Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease

Browning, Jeffrey L.

doi:10.1111/j.1600-065x.2008.00633.x

Cited by 94 publications

(96 citation statements)

References 195 publications

(401 reference statements)

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“…Our data indicated that the progression of an oncogene-driven cancer, which has no obvious connection with chronic inflammation, is also critically dependent on the T cells that express LT. More importantly, blocking LTbR pathway even after the initiation of oncogenesis was still able to stall tumor progression and result in a much benign tumor and smaller burden. A form of LTbR-Ig is currently being tested clinically in the treatment of autoimmune disease, and the preliminary results suggested that such treatment has not been accompanied by any serious side effects that compromise the patients' safety (29). Our data lay a foundation for developing a new therapy which potentially has fewer and less severe side effects than conventional cancer therapy for patients with prostate cancer.…”

Section: Discussionmentioning

confidence: 95%

“…The disappearance of macrophages happened quickly within a week of LTbR-Ig treatment preceding the observed changes in tumor progression. The migration and recruitment of macrophages are commonly regulated by chemokines (28), and LTbR signaling is known to regulate the expression of many chemokines (29). We examined the expression of several chemokines known to control macrophage migration such as MIP-1a, RANTES, and MCP-1.…”

Section: Tumor-infiltrating T Cells Express Lt and Promote Tumor Progmentioning

confidence: 99%

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Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer

Zha

Wang

et al. 2013

Cancer Research

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T-cell responses may be shaped by sterile "danger signals" that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxina 1 b 2 (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTb receptor (LTbR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy. Cancer Res; 73(2); 629-39. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 95%

Section: Tumor-infiltrating T Cells Express Lt and Promote Tumor Progmentioning

confidence: 99%

Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer

Zha

Wang

et al. 2013

Cancer Research

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“…In most of these diseases, elevated expression of LT or its target genes has been detected, supporting LT's role in lymphoid neogenesis (Drayton et al, 2006). Suppression of LTbR signaling by injection of LTbR-Ig was efficacious in the treatment of various inflammatory or autoimmune disease models (Gommerman and Browning, 2003;Ware, 2005;Drayton et al, 2006;Browning, 2008;Haybaeck et al, 2009). …”

Section: Lt and Inflammationmentioning

confidence: 93%

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

et al. 2010

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“…LTA has been implicated as having diverse effects on the pathogenesis of autoimmune disorders. One potential role for membranebound LTA would be to increase the production of ectopic lymphoid tissues in particular organs leading to the development of more efficient local autoreactive responses (24,42). A soluble LTBR-Ig was produced to investigate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen

Suresh

et al. 2010

The Journal of Immunology

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The etiology of salivary gland injury in primary Sjögren’s disease is not well understood. We have previously described a mouse model of Sjögren’s disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren’s disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA−/− mice, the IL14αTG.LTA−/− mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA−/− mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA−/− mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren’s disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren’s disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren’s disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

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Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease

Cited by 94 publications

References 195 publications

Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer

Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

A Role for Lymphotoxin in Primary Sjögren’s Disease

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