDH activity occurs, at variance with the situation recently documented in several animal models of non-insulin-dependent diabetes.

Alanine Transaminase↗

PubMed1998

Disease-protected major histocompatibility complex Ea-transgenic non-obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice.

The non-obese diabetic (NOD) mouse is an animal model for insulin-dependent diabetes that has many similarities to the human disease. NOD mice transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. An Ea transgene mutated in the promoter region, (DeltaY) lacks E expression on most B cells, thymic medullary epithelium and primary antigen-presenting cells, and confers no protection whatsoever. We have used these transgenic NOD mice, together with non-transgenic NOD mice, to study the correlation of E expression and production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma). We show that protected E-transgenic NOD mice have elevated levels of IL-4 compared with non-transgenic mice, both in the thymus and in the periphery. However, susceptible DeltaY-transgenic mice have elevated thymic IL-4 levels, but express almost as little IL-4 as non-transgenic NOD mice in the periphery. This drop in peripheral IL-4 production seen in DeltaY-transgenic mice thus correlates with the decreased E expression in the periphery of DeltaY-transgenic NOD mice. In contrast, there were no differences in IFN-gamma production between the three NOD lines. We suggest that Ea-transgenic NOD mice have E-selected regulatory T cells producing IL-4, which are subsequently activated by E-expressing primary antigen-presenting cells in the periphery. This activation would then be instrumental for the E-mediated protection from disease in NOD mice. Such a process would explain the total absence of protection in DeltaY-transgenic NOD mice, despite their widespread E expression.

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PubMed1992

Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice.

The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. For the precise analysis of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, these subsets must be transferred into recipients that are completely free of T cells and pathological changes. We used athymic NOD nude mice, which congenitally lack mature T cells and are free of insulitis and hyperglycemia up to the age of 60 weeks, as recipients for this purpose. To the nude recipients we transferred either one of a highly purified CD4+ or CD8+ T cell subset derived from non-diabetic female NOD mice; any in vivo increase in the contaminating T cell subsets was prevented by injecting the antibody homologous to it. Most of the T cell-reconstituted recipients were treated with cyclophosphamide to promote the onset of overt diabetes. Transfer of the CD8+ T cell subset alone did not induce insulitis or hyperglycemia. In contrast, transfer of the CD4+ T cell subset alone produced insulitis, but not hyperglycemia, in all the recipients. However, the subsequent transfer of CD8+ T cells into CD4+ T cell-reconstituted recipients induced severe insulitis and hyperglycemia in almost all the recipients. In these diabetic recipients, we observed severe damage of the pancreatic islets and the infiltration of a large number of CD8+ T cells into the remaining islets; insulin-secreting beta cells were no longer detected. These results suggest that CD4+ T cells play a predominant role in the development of insulitis and that CD8+ T cells migrate into the islets and are subsequently, with the aid of CD4+ T cells, differentiated into killer cells which act against beta cells.

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PubMed1993

Complement lytic activity has no role in the pathogenesis of autoimmune diabetes in NOD mice.

The NOD mouse is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta-cells. Although it is clear that T-cells and monocytes are necessary for beta-cell destruction, humoral factors, such as antibodies and complement, may also contribute to tissue damage. Attempts to cure diabetes in experimental models by immunoisolation of transplanted islets has raised the need to protect the islets from the relatively small components of the complement cascade. In this study, we report that NOD mice have no complement lytic activity and that the exclusion of complement is unnecessary in this model. Sera from young NOD mice were unable to lyse sheep red blood cells coated with rabbit antibody. Lytic activity of NOD sera was reconstituted by mixing with C4-deficient CBA sera, but not C5-deficient DBA/2 sera, indicating the presence of C4, but the absence of C5 activity in NOD sera. Lytic activity of NOD sera could be reconstituted with human C5 electrofocused in polyacrylamide gel. The polymerase chain reaction was used to amplify fragments from genomic DNA corresponding to the region of Hc (the gene encoding C5) in DBA/2 mice, which carries a 2-base pair deletion responsible for the lack of C5 protein expression in these mice. DBA/2 and NOD mice from several colonies produced a fragment 2 bases shorter than that generated from the wild-type allele in BALB/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed2003

Passive transfer of flt-3L-derived dendritic cells delays diabetes development in NOD mice and associates with early production of interleukin (IL)-4 and IL-10 in the spleen of recipient mice.

CD11c+/CD11b+dendritic cells (DC) with high levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules have been derived from spleen cells cultured with granulocyte-macrophage colony stimulating factor (GM-CSF) + flt-3L + interleukin (IL)-6 (flt-3L-DC). Investigating in vivo the function of DC in non-obese diabetic mice (NOD), we showed that a single injection of this in vitro-derived subset of DC prevents the development of diabetes into prediabetic female mice. In contrast, DC derived from bone marrow cells cultured with GM-CSF + IL-4 [bone marrow (BM)-DC] induced no protection. Moreover, protection against diabetes following injection of flt-3L-DC was associated with IL-4 and IL-10 production in the spleen and the pancreatic lymph nodes of recipient mice, indicating that this DC population is able to polarize the immune response towards a Th2 pathway. As we shown previously, NOD BM-DC exhibit an enhanced capacity to produce IL-12p70 in response to lipopolysaccharide (LPS) and anti-CD40 stimulation compared to BM-DC from control mice. In contrast, NOD flt-3L-DC, as their control mouse counterpart, produced no IL-12p70 to these stimuli. Our findings show that a subset of DC, characterized by a mature phenotype and the absence of IL-12p70 production can be derived from NOD mouse spleen favouring IL-4 and IL-10 regulatory responses and protection from diabetes development.

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