Diabetic NOD Mice (diabetic + nod_mouse)

Distribution by Scientific Domains

Selected Abstracts

A crucial role for macrophages in the pathology of K/B,,N serum-induced arthritis

Samuel Solomon
Abstract Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen,II antibody-induced arthritis animal model for a long time now. Recently, in the K/B,,N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B,,N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and Fc,RIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-,, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokine-producing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B,,N serum-induced arthritis. Reconstituting clodronate liposome-treated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis. [source]

Partial and transient modulation of the CD3,T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice

IMMUNOLOGY, Issue 1 2010
Devangi S. Mehta
Summary It has been established that a total of 250 ,g of monoclonal anti-mouse CD3 F(ab,)2 fragments, administered daily (50 ,g per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing , cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab,)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3,T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 ,g (total dose 8 ,g) induced 53% remission of diabetes, similarly to the 250 ,g dose regimen, whereas four doses of 1 ,g induced only 16% remission. While the 250 ,g dose regimen produced nearly complete and sustained modulation of the CD3 ,TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual ,-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3,TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. [source]

Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes

IUBMB LIFE, Issue 1 2007
Alexei Y. Savinov
Abstract Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, ,-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes. IUBMB Life, 59: 6-13, 2007 [source]

Glutathione S-transferases and malondialdehyde in the liver of NOD mice on short-term treatment with plant mixture extract P-9801091

R. Petlevski
Abstract Changes in the concentration of glutathione S-transferases (GSTs) and malondialdehyde (MDA) were assessed in the liver of normal and diabetic NOD mice with and without treatment with the plant extract P-9801091. The plant extract P-9801091 is an antihyperglycaemic preparation containing Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum of,cinale Web.), Cichorii radix (Cichorium intybus L.), Juniperi fructus (Juniperus communis L.) , Centaurii herba (Centaurium umbellatum Gilib.), Phaseoli pericarpium (Phaseolus vulgaris L.), Millefolii herba (Achillea millefolium L.), Mori folium (Morus nigra L.), Valerianae radix (Valeriana of,cinalis L.) and Urticae herba et radix (Urtica dioica L). Hyperglycaemia in diabetes mellitus is responsible for the development of oxidative stress (via glucose auto-oxidation and protein glycation), which is characterized by increased lipid peroxide production (MDA is a lipid peroxidation end product) and/or decreased antioxidative defence (GST in the liver is predominantly an , enzyme, which has antioxidative activity). The catalytic concentration of GSTs in the liver was signi,cantly reduced in diabetic NOD mice compared with normal NOD mice (p < 0.01), while the concentration of MDA showed a rising tendency (not signi,cant). The results showed that statistically signi,cant changes in antioxidative defence occurred in the experimental model of short-term diabetes mellitus. A 7-day treatment with P-9801091 plant extract at a dose of 20 mg/kg body mass led to a signi,cant increase in the catalytic concentration of GSTs in the liver of diabetic NOD mice (p < 0.01) and a decrease in MDA concentration (not signi,cant), which could be explained by its antihyperglycaemic effect. Copyright 2003 John Wiley & Sons, Ltd. [source]