White F1 Research Articles

THU0052 Allogenic Mesenchymal Stromal Cells Transplantation in A Murine Model of Sle

BackgroundSystemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by a chronic course and variable severity; despite recent diagnostic and therapeutic advances, the management of the disease remains...

Crystal structure determination of anti‐DNA Fab A52

A52 is a murine monoclonal antibody isolated from autoimmune New Zealand Black/New Zealand White F1 mice that recognizes single and double stranded DNA. This mouse strain spontaneously develops systemic lupus erythematosus-like symptoms and has served as a model for that disease for many years. The 1.62 Å crystal structure of the A52 Fab fragment reveals an H3 complementarity determining region with four closely spaced arginine residues, creating a positively charged surface to accommodate bound DNA.

Reduction of the oestrogenic effect of zearalenone in pigs by a feed additive

Zearalenone is phenolic resorcyclic acid lactone produced by a number of Fusarium species grown on grains, predominantly on maize, in high moisture environment. Due to its oestrogenic effects, feeds contaminated with zearalenone can cause striking negative effects on reproduction primarily in pigs. The aim of the study was to test the efficiency of a feed additive developed for enzymatic decomposition of mycotoxins. A total of sixty 6-week-old conventional Dutch Landrace × Hungarian Large White F1 female pigs weaned at 30 ± 2 days of age were divided into 6 groups of 10 animals. Between 50 and 70 days of age, 4 groups of pigs (experimental) were treated with zearalenone (8 or 16 mg/pig dose) administered every other day via an oesophageal tube; pigs from the other two groups were not treated with zearalenone and served as controls. Throughout the experiment, the diet of two experimental groups and one control group was supplemented with a feed additive (named: Detoxa Plus) at a concentration of 1 kg/tonne; pigs from the other control group received neither zearalenone treatment, nor the feed additive. Pigs’ live weight, weight of ovaries and uterus, histological characteristics of the ovaries, uterus, vagina, spleen and lymph nodes, liver concentrations of zearalenone and its metabolites (α- and β-zearalenol) were studied. This study showed the preventive capacity of the feed additive against zearalenone. Positive effects included the prevention of uterine enlargement, beneficial effects on the histopathological scores of ovaries, uterus and vagina and reduced concentration of zearalenone and metabolites in the liver. This study demonstrates for the first time that due to its enzymatic activity Detoxa Plus renders zearalenone contaminated feeds less toxic.

Effects of adjuvants for human use in systemic lupus erythematosus (SLE)-prone (New Zealand black/New Zealand white) F1 mice

The safety of four different adjuvants was assessed in lupus-prone New Zealand black/New Zealand white (BW)F1 mice. Four groups of mice were injected intraperitoneally with incomplete Freund's adjuvant (IFA), complete Freund's adjuvant (CFA), squalene (SQU) or aluminium hydroxide (ALU). An additional group received plain phosphate-buffered saline (PBS) (UNT group). Mice were primed at week 9 and boosted every other week up to week 15. Proteinuria became detectable at weeks 17 (IFA group), 24 (CFA group), 28 (SQU and ALU groups) and 32 (UNT group). Different mean values were obtained among the groups from weeks 17 to 21 [week 17: one-way analysis of variance (anova) P = 0·016; weeks 18 and 19: P = 0·048; weeks 20 and 21: P = 0·013] being higher in the IFA group than the others [Tukey's honestly significant difference (HSD) post-test P < 0·05]. No differences in anti-DNA antibody levels were observed among groups. Anti-RNP/Sm antibody developed at week 19 in only one CFA-treated mouse. Mean mouse weight at week 18 was lower in the ALU group than the IFA (Tukey's HSD post-test P = 0·04), CFA (P = 0·01) and SQU (P < 0·0001) groups, while the mean weight in the SQU group was higher than in the IFA (P = 0·009), CFA (P = 0·013) and UNT (P = 0·005) groups. The ALU group weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of ALU in the late post-immunization period. Thus, SQU was the least toxic adjuvant as it did not (i) accelerate proteinuria onset compared to IFA; (ii) induce toxicity compared to ALU or (iii) elicit anti-RNP/Sm autoantibody, as occurred in the CFA group.

Characterizations of Shell and Mantle Edge Pigmentation of a Pacific Oyster, Crassostrea gigas, in Korean Peninsula.

The objectives of this study were to investigate color patterns of shell and mantle edge pigmentation of a Pacific oyster, C. gigas, and to estimate variance components of the two colors. A sample of 240 F0 oysters was collected from six aquaculture farms in Tongyeong, Korea to measure shell color and mantle edge pigmentation. Among the F0s, male and female individuals with black (white) shell and black (white) mantle edge were selected and mated to generate three F1 full-sib black (white) cross families (N = 265). Two and four F2 cross families (N = 286) were also produced from black and white F1 selected individuals, respectively. Variance component estimates due to residuals and families within color were obtained using SAS PROC VARCOMP procedures to estimate heritability of shell and mantle edge pigmentation. In the F0 generation, about 29% (11%) had black (white) color for both shell and mantle edge. However, in the F1 and F2 black (white) cross families, 75% (67%) and 100% (100%) of oysters had black (white) shell colors, and 59% (23%) and 79% (55%) had black (white) mantle edge, respectively. Spearman correlation coefficients between shell and mantle edge color were 0.25, 0.74, and 0.92 in F0, F1, and F2 generations, respectively, indicating that, with generations of selection process, an individual with black (white) shell color is more likely to have black (white) mantle edge pigmentation. This suggests that shell color could be a good indicator trait for mantle edge pigmentation if selection of both the colors is implemented for a couple of generations. Estimates of heritability were 0.41 and 0.77 for shell color and 0.27 and 0.08 for mantle edge pigmentation in the F1 and F2 generations, respectively, indicating that, in general, significant proportions of phenotypic variations for the shell and mantle edge colors are explained by genetic variations between individuals. These results suggest that the two color traits are inheritable and correlated, enabling effective selection on shell and mantle edge color.

Blockade of Programmed Death-1 in Young (New Zealand Black × New Zealand White)F1 Mice Promotes the Suppressive Capacity of CD4+ Regulatory T Cells Protecting from Lupus-like Disease

Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8(+)Foxp3(+) T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD4(+) T(reg)) that can control autoimmunity in (New Zealand Black × New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4(+) T(reg). In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4(+) T(reg) (PD1(lo)CD4(+) T(reg)). PD1(lo)CD4(+) T(reg) had an increased ability to promote B cell apoptosis and to suppress CD4(+) Th as compared with CD4(+) T(reg) with elevated PD-1 expression (PD1(hi)CD4(+) T(reg)). When PD-1 expression on CD4(+) T(reg) was blocked in vitro, PD1(lo)CD4(+) T(reg) suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4(+) T(reg) depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.

AB0133 Urinary neutrophil gelatinase-associated lipocalin and monocyte chemoattractant protein-1 in a murine model of systemic lupus erythematosus

BackgroundNeutrophil Gelatinase-Associated Lipocalin (NGAL) and Monocyte Chemoattractant Protein-1 (MCP-1) are promising biomarkers in lupus nephritis (LN). Recent data in human and mice systemic lupus erythematosus (SLE) highlight their potential involvement...

Effects of a controlled heat stress during late gestation, lactation, and after weaning on thermoregulation, metabolism, and reproduction of primiparous sows1

Heat stress (HS) causes seasonal infertility in sows and decreases reproductive efficiency. The objective was to examine thermoregulation, metabolic responses, and reproduction in sows exposed to HS or thermoneutral (TN) conditions during different phases of a production cycle (gestation, lactation, and breeding). Fifty-eight first-parity Landrace (n = 26) or Landrace × Large White F1 (n = 32) sows were rotated through environmental chambers for 57 d beginning in late gestation. The ambient temperature sequences included either TN (18°C to 20°C) or HS (24°C to 30°C) for each production phase with the following treatment groups: TN-TN-TN (n = 15), TN-HS-TN (n = 14), HS-TN-HS (n = 14), and HS-HS-HS (n = 15) for gestation-farrowing-breeding (20, 24, and 13 d, respectively). Regardless of the temperature treatment, rectal temperatures were greater (P < 0.001) during lactation (39.36°C ± 0.01°C) than during the gestation (38.27°C ± 0.01°C) or the breeding period (38.77°C ± 0.01°C). The increase in rectal temperature (P < 0.001) and respiration rate (P < 0.001) in response to the HS was greatest during lactation. There was an effect of day (P < 0.001) on serum IGF-1 and insulin concentrations because both insulin and IGF-1 increased after farrowing. Compared with HS sows, the TN sows had greater feed intake (P < 0.001) and greater serum concentrations of insulin (early lactation; P < 0.05) and IGF-1 (late lactation; P < 0.05) when they were lactating. The effects of HS on sow BW, back fat, and loin eye area were generally not significant. Average BW of individual piglets at weaning was approximately 0.5 kg lighter for the sows in the HS farrowing room (P < 0.05). Weaning-to-estrus interval, percentage sows inseminated after weaning, subsequent farrowing rate, and subsequent total born were not affected by treatment. In summary, regardless of ambient temperature, sows undergo pronounced and sustained changes in rectal temperature when they transition through gestation, lactation, weaning, and rebreeding. The effects of HS on rectal temperature, respiration rate, feed intake, and metabolic hormones were greatest during lactation. The controlled HS that we imposed affected piglet weaning weight, but rebreeding and subsequent farrowing performance were not affected.

Sialoadhesin ligand expression identifies a subset of CD4+Foxp3- T cells with a distinct activation and glycosylation profile.

Sialoadhesin (Sn) is a sialic acid-binding Ig-like lectin expressed selectively on macrophage subsets. In a model of experimental autoimmune encephalomyelitis, Sn interacted with sialylated ligands expressed selectively on CD4(+)Foxp3(+) regulatory T cells (Tregs) and inhibited their proliferation. In this study, we examined the induction of Sn ligands (SnL) on all splenic CD4(+) T cells following in vitro activation. Most CD4(+) Tregs strongly upregulated SnL, whereas only a small subset of ~20% CD4(+)Foxp3(-) T cells (effector T cells [Teffs]) upregulated SnL. SnL(+) Teffs displayed higher levels of activation markers CD25 and CD69, exhibited increased proliferation, and produced higher amounts of IL-2 and IFN-γ than corresponding SnL(-) Teffs. Coculture of activated Teffs with Sn(+) macrophages or Sn(+) Chinese hamster ovary cells resulted in increased cell death, suggesting a regulatory role for Sn-SnL interactions. The key importance of α2,3-sialylation in SnL expression was demonstrated by increased binding of α2,3-linkage-specific Maackia amurensis lectin, increased expression of α2,3-sialyltransferase ST3GalVI, and loss of SnL following treatment with an α2,3-linkage-specific sialidase. The induction of SnL on activated CD4(+) T cells was dependent on N-glycan rather than O-glycan biosynthesis and independent of the mucin-like molecules CD43 and P-selectin glycoprotein ligand-1, previously implicated in Sn interactions. Induction of ligands on CD4(+)Foxp3(-) Teffs was also observed in vivo using the New Zealand Black × New Zealand White F1 murine model of spontaneous lupus and SnL levels on Teffs correlated strongly with the degree of proteinuria. Collectively, these data indicate that SnL is a novel marker of activated CD4(+) Teffs that are implicated in the pathogenesis of autoimmune diseases.

L Chain Allelic Inclusion Does Not Increase Autoreactivity in Lupus-Prone New Zealand Black/New Zealand White Mice

L chain allelic inclusion has been proposed as a B cell tolerance mechanism in addition to clonal deletion, clonal anergy, and receptor editing. It is said to rescue autoreactive B cells from elimination by diluting out the self-reactive BCR through the expression of a second innocuous L chain. In autoimmune animals, such as lupus-prone mice, allelically included B cells could be activated and produce pathogenic autoantibodies. We have previously shown that anti-DNA hybridomas from diseased New Zealand Black/New Zealand White F1 mice exhibit nearly perfect allelic exclusion. In the current study, we have analyzed single B cells from these and from nonautoimmune mice. In addition, we have cloned and expressed the Ig variable regions of several L chain-included B cells in cell culture. We find that although the number of L chain-included B cells increases as a result of receptor editing, the majority of such cells do not retain an autoreactive HxL chain combination and, therefore, allelic inclusion in itself does not serve as a B cell tolerance mechanism in these autoimmune mice.

Sialoadhesin deficiency does not influence the severity of lupus nephritis in New Zealand Black x New Zealand White F1 mice

IntroductionSystemic lupus erythematosus (SLE) is a chronic inflammatory condition with multisystem involvement. One of the key features of the disease is the upregulation of type I interferons, resulting in the so-called “interferon signature”. Recent flow cytometric and transcriptomic studies identified Sialoadhesin (Sn, CD169) as an important interferon-induced blood monocyte biomarker in diseased patients. To investigate a potential causative role of Sn in SLE, we generated NZBWF1 (New Zealand Black x New Zealand White F1) mice lacking Sn and compared onset and progression of disease with NZBWF1 expressing normal levels of Sn.MethodsSn expression in renal tissues of pre-diseased and diseased NZBWF1 mice was evaluated by Quantitative real time PCR (QPCR) and immunohistochemistry. Sn−/− NZBWF1 mice were generated by speed congenics. Disease severity of Sn+/+ and Sn−/− NZBWF1 mice was assessed by serum immunoassays, flow cytometry, light microscopy and immunohistochemistry.ResultsRenal tissues from proteinuric NZBWF1 mice exhibited a significant upregulation of Sn mRNA and protein expression following disease onset. Further immunohistochemical analysis showed that Sn+ macrophages assumed a distinct periglomerular distribution and, unlike CD68+ macrophages, were not present within the glomeruli. Analysis of disease severity in Sn−/− and Sn+/+ NZBWF1 mice revealed no significant differences in the disease progression between the two groups although Sn-deficient mice showed a more rapid onset of proteinuria.ConclusionsThese data confirm a positive correlation of Sn with disease activity. However, Sn deficiency does not have a significant effect on the severity and progression of lupus nephritis in the NZBWF1 mouse model.

Bunching Onion Culture in Greenhouse and Hoop House

Extending the season can provide opportunities for vegetable producers. Bunching onion, or scallions (Allium fistulosum L.), is a crop that can be a candidate for protected production used to extend the growing season. The cvs. Evergreen Hardy White (white), Deep Purple (red), and Nabechan F1 (white) were sown at monthly intervals from Sept. 2010 to Aug. 2011 in containers under greenhouse and hoop house conditions at Lane, OK. Days to harvest and yield variables were determined. Crop failure occurred in a greenhouse for all plants sown in July, for ‘Deep Purple’ sown in August, and for those sown in a hoop house in February and March and May through August, days to harvest was generally less for plants sown in the greenhouse, and for ‘Deep Purple’, but all plants took longer to reach marketable size than is indicated for field production. Yields for plants grown in the greenhouse were higher than for those grown in the hoop house. Greenhouse production provides more flexibility and protection from environmental conditions so that bunching onions can be grown for extended season production. However, environmental controls under greenhouse conditions need to be refined to reduce length of growing season while maintaining, or improving, yields of optimally sized plants. Programs to improve nutrition in school systems and introduction of “Farm to School” and “extended season” initiatives present opportunities for production of some vegetables including bunching onion, or scallions. “Farm to School” programs allow the use of fresh, locally grown foods to be incorporated into school menus. Bunching onions can be used fresh or prepared items. Use of protected culture in greenhouses and hoop houses may allow for extended season production of these onions so that they can be used during non-typical growing periods especially, when locally produced field-grown crops are not available.

P099 Myd88 gene knockout inhibits the development of lupus-like disease in NZB/W F1 mice

The New Zealand Black (NZB) × New Zealand White (NZW) F1 hybrid female mice (NZB/WF1) develop a disease closely resembling human systemic lupus erythematosus (SLE), characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. Recently, innate immune responses have been reported to play an important role in the development of autoimmune disease. In this study we investigated the role of Myd88 protein (an important regulator of innate immune signaling pathways) in the pathogenesis of lupus-like disease in Myd88 knockout NZB/W F1 mice. The Myd88-deficient mice were backcrossed separately in the NZB and NZW backgroud. Heterozygous NZB as well as NZW of F10 backcross generation were intercrossed to achieve Myd88 -/- NZB/W F1 mice (KO) and Myd88 +/+ NZB/W F1 mice (WT). WT and Myd88 KO mice were compared for serum concentrations of anti-dsDNAantibody, biochemical markers of active disease (BUN, Cr, Alb, TP, T-CHO, protein urea), histological analysis of kidney pathology and mortality. Compared with WT mice, Myd88 KO mice featured significantly reduced serum concentrations of anti-dsDNAantibody, reduced levels of biochemical markers of active disease, reduced kidney pathology and reduced mortality. Our result indicates that innate immunity participates in the pathogenesis of lupus prone mice and Myd88 is its important regulator.

B Cell Tolerance and Positive Selection in Lupus

Systemic lupus erythematosus is considered a prototype of systemic autoimmune diseases; however, despite considerable advances in recent years in the understanding of basic mechanisms in immunology, little progress has been made in elucidating the etiology and pathogenesis of this disease. This even holds for inbred mice, such as the lupus-prone New Zealand Black/New Zealand White F(1) mice, which are all genetically programmed to develop lupus at a predetermined age. This frustrating state of affairs calls for a fundamental change in our scientific thinking and the opening of new directions in lupus research. In this study, we suggest that intrinsic B cell tolerance mechanisms are not grossly impaired in lupus-prone mice, but that an unusually strong positive selection event recruits a small number of autoreactive B cells to the germinal centers. This event could be facilitated by nucleic acid-protein complexes that are created by somatic changes in the susceptible animal.

Early treatment with glucocorticoids or cyclophosphamide retains the slit diaphragm proteins nephrin and podocin in experimental lupus nephritis

Renal podocytes and their slit diaphragms ensure the integrity of renal basement membrane and prevent urinary protein loss. We have previously reported that decreases of the podocyte slit diaphragm proteins nephrin and podocin represent early events in the podocytopathy of lupus nephritis (LN). We asked whether immunosuppressive agents such as glucocorticoids and cyclophosphamide may have direct effects on podocytes. We assessed in New Zealand Black/New Zealand White (NZB/W) F1 LN mice glomerular nephrin and podocin expression and localization by the use of Western blot and immunofluorescence; mRNA levels were measured by real-time polymerase chain reaction (PCR) and renal histology by light and electron microscopy. Early treatment with glucocorticoids and cyclophosphamide halted the histologic alterations associated with LN, preserving podocyte foot processes. Nephrin and podocin protein expression significantly increased in both glucocorticoid and cyclophosphamide groups as early as after three months of therapy. Real-time PCR revealed similar enhancement in nephrin and podocin mRNA levels after three to six months of treatment. This study documents that early treatment in experimental LN with glucocorticoids or cyclophosphamide preserves slit diaphragm proteins in podocytes and halts histological changes of the glomeruli, thus raising the possibility of a direct protective effect of these drugs on podocytes.

Gilt development traits associated with genetic line, diet and fertility

The objective was to associate gilt development traits with genetic line, diet and fertility group (FG). Gilts (n=1225) were reared from 162 to 265 days of age at a gilt development unit (GDU) and sent to sow farms. Females were Landrace (L), Large White (LW), L and LW F1 or L and LW composite. Estrous traits included age at puberty (AGEPUB), length of estrus (LOE), maximum strength of standing reflex with (MSRBOAR) or without (MSRNOBOAR) a boar present, total strength of standing reflex with (TSRBOAR) or without (TSRNOBOAR) a boar present, vulva redness (VR), strength of vulva reddening and swelling (VISUAL VULVA) and vulva width (VW). Growth and body composition traits were puberty weight, days to 114kg and 10th rib backfat (BF) and loin muscle area (LMA) at 114kg and puberty. Structural conformation traits included muscle mass, rib width, front leg side view, rear leg side view, front legs front view, rear legs rear view and locomotion (LOC). Sow farm entry traits were age, weight, BF and LMA. Sow traits included whether or not a gilt farrowed (STAY), age at first farrowing and total number born (TNB). Fertility groups were; FG0=did not reach puberty at the GDU (NOPUB), did not farrow (DNF); FG1=reached puberty at the GDU (YESPUB), DNF; FG2=NOPUB, farrowed; FG3=YESPUB, farrowed. Genetic lines differed (P<0.05) for estrous traits LOE, TSRBOAR, MSRNOBOAR, TSRNOBOAR, VR, VISUAL VULVA and VW. Females fed restrictively vs. ad libitum had a longer (P<0.05) LOE (2.18 vs. 2.03d), higher (P<0.05) TSRBOAR (15.4 vs. 14.0) and younger (P<0.05) AGEPUB (219 vs. 225d). Fertility groups 0, 1, 2 and 3 contained 45 (4%), 255 (24%), 66 (6%) and 698 (66%) gilts, respectively. Gilts from FG3 in comparison to FG1 had a longer (P<0.05) LOE (2.16 vs. 2.06d), greater (P<0.05) MSRBOAR (7.6 vs. 7.4) and greater (P<0.05) TSRBOAR (15.4 vs. 14.6). Fertility group 0 had less (P<0.05) BF, poorer (P<0.05) LOC and was narrower (P<0.05) ribbed compared with the other FG's. Based on these results it was concluded that gilts with LOE ≤1 day or weak standing reflexes were less likely to farrow a litter.

Murine lupus strains differentially model unique facets of human lupus serology

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by the production of anti-nuclear autoantibodies that lead to subsequent end organ damage. Previous array-based studies in patients with SLE have shown that high immunoglobulin (Ig)G anti-nuclear autoantibody reactivity was associated with severe renal lupus, whereas IgM polyreactivity was associated with less severe disease. To ascertain how different murine lupus strains recapitulate these different autoantibody profiles seen in patients, serum from New Zealand black (NZB)/NZ white (W) F(1), Murphy Roths large (MRL)/lpr, NZ mixed (M)2410 and BXSB strains were compared using a comprehensive array-based screen. The array results were verified using enzyme-linked immunosorbent assays (ELISAs). Serum from MRL/lpr mice exhibited high levels of IgG anti-nuclear antibodies as well as anti-glomerular antibodies and variable levels of antibodies to myosin, Matrigel and thyroglobulin. Elevated anti-nuclear IgG antibodies were associated with severe nephritis in this strain. In contrast, NZM2410 mice exhibited lower IgG autoantibody levels with less severe nephritis but a significantly higher polyreactive IgM autoantibody profile. ELISA analysis confirmed these results. The NZB/NZW F(1) and BXSB strains exhibited an intermediate serological profile. Hence, just as in patients with SLE, whereas strong IgG reactivity to nuclear antigens is associated with severe renal disease, a polyreactive IgM seroprofile is also less ominous in murine lupus.

Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren’s syndrome‐like disease

Sjögren's syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. This study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of SS-like disease. Female New Zealand Black X New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland-infiltrating cells were characterized by flow cytometry. Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C)-treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates, and these were followed by CD4+ T cells. Our data clearly demonstrate that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for SS-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of SS.

Blockade of Programmed death-1 induces functional CD4+ regulatory T cells to resist apoptosis in (New Zealand Black x New Zealand White)F1 lupus-prone mice (115.25)

Abstract PD-1 is a negative regulatory signal in T cells. We hypothesize that regulation of PD-1 signaling is required for maintenance of functional regulatory T cells (Treg) and subsequent control of autoimmunity in BWF1 mice, and that regulatory capacity of the cells is sustained in part by resistance to apoptosis, resulting in Treg survival. By toleration with an artificial peptide pCons, we have shown induction of CD4+ and CD8+ Foxp3+Treg with reduced of PD-1 expression decrease anti-dsDNA and nephritis and prolong survival. The same outcomes are observed when PD-1 expression is blocked by a neutralizing antibody. Here, anti-PD1 or pCons treatments maintained total numbers of functional suppressive Foxp3+CD4+CD25+ T cells between 10 and 40 weeks of age. The decline in IL-2 was significantly delayed by anti-PD1, and TGF-β production was increased. These CD4+Treg were resistant to spontaneous apoptosis, suppressed CD4+CD25- T cell proliferation, and induced apoptosis in B cells. In particular, Fas and FasL are two candidate molecules in the apoptotic pathways that were upregulated in splenic CD4+Treg upon pCons-tolerization or PD-1 blockade. To conclude, PD-1 is central in control of some regulatory T cells that suppress autoimmunity; their PD-1 expression may need fine tuning to permit the cells to survive and retain suppressive capacities. A mechanism by which PD-1 sustains these Treg is by reducing their susceptibility to apoptosis, which may relate to altering Fas/FasL pathway.

CD4 T cells producing IL-10 have a beneficial effect in murine lupus

Background and objectivesSystemic lupus erythematosus is a severe systemic chronic autoimmune disease and New Zealand black × New Zealand white (NZB/W) F1 mice are commonly used to study this disease....