Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas.

Abstract

Tumor necrosis factor 13 (TNF-P) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-fl in the regulation of infamation and type 1 diabetes, we produced transgenic mice in which the murine TNF-fi gene was regulated by the rat insulin H promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-f8 in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes.The relationship between inflammation and autoimmunity is of considerable interest. Our goal was to determine whether the inappropriate expression of inflammatory cytokines within the islets of Langerhans would be sufficient to induce an inflammatory infiltrate and, if so, whether that inflammatory infiltrate was a sufficient condition to lead to insulindependent diabetes mellitus (IDDM). Such a model could prove useful in defining basic mechanisms of autoimmune pathogenesis and provide insight into prophylaxis and treatment. Although little is known about the contribution of tumor necrosis factor 1 (TNF-(3) to the inflammatory response in vivo, several in vitro studies implicate TNF-13 in processes that may contribute to inflammation and pathogenesis in general and in IDDM in particular. TNF-,B activates human endothelial cells in vitro to express a number of leukocyte adhesion molecules (1), and major histocompatibility complex class I and class II molecules (2) and also synergizes with interferon 'y (IFN-y) in inducing HLA class II gene expression in human islets (3). As such, TNF-,8 might be expected to enhance lymphocyte traffic and antigen presentation to T cells in those tissues in which the cytokine is present.IDDM is an autoimmune inflammatory disease that results in destruction of 3 cells in the pancreatic islets of Langerhans. The trigger for this inflammation, presumably due to reactivity with an as yet unidentified autoantigen, has not been defined. Susceptibility to diabetes in the human population, and in rodent models of the disease, is linked to the major histocompatibility complex. Recently, it was shown that diabetic individuals heterozygous for DR3.4 have a higher frequency of a particular TNF-,( polymorphism (a 10.5-kilobase Nco I restriction fragment length polymorphism) than nondiabetic DR3.4 individuals (4). This implicates additional genes that are linked to the major histocompatibility complex on chromosome 6, such as TNF, in diabetes.In the present study, we addressed two issues with respect to the biological activity of TNF-,B in vivo. We demonstrate that local production of TNF-,f is sufficient to initiate and maintain an islet-specific inflammatory response consisting primarily ofB and T lymph...

Lymphotoxin β–mediated stimulation of synoviocytes in rheumatoid arthritis

“…Additionally, FLS exposed to LT␤ show induction of inflammatory chemokines, namely CCL5, CCL2, and CXCL8 (Figure 6), which elicit vigorous chemotactic responses of T cells (Figures 7 and 8). Similar LT␤-mediated up-regulation of chemokines and adhesion molecules has been shown in a variety of tumor cells lines, endothelial cells, and FDCs (24)(25)(26)(27)(28) and in the induction of chronic inflammation and lymphoid development in transgenic animals (24,(29)(30)(31)). The precise molecular pathway for the LT␣1␤2-mediated induction of chemokines and adhesion molecules is not yet known.…”

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

“…The role of LT in the context of lymphoid neogenesis, development of autoimmune diseases and inflammatory disorders was further investigated in vivo (Picarella et al, 1992;Kratz et al, 1996;Luther et al, 2000;Drayton et al, 2003Drayton et al, , 2006Gommerman and Browning, 2003;Martin et al, 2004;Heikenwalder et al, 2005Heikenwalder et al, , 2008Haybaeck et al, 2009). These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues.…”

“…These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues. LTa or LTab expression under the control of the rat insulin promoter II (RIP) induces chemokine expression and follicular lymphocytic infiltrations with mature follicular dendritic cell networks, resulting in chronic insulitis and glomerulonephritis (Picarella et al, 1992;Kratz et al, 1996;Drayton et al, 2003). Inflamed sites in RIPLTa or RIPLTab mice are vascularized with endothelia showing morphologic characteristics of high endothelial venules (Picarella et al, 1992;Cuff et al, 1999;Drayton et al, 2003).…”

“…LTa or LTab expression under the control of the rat insulin promoter II (RIP) induces chemokine expression and follicular lymphocytic infiltrations with mature follicular dendritic cell networks, resulting in chronic insulitis and glomerulonephritis (Picarella et al, 1992;Kratz et al, 1996;Drayton et al, 2003). Inflamed sites in RIPLTa or RIPLTab mice are vascularized with endothelia showing morphologic characteristics of high endothelial venules (Picarella et al, 1992;Cuff et al, 1999;Drayton et al, 2003). Further, it has been reported that LTbR signaling is a requirement for the homeostatic control of high endothelial venule differentiation and function (Browning et al, 2005).…”

Blown Away: The Unexpected Role of Lymphotoxin in Lymphoid Organ Development

“…In studies that began before the Chaplin laboratory report, Ruddle and colleagues (19) had shown using transgenic mice that LTa was sufficient to promote lymphocyte-rich infiltrates in nonlymphoid tissue. Later, using more refined anatomical assessments, they observed that the infiltrates took on many of the organized features of a lymphoid tissue, indicating that LTa was sufficient to induce lymphoid neogenesis (20).…”