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Anne Davidson

Publications and source records attributed to Anne Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of Helicobacter hepaticus-induced colitis by IL-10 requires the p50/p105 subunit of NF-kappa B.

Defects within the innate immune system sensitize NF-kappaB-deficient (p50(-/-); p65(+/-)) mice to Helicobacter hepaticus (Hh)-induced colitis. Because IL-10 plays a central role in the inhibition of Hh-induced colitis, we hypothesized that the ability of IL-10 to inhibit the innate inflammatory response to Hh may be compromised in NF-kappaB-deficient mice. To test this hypothesis, we evaluated the ability of an IL-10-Ig fusion protein with IL-10-like properties to inhibit Hh-induced colitis in RAG-2(-/-) (RAG) and p50(-/-); p65(+/-); RAG-2(-/-) (3X/RAG) mice. As expected, IL-10-Ig efficiently inhibited the development of colitis in RAG mice. In contrast, the ability of IL-10-Ig to inhibit colitis was compromised in 3X/RAG mice. The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50(-/-); RAG-2(-/-) (p50/RAG) mice. Radiation chimeras demonstrated that the presence of p50/p105 within hemopoietic cells of the innate immune system was necessary for efficient inhibition of colitis by IL-10-Ig. Consistent with a defect in the suppressive effects of IL-10 in the absence of p50/p105, we found that the ability of IL-10 to control LPS-induced expression of IL-12 p40 was significantly compromised in macrophages lacking p50/p105. These results suggest that the absence of the p50/p105 subunit of NF-kappaB within hemopoietic cells of the innate immune system interferes with the ability of IL-10 to suppress inflammatory gene expression and Hh-induced colitis.

Animals↗
PubMed2006

Similarities and differences between selective and nonselective BAFF blockade in murine SLE.

B cells have multiple roles in immune activation and inflammation separate from their capacity to produce antibodies. B cell depletion is currently under intense investigation as a therapeutic strategy for autoimmune diseases. The TNF family members B cell-activating factor of the TNF family (BAFF) and its homolog A proliferation-inducing ligand (APRIL) are B cell survival and differentiation factors and are therefore rational therapeutic targets. We compared the effects of BAFF receptor-Ig, which blocks only BAFF, with those of transmembrane activator and calcium modulator ligand interactor-Ig, which blocks both BAFF and APRIL, in a murine SLE model. Both reagents prolonged the life of NZB/W F1 mice when given either before or after disease onset. Many immunologic effects of the 2 reagents were similar, including B cell and B cell subset depletion and prevention of the progressive T cell activation and dendritic cell accumulation that occurs with age in NZB/W mice without substantial effects on the emergence of the IgG anti-double-stranded DNA response. Furthermore, both reagents inhibited the T cell-independent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, but not blockade of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T cell-dependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for the treatment of autoimmune and malignant diseases.

Animals↗
PubMed2006

Pathogenesis and treatment of systemic lupus erythematosus nephritis.

PURPOSE OF REVIEW: Glomerulonephritis is a challenging complication of systemic lupus erythematosus that still results in kidney loss in up to 30% of patients. In this review we highlight the development of integrated efforts to link pathogenesis with disease definition and new therapeutics. RECENT FINDINGS: Immune complex deposition in the kidney initiates an inflammatory cascade that causes glomerular disease but there are many modulating factors including genetic predisposition, products of the innate immune system, cytokines, complement and activated cells (both renal and immune). Animal models can help dissect potential disease mechanisms but the study of multiple models will be required since there are multiple subsets of human disease. Recent therapeutic studies in humans address the distinction between therapies for remission induction and remission maintenance. Multiple studies confirm the therapeutic equivalence of mycophenolate mofetil and cyclophosphamide in induction of remission but results are still far from ideal. The next few years should see the testing of new biologic reagents in humans. Another area of interest is the search for noninvasive measures of disease and disease response. SUMMARY: Although there has been remarkable progress in our understanding of the immunology and phenotype of lupus nephritis current therapies have insufficient efficacy. As new therapies emerge, improved clinical design coupled with mechanistic studies will be needed to identify agents that may be effective only in some patient subpopulations.

Animals↗
PubMed2005

Expansion and hyperactivity of CD1d-restricted NKT cells during the progression of systemic lupus erythematosus in (New Zealand Black x New Zealand White)F1 mice.

CD1d-restricted NKT cells expressing invariant TCR alpha-chain rearrangements (iNKT cells) have been reported to be deficient in humans with a variety of autoimmune syndromes and in certain strains of autoimmune mice. In addition, injection of mice with alpha-galactosylceramide, a specific glycolipid agonist of iNKT cells, activates these T cells and ameliorates autoimmunity in several different disease models. Thus, deficiency and reduced function in iNKT cells are considered to be risk factors for the development of such diseases. In this study we report that the development of systemic lupus erythematosus in (New Zealand Black (NZB) x New Zealand White (NZW))F(1) mice was paradoxically associated with an expansion and activation of iNKT cells. Although young (NZB x NZW)F(1) mice had normal levels of iNKT cells, these expanded with age and became phenotypically and functionally hyperactive. Activation of iNKT cells in (NZB x NZW)F(1) mice in vivo or in vitro with alpha-galactosylceramide indicated that the immunoregulatory role of iNKT cells varied over time, revealing a marked increase in their potential to contribute to production of IFN-gamma with advancing age and disease progression. This evolution of iNKT cell function during the progression of autoimmunity may have important implications for the mechanism of disease in this model of systemic lupus erythematosus and for the development of therapies using iNKT cell agonists.

Animals↗
PubMed2005

Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential.

OBJECTIVE: Cross-reactivity with kidney antigens is believed to be a critical determinant in the renal pathogenicity of anti-double-stranded DNA (anti-dsDNA) antibodies. Murine nephritogenic anti-dsDNA antibodies have been shown to cross-react with alpha-actinin, and anti-alpha-actinin antibodies have been found to be deposited in the kidneys of lupus mice with active nephritis. Furthermore, in humans with systemic lupus erythematosus (SLE), it has been found that a greater proportion of polyclonal IgG anti-dsDNA antibodies from patients with renal involvement bind to alpha-actinin than do those from patients without renal disease. We undertook this study to substantiate a direct link between cross-reactive anti-dsDNA/anti-alpha-actinin antibodies and the pathogenesis of lupus nephritis in humans. METHODS: A panel of 10 anti-dsDNA and/or anti-alpha-actinin antibodies was generated by Epstein-Barr virus transformation of lymphocytes from patients with SLE and was extensively characterized. Antibody binding was studied by enzyme-linked immunosorbent assay and Western blotting. Antibody potential for pathogenicity was assessed by measuring binding to isolated glomeruli and mesangial cells and by evaluation of histologic features of the kidney following injection in vivo. RESULTS: All anti-dsDNA antibodies isolated also bound alpha-actinin. Cross-reactive antibodies bound to mesangial cells and to isolated glomeruli ex vivo. Binding to glomeruli was not inhibited by DNase treatment, but could be abrogated by alpha-actinin. Furthermore, histopathologic abnormalities seen in mice injected intraperitoneally with a cross-reactive cell line included fusion of podocyte foot processes and subepithelial and subendothelial deposition. CONCLUSION: These studies provide strong support for the hypothesis that alpha-actinin is a major cross-reactive target for anti-dsDNA antibodies in SLE patients. Cross-reactive anti-dsDNA/anti-alpha-actinin antibodies from SLE patients are pathogenic and may contribute to the kidney lesions in lupus nephritis.

Actinin↗
PubMed2005

Discitis in toddlers: a case series and review.

UNLABELLED: Toddlers commonly present to medical services with non-specific symptoms. The presence of refusal to walk and nocturnal waking with crying should alert clinicians to the possibility of discitis. CONCLUSION: Features that may alert clinicians to the diagnosis of discitis in young children are reviewed.

Age Factors↗
PubMed2005

Systemic lupus erythematosus presenting with features suggestive of human immunodeficiency virus infection.

We describe 8 patients who presented with fever, weight loss, anemia, and oral and/or esophageal candidiasis, and who were initially thought to have human immunodeficiency virus (HIV) infection or lymphoma. These patients fulfilled American College of Rheumatology criteria for systemic lupus erythematosus (SLE) because of arthralgias or arthritis, hematological derangements, and immunological abnormalities. Treatment was delayed because SLE did not immediately enter into the differential diagnosis. All patients had a rapid response to corticosteroids, with defervescence of fever, decrease in lymphadenopathy within 24-48 hours, and complete resolution of lymphadenopathy and other signs and symptoms of illness in 7-10 days. It is important to recognize this mode of SLE presentation in patients who test negative for HIV infection so that the appropriate diagnostic evaluation and initiation of treatment can be expedited.

Adult↗
PubMed2004

Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus.

B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F(1) mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4(+) T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F(1) mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.

Abatacept↗
PubMed2004

The current status of targeting BAFF/BLyS for autoimmune diseases.

It is increasingly recognized that B cells have multiple functions that contribute to the pathogenesis of autoimmunity. Specific targeting of B cells might therefore be an appropriate therapeutic intervention. The tumor necrosis factor-like molecule BAFF (BLyS) is a key B cell survival factor and its receptors are expressed on most peripheral B cells. Several different BAFF antagonists are under development and in early clinical trials. We review here the rationale for BAFF blockade, and its predicted mechanism of action in autoimmune diseases.

Animals↗
PubMed2004

BAFF binding to T cell-expressed BAFF-R costimulates T cell proliferation and alloresponses.

Binding of the TNF family member, B cell activating factor (BAFF), to its receptor (BAFF-R, TNFRSF13C) is required for generation and maintenance of mature B cells, but there are no data as to any role for the BAFF/BAFF-R pathway in T cell functions. We report that the binding of BAFF to BAFF-R expressed by a subset of primarily CD4(+) T cells costimulates T cell activation and allo-proliferation in vitro and in vivo, and that mice with a mutation in the BAFF-R, or with a targeted deletion of BAFF, show prolonged cardiac allograft survival as compared to wild-type or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)(-/-) controls. Taken together, these data indicate the BAFF/BAFF-R pathway contributes to both T and B cell responses and may be an attractive target for control of acute and chronic allograft rejection.

Animals↗
PubMed2004

Induction of B7-1 in podocytes is associated with nephrotic syndrome.

Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.

Actins↗
PubMed2003

Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues.

We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, was observed in 31 of 77 (40%) tissues and 5 of 11 (45%) cell lines. Tandem base-pair substitutions encoding V599R and V599K amino acid changes were observed in two cases. Novel findings with respect to melanoma include a cell line possessing a 2 base-pair substitution in BRAF exon 11 and a case harboring mutations in both BRAF exon 11 and N-RAS exon 3. Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients.

Exons↗
PubMed2003

Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition.

NZB/W F(1) mice with established nephritis were treated with a single dose of cyclophosphamide with or without a 2-wk course of murine CTLA4Ig, either alone or in combination with anti-CD154. Sixty to 80% of treated mice entered remission, and remission could be reinduced following relapse. A decrease in the frequency of anti-DNA-producing B cells and activated T cells was observed in treated mice, but this effect lasted only 3-6 wk, while remissions were sustained for up to 20 wk. Light microscopy of the kidneys of mice in remission revealed less glomerular inflammation, less tubular damage, and less infiltration of inflammatory cells. By immunofluorescence, however, IgG and C3 staining of glomeruli was no different in treated mice vs controls. Since chemokines and their receptors play an important role in inflammatory cell infiltration of affected organs in autoimmune diseases, we examined chemokine expression in the kidneys. Decreases in the expression of inflammatory cytokines and chemokines were evident in mice in the early stages of remission, but these differences were no longer present in late remission. Increased expression of CXCL13 was detected in the inflammatory infiltrates of the control NZB/NZW mice. Strikingly, we could not detect any CXCL13 in the kidneys of the treated group even in late remission. These findings suggest that costimulatory blockade together with cyclophosphamide influence the activation state of renal CD11c-positive cells and therefore lead to less B and T cell infiltration and nephritis.

Abatacept↗
PubMed2003

Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus.

OBJECTIVE: To determine the immunologic effects of anti-CD154 (CD40L) therapy in the (NZB x NZW)F(1) mouse model of systemic lupus erythematosus. METHODS: Twenty-week-old and 26-week-old (NZB x NZW)F(1) mice were treated with continuous anti-CD154 therapy. Mice were followed up clinically, and their spleens were studied at intervals for B and T cell numbers and subsets and frequency of anti-double-stranded DNA (anti-dsDNA)-producing B cells. T cell-dependent immunity was assessed by studying the humoral response to the hapten oxazolone. RESULTS: IgG anti-dsDNA antibodies decreased during therapy and disease onset was delayed, but immune tolerance did not occur. During treatment, there was marked depletion of CD19+ cells in the spleen; however, autoreactive IgM-producing B cells could still be detected by enzyme-linked immunospot assay. In contrast, few IgG- and IgG anti-dsDNA-secreting B cells were detected. Eight weeks after treatment cessation, the frequency of B cells producing IgG anti-dsDNA antibodies was still decreased in 50% of the mice, and activation and transition of T cells from the naive to the memory compartment were blocked. Anti-CD154 treatment blocked both class switching and somatic mutation and induced a variable period of relative unresponsiveness of IgG anti-dsDNA-producing B cells, as shown by decreased expression of the CD69 marker and failure to generate spontaneous IgG anti-dsDNA-producing hybridomas. Treated mice mounted an attenuated IgM response to the hapten oxazolone and produced no IgG antioxazolone antibodies. CONCLUSION: Anti-CD154 is a B cell-depleting therapy that affects multiple B cell subsets. Activation of both B and T cells is prevented during therapy. After treatment cessation, autoreactive B cells progress through a series of activation steps before they become fully competent antibody-producing cells. The general immunosuppression induced during treatment will need to be taken into account when using B cell-depleting regimens in humans.

Amino Acid Sequence↗
PubMed2003

Co-stimulatory blockade in the treatment of murine systemic lupus erythematosus (SLE).

Although the life span of patients with systemic lupus erythematosus (SLE) has improved considerably over the last several decades, the toxicities of chronic immunosuppressive therapy are major causes of morbidity and mortality. Safer and more effective therapies for SLE are clearly needed. SLE is characterized by excessive activation of both B and T lymphocytes. Activation of these cells requires both antigen engagement and co-stimulatory signals from interacting lymphocytes (Carreno, B.M. M. Collins, 2002, Annu. Rev. Immunol. 20: 29-53; Grewal, I.S. R.A. Flavell, 1998, Annu. Rev. Immunol. 16: 111-135). Thus, blockade of co-stimulatory signals offers a new therapeutic approach to SLE. Our short-term goal has been to understand the effect of co-stimulatory blocking reagents on the development, selection, and activation of pathogenic anti-dsDNA antibody producing B cells in mice genetically pre-determined to develop SLE and showing signs of either early or advanced disease activity. Our long-term goal is to use the knowledge we gain to design therapeutic regimens for humans that avoid the complications of long-term immunosuppression. As new co-stimulatory molecules are discovered, studying their mechanism of action in animal models and their clinical utility in human autoimmune disease should lead both to a new understanding of disease pathogenesis and also to safer and more effective therapies.

Abatacept↗
PubMed2002

Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus.

Short-term combination therapy with the costimulatory antagonists CTLA4Ig and anti-CD40 ligand induces prolonged suppression of disease onset in New Zealand Black/New Zealand White F(1) systemic lupus erythematosus-prone mice. To determine the mechanism for this effect, 20- to 22-wk-old New Zealand Black/New Zealand White F(1) mice were treated with six doses each of CTLA4Ig and anti-CD40 ligand Ab over 2 wk. Combination-treated mice, but not mice treated with either agent alone, had prolonged survival and the production of pathogenic IgG anti-dsDNA Ab was suppressed. Twenty weeks after completion of treatment the frequency of activated B cells producing anti-dsDNA Ab was decreased, and the abnormal transition of T cells from the naive to the memory compartment was blocked. Combination treatment partially suppressed class switching and decreased the frequency of somatic mutations in the V(H)BW-16 gene, which is expressed by pathogenic anti-DNA Abs. Treated mice were still able to respond to the hapten oxazolone when it was given 8 wk after treatment initiation, and they mounted a somatically mutated IgG anti-oxazolone response that was noncross-reactive with dsDNA. Fifty to 60% of previously treated mice, but only 14% of previously untreated mice, responded within 2-3 wk to a second course of therapy given at the onset of fixed proteinuria and remained well for a further 3-4 mo. Although this treatment had no immediate effect on serum anti-dsDNA Abs or on the abnormal T cell activation observed in sick mice, 25% of treated mice lived for >18 mo compared with 5% of untreated controls. These results suggest that the effect of costimulatory blockade in remission induction must be mediated by a different mechanism than is demonstrated in the disease prevention studies.

Abatacept↗