CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis.

Gerritse, Koen; Laman, Jon D.; Noelle, Randolph J.; Aruffo, Alejandro; Ledbetter, Jeffrey A.; Boersma, W.J.A.; Claassen, Eric

doi:10.1073/pnas.93.6.2499

Cited by 468 publications

(374 citation statements)

References 28 publications

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“…For example, anti-CD40L MAb therapy blocks the development or progression of disease in animal models of RA (collagen-induced arthritis) (30), SLE (22), and multiple sclerosis (experimental allergic encephalomyelitis [EM]) (31). The precise mechanism(s) by which CD40L-CD40 interactions contribute to disease immunopathogenesis in these models is unknown.…”

Section: Discussionmentioning

confidence: 99%

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

Yellin

D’Agati

Parkinson

et al. 1997

Arthritis & Rheumatism

145

115

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Objective. To investigate potential mechanisms by which CD40L-mediated signals may be involved in the pathogenesis of lupus glomerulonephritis (GN).Methods. Renal in situ CD40L and CD40 expression was examined in patient biopsy specimens. Immunohistochemical studies were performed on frozen sections utilizing anti-CD40L monoclonal antibody (MAb), anti-CD40 MAb, or control MAb. As controls, we analyzed normal kidney specimens and specimens obtained from patients with IgA nephropathy, focal segmental glomerulosclerosis, minimal change disease, idiopathic membranous GN, and antineutrophil cytoplasmic antibodypositive pauci-immune GN. Staining distribution was noted and staining intensity scored on a semiquantitative scale of 0 (no staining) to 3+ (intense staining).Results. In normal kidney, CD40 was expressed on parietal epithelial cells, mesangial cells, endothelial cells, and distal tubules but not proximal tubules. Glomerular and tubular CD40 expression was markedly up-regulated in class I11 and class IV lupus GN, where there was intense staining of crescents, proximal and distal tubules, and interstitial mononuclear cells. In contrast, CD40 expression in class V lupus GN was similar to that in normal kidney. Interstitial mononuclear cells expressing CD40L were present in class IV lupus GN. However, these findings were not unique to lupus GN: up-regulation of CD40 and CD40L expres- Submitted for publication June 3, 1996; accepted in revised form July 17, 1996. sion was similarly observed in other inflammatory renal diseases.Conclusion. This study shows that CD40 is expressed on a variety of renal parenchymal and nonparenchymal cells in normal kidney. Renal CD40 expression is up-regulated in class I11 and class IV lupus nephritis, as well as in other inflammatory renal diseases, and is associated with the presence of CD40L+ mononuclear cells.

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Section: Discussionmentioning

confidence: 99%

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

Yellin

D’Agati

Parkinson

et al. 1997

Arthritis & Rheumatism

145

115

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“…MS in humans Gerritse et al, 1996 , double staining for cell surface CD40 expression and intracytoplasmic acid Ž phosphatase activity was performed see Fig. 2d for an .…”

Section: Co-expression Of Cd40 and Acid Phosphatasementioning

confidence: 99%

“…In addition, it was found that CD40 is abundantly expressed by infiltrating macrophages in autopsy brain material of MS-patients, while CD40L-ex-Ž . pression is more limited Gerritse et al, 1996 . The current study demonstrates that analogous to MS, in marmoset EAE the brain is infiltrated by macrophages expressing Ž .…”

Section: Accessory Molecules: Cd40-cd40lmentioning

confidence: 99%

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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Ž .Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis MS and experimental autoimmune Ž . encephalomyelitis EAE in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of Ž . marmoset monkeys Callithrix jacchus with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions Ž . Ž . may result from local CD40-CD40L interactions. CD40 ligand CD40L and B7-2 CD86 were also expressed, but to a lower extent, Ž . while B7-1 CD80 expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual Ž . lesions during active disease IFN-a, IFN-g , TNF-a, IL-1a , IL-1b, IL-2, IL-4, IL-10 and IL-12 . This suggests that relative levels rather than sequential expression of Th1-and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention. q

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“…Moreover, CD40 ligation induces expression of adhesion molecules such as CD54, CD62E, and CD106 on endothelial cells, suggesting that CD40 signaling plays an important role in leukocyte extravasation to sites of inflammation (5,6). In recent years, greater attention has been paid to the role of CD40-CD40L interactions in the immunopathogenesis of some autoimmune diseases, where T or B cells have a prominent role, such as systemic lupus erythematosus (7), rheumatoid arthritis (8), and multiple sclerosis (9) as well as in allograft rejection (10). Administration of mAb directed against CD40L has been shown to effectively inhibit inflammatory responses in a variety of animal models such as experimental allergic encephalomyelitis (9,11), lupus nephritis (12), collagen-induced arthritis (13), atherosclerosis (14), and spontaneous autoimmune diabetes (15).…”

Section: Prevention Of Experimental Colitis In Scid Micementioning

confidence: 99%

Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions

Liu¹,

Geboes

Colpaert³

et al. 2000

The Journal of Immunology

119

103

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Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-γ, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.

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CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis.

Abstract: We investigated the role of CD40-CD40 ligand (

Cited by 468 publications

References 28 publications

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions

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