The Experts below are selected from a list of 936 Experts worldwide ranked by ideXlab platform
Nancy H. Ruddle - One of the best experts on this subject based on the ideXlab platform.
-
Chronic Inflammation Caused by Lymphotoxin Is Lymphoid Neogenesis
2013Co-Authors: Er Kratz, Antonio Campos-neto, Matthew S. Hanson, Nancy H. RuddleAbstract:In presenting a unifying concept for chronic inflammation and Lymphoid Organogenesis, we suggest that lymphotoxin's (LT, LT-ot, TNF-J3) crucial role in these processes is pivotal and similar. Chronic inflammatory lesions that developed in the kidney and pancreas at the sites of transgene expression in rat insulin promoter-LT (RIP-LT) mice resembled lymph nodes with regard to cellular composition (T cells, B cells, plasma cells, and antigen-presenting cells), delineated T and B cell areas, primary and secondary follicles, characteristic morphologic and antigenic (ICAM-1, VCAM-1, MAdCAM-1, and PNAd) features of high endothelial venules, and ability to respond to antigen and undergo Ig class switching when obtained from mice immunized with SRBC. The vascular changes, with the exception of PNAd, appear to be the direct consequence of transgene derived LT expression, as they were also observed in RIP-LT mice lacking mature T and B cells. These data show that LT-induced chronic inflammation has the characteristics of organized Lymphoid tissue. C hronic inflammation, a complex pathophysiologic process characterized by an accumulation of mononuclea
-
blocking lymphotoxin signaling abrogates the development of ectopic Lymphoid tissue within cardiac allografts and inhibits effector antibody responses
The FASEB Journal, 2012Co-Authors: Reza Motallebzadeh, Nancy H. Ruddle, Sylvia Rehakova, Thomas M Conlon, Thet Su Win, Chris J Callaghan, Martin Goddard, Eleanor M Bolton, Andrew J Bradley, G J PettigrewAbstract:Tertiary Lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for Lymphoid Organogenesis, abrogates TLO development. TLOs (defined as discrete Lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipi...
-
blocking lymphotoxin signaling abrogates the development of ectopic Lymphoid tissue within cardiac allografts and inhibits effector antibody responses
The FASEB Journal, 2012Co-Authors: Reza Motallebzadeh, Nancy H. Ruddle, Sylvia Rehakova, Thomas M Conlon, Thet Su Win, Chris J Callaghan, Martin Goddard, Eleanor M Bolton, Andrew J Bradley, G J PettigrewAbstract:Tertiary Lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for Lymphoid Organogenesis, abrogates TLO development. TLOs (defined as discrete Lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipients primed for autoantibody before transplantation rejected grafts rapidly, but this accelerated rejection was prevented by postoperative administration of LTβR-Ig (median survival time: 18 vs. >50 d, respectively, P=0.003). Our results provide the first demonstration that TLOs develop within chronically rejecting heart allografts, are predominantly B cell in origin, and can be targeted pharmacologically to inhibit effector humoral responses.
-
iκb kinase complex α kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal associated Lymphoid tissue
Journal of Immunology, 2004Co-Authors: Danielle L Drayton, Xiaoyan Ying, Giuseppina Bonizzi, Shan Liao, Michael Karin, Nancy H. RuddleAbstract:The lymphotoxin (LT) β receptor plays a critical role in secondary Lymphoid Organogenesis and the classical and alternative NF-κB pathways have been implicated in this process. IKKα is a key molecule for the activation of the alternative NF-κB pathway. However, its precise role and target genes in secondary Lymphoid Organogenesis remain unknown, particularly with regard to high endothelial venules (HEV). In this study, we show that IKKαAA mutant mice, who lack inducible kinase activity, have hypocellular lymph nodes (LN) and nasal-associated Lymphoid (NALT) tissue characterized by marked defects in microarchitecture and HEV. In addition, IKKαAA LNs showed reduced Lymphoid chemokine CCL19, CCL21, and CXCL13 expression. IKKαAA LN- and NALT-HEV were abnormal in appearance with reduced expression of peripheral node addressin (PNAd) explained by a severe reduction in the HEV-associated proteins, glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1), and high endothelial cell sulfotransferase, a PNAd-generating enzyme that is a target of LTαβ. In this study, analysis of LTβ−/− mice identifies GlyCAM-1 as another LTβ-dependent gene. In contrast, TNFRI−/− mice, which lose classical NF-κB pathway activity but retain alternative NF-κB pathway activity, showed relatively normal GlyCAM-1 and HEC-6ST expression in LN-HEV. In addition, in this communication, it is demonstrated that LTβR is prominently expressed on LN- and NALT-HEV. Thus, these data reveal a critical role for IKKα in LN and NALT development, identify GlyCAM-1 and high endothelial cell sulfotransferase as new IKKα-dependent target genes, and suggest that LTβR signaling on HEV can regulate HEV-specific gene expression.
-
ectopic ltαβ directs Lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a hev restricted sulfotransferase
Journal of Experimental Medicine, 2003Co-Authors: Danielle L Drayton, Xiaoyan Ying, Jason Lee, Werner Lesslauer, Nancy H. RuddleAbstract:Lymph node (LN) function depends on T and B cell compartmentalization, antigen presenting cells, and high endothelial venules (HEVs) expressing mucosal addressin cell adhesion molecule (MAdCAM-1) and peripheral node addressin (PNAd), ligands for naive cell entrance into LNs. Luminal PNAd expression requires a HEV-restricted sulfotransferase (HEC-6ST). To investigate LTαβ's activities in Lymphoid Organogenesis, mice simultaneously expressing LTα and LTβ under rat insulin promoter II (RIP) control were compared with RIPLTα mice in a model of Lymphoid neogenesis and with LTβ−/− mice. RIPLTαβ pancreata exhibited massive intra-islet mononuclear infiltrates that differed from the more sparse peri-islet cell accumulations in RIPLTα pancreata: separation into T and B cell areas was more distinct with prominent FDC networks, expression of Lymphoid chemokines (CCL21, CCL19, and CXCL13) was more intense, and L-selectin+ cells were more frequent. In contrast to the predominant abluminal PNAd pattern of HEV in LTβ−/− MLN and RIPLTα pancreatic infiltrates, PNAd was expressed at the luminal and abluminal aspects of HEV in wild-type LN and in RIPLTαβ pancreata, coincident with HEC-6ST. These data highlight distinct roles of LTα and LTαβ in Lymphoid Organogenesis supporting the notion that HEC-6ST–dependent luminal PNAd is under regulation by LTαβ.
Liang Zhou - One of the best experts on this subject based on the ideXlab platform.
-
ikaros inhibits group 3 innate Lymphoid cell development and function by suppressing the aryl hydrocarbon receptor pathway
Immunity, 2016Co-Authors: Jennifer J Heller, John W Bostick, Aileen Lee, Hilde Schjerven, Philippe Kastner, Susan Chan, Zongming E Chen, Liang ZhouAbstract:Group 3 innate Lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros, encoded by Ikzf1, is essential for the development of RORγt(+) fetal Lymphoid tissue inducer (LTi) cells and Lymphoid Organogenesis, but its role in postnatal ILC3s is unknown. Here, we show that small-intestinal ILC3s had lower Ikaros expression than ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc-finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt(+) ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to being required for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease.
-
aryl hydrocarbon receptor promotes rorγt group 3 ilcs and controls intestinal immunity and inflammation
Seminars in Immunopathology, 2013Co-Authors: Liang ZhouAbstract:Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate Lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptor (RORγt)+ group 3 ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ group 3 ILCs (e.g., Lymphoid tissue inducer cells) are required for Lymphoid Organogenesis. In adult mice, RORγt+ group 3 ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ group 3 ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ group 3 ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells. In this review, we will focus on the development and function of RORγt+ group 3 ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. A better understanding of the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.
Thomas Hehlgans - One of the best experts on this subject based on the ideXlab platform.
-
lymphatic endothelial cells control initiation of lymph node Organogenesis
Immunity, 2017Co-Authors: Lucas Onder, Thomas Hehlgans, Klaus Pfeffer, Urs Morbe, Natalia Pikor, Mario Novkovic, Hung Wei Cheng, Burkhard Becher, Ari Waisman, Thomas RulickeAbstract:Lymph nodes (LNs) are strategically situated throughout the body at junctures of the blood vascular and lymphatic systems to direct immune responses against antigens draining from peripheral tissues. The current paradigm describes LN development as a programmed process that is governed through the interaction between mesenchymal Lymphoid tissue organizer (LTo) cells and hematopoietic Lymphoid tissue inducer (LTi) cells. Using cell-type-specific ablation of key molecules involved in Lymphoid Organogenesis, we found that initiation of LN development is dependent on LTi-cell-mediated activation of lymphatic endothelial cells (LECs) and that engagement of mesenchymal stromal cells is a succeeding event. LEC activation was mediated mainly by signaling through receptor activator of NF-κB (RANK) and the non-canonical NF-κB pathway and was steered by sphingosine-1-phosphate-receptor-dependent retention of LTi cells in the LN anlage. Finally, the finding that pharmacologically enforced interaction between LTi cells and LECs promotes ectopic LN formation underscores the central LTo function of LECs.
-
The Journal of Experimental Medicine CORRESPONDENCE
2013Co-Authors: Rolf Gr Ä Bner, Rainer Spanbroek, Michael Beer, Markus Hildner, Katharina Ö L Tzer, Ö Rte D Radke, Catherine A. Reardon, Godfrey S. Getz, Thomas HehlgansAbstract:Lymphotoxin � receptor signaling promotes tertiary Lymphoid Organogenesis in the aort
-
CCL19-Cre transgenics: targeting lymph node fibroblastic reticular cells in vivo
Journal of Immunology, 2012Co-Authors: Burkhard Ludewig, Lucas Onder, Thomas Rulicke, Qian Chai, Elke Scandella, Tim Sparwasser, Sanjiv A. Luther, Volker Thiel, Thomas HehlgansAbstract:The paracortex of lymph nodes (LNs) harbors a sponge-like scaffold of stromal cells known as fibroblastic reticular cells (FRCs). A major function of FRCs is to build and enwrap the conduit system of collagen fibers that directs interstitial fluids from the afferent lymph through the T-cell zone to HEVs. Furthermore, FRCs regulate T-cell migration and survival by producing the chemokines CCL19 and CCL21. To gain further knowledge on the biology of FRCs and possibly other stromal cell subsets, we have generated a bacterial artificial chromosome (BAC)-transgenic mouse model that utilizes the CCL19 promoter to direct the Cre-recombinase to LN stromal cells. Crossing of CCL19-Cre mice to the R26-EYFP reporter revealed that transgene expression in LNs was almost exclusively confined to podoplanin+CD31- cells. Likewise, transgene activity in spleens and Peyer’s patches of CCL19-Cre mice was largely restricted to FRC-like cells, i.e. stromal cells within the T cell zone and the T-B border. Selective ablation of the lymphotoxin-beta receptor on CCL19-Cre-positive cells resulted in profound changes in the development and organization of secondary Lymphoid organs. Taken together, stromal CCL19-Cre expression is well-suited (i) to characterize the development of LN FRCs in vivo, (ii) to molecularly dissect the contribution of stromal cells to Lymphoid Organogenesis, and (iii) to address the function of LN FRCs in the generation of innate and adaptive immune responses.
-
Mouse Aorta Smooth Muscle Cells Differentiate Into Lymphoid Tissue Organizer-Like Cells on Combined Tumor Necrosis Factor Receptor-1/Lymphotoxin β-Receptor NF-κB Signaling
Arteriosclerosis thrombosis and vascular biology, 2010Co-Authors: Katharina Lötzer, Sandra Döpping, Sabine Connert, Rolf Gräbner, Rainer Spanbroek, Birgit Lemser, Michael Beer, Markus Hildner, Thomas Hehlgans, Michael Van Der WallAbstract:Objective— Mouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin β-receptor (LTβR). Circumstantial evidence has linked the SMC LTβR to tertiary Lymphoid Organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTβR signaling in cultured SMC. Methods and Results— TNFR-1 signaling activated the classical RelA NF-κB pathway, whereas LTβR signaling activated the classical RelA and alternative RelB NF-κB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB. Microarrays showed that simultaneous TNFR-1/LTβR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of Lymphoid tissue organizers, which control tertiary Lymphoid Organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTβR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTβR–activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr −/− SMC indicated that LTβR-RelB activation was obligatory to generate the Lymphoid tissue organizer phenotype. Conclusion— SMC may participate in the formation of tertiary Lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.
-
activation of the lymphotoxin beta receptor induces nfκb dependent interleukin 6 and mip 2 secretion in mouse fibrosarcoma cells
European Cytokine Network, 2003Co-Authors: Thomas Hehlgans, Peter Stopfer, Peter Muller, Daniela N MannelAbstract:Activation of the lymphotoxin beta-receptor (LTbetaR), a member of the tumor necrosis factor receptor family, plays a crucial role in Lymphoid Organogenesis and tumor development. Lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) and LIGHT have been identified as membrane anchored ligands for the LTbetaR. While LTbetaR is expressed on a wide range of cell types e.g. fibroblasts and monocytes, the ligands are expressed only on activated lymphocytes and NK cells. In order to characterize LTbetaR expression and the biological consequences of LTbetaR activation rat anti-mouse LTbetaR monoclonal antibodies were generated. These antibodies recognized a mouse LTbetaR-Ig fusion protein as well as endogenous LTbetaR on a variety of mouse fibroblast and fibrosarcoma cell lines. Specificity was demonstrated by the lack of binding to LTbetaR-deficient embryonic fibroblasts. Competitive binding studies revealed that three different epitopes were recognized by the monoclonal antibodies. Two of the monoclonals activated the LTbetaR and induced activation of NFkappaB and secretion of MIP-2 and IL-6 in L929 mouse fibroblast cells. MIP-2 and IL-6 secretion was NFkappaB-dependent because IkappaB-transfected cells released significantly reduced amounts of both mediators.
Mitsuru Matsumoto - One of the best experts on this subject based on the ideXlab platform.
-
Brief Definitive Report Essential Role of Nuclear Factor (NF)-�B–inducing Kinase and Inhibitor of �B (I�B) Kinase � in NF-�B Activation through Lymphotoxin � Receptor, but Not through Tumor Necrosis Factor Receptor I
2013Co-Authors: Akemi Matsushima, Paul D Rennert, Tsuneyasu Kaisho, Hiroyasu Nakano, Kyoko Kurosawa, Daisuke Uchida, Kiyoshi Takeda, Shizuo Akira, Mitsuru MatsumotoAbstract:Both nuclear factor (NF)-�B–inducing kinase (NIK) and inhibitor of �B (I�B) kinase (IKK) have been implicated as essential components for NF-�B activation in response to many external stimuli. However, the exact roles of NIK and IKK � in cytokine signaling still remain controversial. With the use of in vivo mouse models, rather than with enforced gene-expression systems, we have investigated the role of NIK and IKK � in signaling through the type I tumor necrosis factor (TNF) receptor (TNFR-I) and the lymphotoxin � receptor (LT�R), a receptor essential for Lymphoid Organogenesis. TNF stimulation induced similar levels of phosphorylation and degradation of I�B � in embryonic fibroblasts from either wild-type or NIK-mutant mice. In contrast, LT�R stimulation induced NF-�B activation in wild-type mice, but the response was impaired in embryonic fibroblasts from NIK-mutant and IKK�-deficient mice. Consistent with the essential role of IKK � in LT�R signaling, we found that development of Peyer’s patches was defective in IKK�-deficient mice. These results demonstrate that both NIK and IKK � are essential for the induction of NF-�B through LT�R, whereas the NIK–IKK� pathway is dispensable in TNFR-I signaling. Key words: alymphoplasia • cytokine signaling • I�B • Akt kinase • Peyer’s patc
-
essential role of nuclear factor nf κb inducing kinase and inhibitor of κb iκb kinase α in nf κb activation through lymphotoxin β receptor but not through tumor necrosis factor receptor i
Journal of Experimental Medicine, 2001Co-Authors: Akemi Matsushima, Paul D Rennert, Tsuneyasu Kaisho, Hiroyasu Nakano, Kyoko Kurosawa, Daisuke Uchida, Kiyoshi Takeda, Shizuo Akira, Mitsuru MatsumotoAbstract:Both nuclear factor (NF)-κB–inducing kinase (NIK) and inhibitor of κB (IκB) kinase (IKK) have been implicated as essential components for NF-κB activation in response to many external stimuli. However, the exact roles of NIK and IKKα in cytokine signaling still remain controversial. With the use of in vivo mouse models, rather than with enforced gene-expression systems, we have investigated the role of NIK and IKKα in signaling through the type I tumor necrosis factor (TNF) receptor (TNFR-I) and the lymphotoxin β receptor (LTβR), a receptor essential for Lymphoid Organogenesis. TNF stimulation induced similar levels of phosphorylation and degradation of IκBα in embryonic fibroblasts from either wild-type or NIK-mutant mice. In contrast, LTβR stimulation induced NF-κB activation in wild-type mice, but the response was impaired in embryonic fibroblasts from NIK-mutant and IKKα-deficient mice. Consistent with the essential role of IKKα in LTβR signaling, we found that development of Peyer's patches was defective in IKKα-deficient mice. These results demonstrate that both NIK and IKKα are essential for the induction of NF-κB through LTβR, whereas the NIK–IKKα pathway is dispensable in TNFR-I signaling.
-
role of tnf ligand and receptor family in the Lymphoid Organogenesis defined by gene targeting
The Journal of Medical Investigation, 1999Co-Authors: Mitsuru MatsumotoAbstract:The molecular basis of Lymphoid Organogenesis has recently been elucidated using gene-targeted mice. Mice deficient in lymphotoxin-alpha (LT alpha) lack lymph nodes and Peyer's patches. The action of LT alpha in Lymphoid Organogenesis is mediated mostly by the membrane form of LT by a mechanism independent of TNF receptor I (TNFR-I) or II (TNFR-II). Additionally, follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LT alpha-deficient mice. Mice deficient in either TNFR-I or LT beta R also fail to develop splenic FDC clusters and germinal centers, indicating that signaling through both TNFR-I and LT beta R is required for the development of these structures. The mechanisms underlying the defective Lymphoid Organogenesis in LT alpha-deficient mice, together with a natural mutant strain, alymphoplasia (aly) mice, which manifest a quite similar phenotype to LT alpha-deficient mice, were investigated by generating aggregation chimeras. These studies demonstrate that LT alpha and the aly gene product together control Lymphoid Organogenesis with a close mechanistic relationship in their biochemical pathways through governing distinct cellular compartments; the former acting as a circulating ligand and the latter as a LT beta R-signaling molecule expressed by the stroma of the Lymphoid organs.
-
involvement of distinct cellular compartments in the abnormal Lymphoid Organogenesis in lymphotoxin alpha deficient mice and alymphoplasia aly mice defined by the chimeric analysis
Journal of Immunology, 1999Co-Authors: Mitsuru Matsumoto, Kikue Iwamasa, Paul D Rennert, Takuji Yamada, Rika Suzuki, Akemi Matsushima, Masaru Okabe, Shigeru Fujita, Minesuke YokoyamaAbstract:Both lymphotoxin-α (LTα)-deficient mice and alymphoplasia ( aly ) mice, a natural mutant strain, manifest a quite similar phenotype: lack of lymph nodes (LN) and Peyer’s patches (PP), with disturbed spleen architecture. The mechanisms underlying the defective Lymphoid Organogenesis in these mice were investigated by generating aggregation chimeras; ex vivo fused morulae were implanted into pseudo-pregnant host females and allowed to develop to term. Chimeric mice between LTα-deficient mice and wild-type mice restored LN and PP almost completely, suggesting that LTα expressed by circulating bone marrow-derived cells is essential for Lymphoid Organogenesis as well as for organization of spleen architecture. By contrast, chimeric mice between aly mice and wild-type mice showed only limited restoration of LN and PP. This suggests that the putative aly gene product does not act as a circulating ligand for Lymphoid Organogenesis, like LTα. Rather, abnormal development of Lymphoid organs in aly mice seems most likely due to the defective development of the incipient stromal cells of the LN and PP. Supporting this hypothesis, up-regulation of VCAM-1 on aly mouse embryonic fibroblasts by signals through LTβR, which is exclusively expressed by nonLymphoid cells, was disturbed. These studies demonstrate that LTα and the putative aly gene product together control Lymphoid Organogenesis with a close mechanistic relationship in their biochemical pathways through governing the distinct cellular compartments, the former acting as a circulating ligand and the latter as a LTβR-signaling molecule expressed by the stroma of the Lymphoid organs.
G J Pettigrew - One of the best experts on this subject based on the ideXlab platform.
-
blocking lymphotoxin signaling abrogates the development of ectopic Lymphoid tissue within cardiac allografts and inhibits effector antibody responses
The FASEB Journal, 2012Co-Authors: Reza Motallebzadeh, Nancy H. Ruddle, Sylvia Rehakova, Thomas M Conlon, Thet Su Win, Chris J Callaghan, Martin Goddard, Eleanor M Bolton, Andrew J Bradley, G J PettigrewAbstract:Tertiary Lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for Lymphoid Organogenesis, abrogates TLO development. TLOs (defined as discrete Lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipi...
-
blocking lymphotoxin signaling abrogates the development of ectopic Lymphoid tissue within cardiac allografts and inhibits effector antibody responses
The FASEB Journal, 2012Co-Authors: Reza Motallebzadeh, Nancy H. Ruddle, Sylvia Rehakova, Thomas M Conlon, Thet Su Win, Chris J Callaghan, Martin Goddard, Eleanor M Bolton, Andrew J Bradley, G J PettigrewAbstract:Tertiary Lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for Lymphoid Organogenesis, abrogates TLO development. TLOs (defined as discrete Lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipients primed for autoantibody before transplantation rejected grafts rapidly, but this accelerated rejection was prevented by postoperative administration of LTβR-Ig (median survival time: 18 vs. >50 d, respectively, P=0.003). Our results provide the first demonstration that TLOs develop within chronically rejecting heart allografts, are predominantly B cell in origin, and can be targeted pharmacologically to inhibit effector humoral responses.
