Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function

Gousopoulos, Epameinondas; Proulx, Steven T.; Bachmann, Stephan; Scholl, Jeannette; Dionyssiou, Dimitrios; Demiri, Efterpi; Halin, Cornelia; Dieterich, Lothar C.; Detmar, Michael

doi:10.1172/jci.insight.89081

Cited by 74 publications

(81 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the depletion of Treg cells exacerbates edema and fibrosis and is associated with increased infiltration of immune cells with a mixed Th1/Th2 cytokine profile (Gousopoulos et al, 2016a). Conversely, expansion of T regulatory cells significantly reduced lymphedema development by attenuating the tissue inflammation in lymphedema (Gousopoulos et al, 2016a). However, these cells may also participate to the local immune suppression observed in lymphedema, which is consistent with the recurrence of soft tissue infections observed in this disease (Sharkey et al, 2017;Garcia Nores et al, 2018).…”

Section: Role Of Inflammationsupporting

confidence: 54%

“…Studies by the group of B. J. Mehrara and M. Detmar showed in clinical and experimental lymphedema that the majority of the cells that accumulate chronically in lymphedematous tissues are CD4 + T cells and that they contribute to the pathological changes including fibrosis (Avraham et al, 2010(Avraham et al, , 2013Zampell et al, 2012c;Savetsky et al, 2014;Gousopoulos et al, 2016b). Further phenotypic characterization of the infiltrating CD4 + T cells revealed that there is a mix of Th1, Th2, and regulatory T cells (Avraham et al, 2013;Gousopoulos et al, 2016a). Notably, the blockade of Th2 differentiation but not Th1 differentiation was effective in preventing the development of lymphedema, and in established cases, treating it (Avraham et al, 2013;Ly et al, 2019).…”

Section: Role Of Inflammationmentioning

confidence: 99%

“…In contrast to the pathogenic role of Th2 cells in lymphedema, T regulatory (Treg) cells seem to limit the pathological changes in lymphedema. Indeed, the depletion of Treg cells exacerbates edema and fibrosis and is associated with increased infiltration of immune cells with a mixed Th1/Th2 cytokine profile (Gousopoulos et al, 2016a). Conversely, expansion of T regulatory cells significantly reduced lymphedema development by attenuating the tissue inflammation in lymphedema (Gousopoulos et al, 2016a).…”

Section: Role Of Inflammationmentioning

confidence: 99%

See 2 more Smart Citations

The Unresolved Pathophysiology of Lymphedema

et al. 2020

View full text Add to dashboard Cite

Lymphedema is the clinical manifestation of impaired lymphatic transport. It remains an under-recognized and under-documented clinical condition that still lacks a cure. Despite the substantial advances in the understanding of lymphatic vessel biology and function in the past two decades, there are still unsolved questions regarding the pathophysiology of lymphedema, especially in humans. As a consequence of impaired lymphatic drainage, proteins and lipids accumulate in the interstitial space, causing the regional tissue to undergo extensive and progressive architectural changes, including adipose tissue deposition and fibrosis. These changes are also associated with inflammation. However, the temporal sequence of these events, the relationship between these events, and their interplay during the progression are not clearly understood. Here, we review our current knowledge on the pathophysiology of lymphedema derived from human and animal studies. We also discuss the possible cellular and molecular mechanisms involved in adipose tissue and collagen accumulation during lymphedema. We suggest that more studies should be dedicated to enhancing our understanding of the human pathophysiology of lymphedema to pave the way for new diagnostic and therapeutic avenues for this condition.

show abstract

Section: Role Of Inflammationsupporting

confidence: 54%

Section: Role Of Inflammationmentioning

confidence: 99%

Section: Role Of Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

The Unresolved Pathophysiology of Lymphedema

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Cx43 is known to be expressed by mesenchymal stem cells, which can affect lymphangiogenesis (Valiunas et al, 2004; Buttler et al, 2013; Maertens et al, 2014), as well as macrophages and lymphocytes (Glass et al, 2015), which have been implicated in pathological lymphangiogenesis (Betterman and Harvey, 2016). In addition, Cx43 expression in thymic regulatory T cell precursors enhances the production of Foxp3 + regulatory T cells (Kuczma et al 2011), a population of cells which were recently shown to modulate lymphedema and promote lymphatic vessel function (Gousopoulos et al, 2016). During development, lymphangiogenesis in the diaphragm is regulated by macrophages, which are closely associated with the sprouting tips of lymphatic vessels (Ochsenbein et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

View full text Add to dashboard Cite

Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43−/− mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43ΔLEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

show abstract

“…The lymphatic vasculature is critical to immunity with one of its major roles being the trafficking of immune cells . High VEGF‐C expression in experimental mouse models has previously been found to promote lymphatic vessel enlargement with lymphatic endothelial cell proliferation . Recently, several studies have found that dilated lymphatic vessels exhibit impaired transport capacity, making immune cells difficult to transport into the tumor.…”

Section: Discussionmentioning

confidence: 99%

Clinical importance of VEGFC and PD‐L1 co‐expression in lung adenocarcinoma patients

et al. 2020

View full text Add to dashboard Cite

Background: Vascular endothelial growth factor C (VEGFC), an activator of lymphangiogenesis, is newly identified as an immunomodulator which can regulate the immune system so that tumor cells more easily escape immune surveillance. Evidence has shown programmed cell death-ligand 1 (PD-L1) can also suppress the immune response. Nevertheless, the clinical significance of coexpression of VEGFC and PD-L1 for predicting outcomes in patients with lung adenocarcinoma has not yet been determined. Methods: A total of 114 patients with lung adenocarcinoma who underwent surgeries at were retrospectively reviewed. Tissue specimens were collected for immunohistochemistry of VEGFC and PD-L1 which were analyzed with an H-score system. Results: In this study, 57 (50.0%) and 47 (41.2%) patients were classified as VEGFC high expression and PD-L1 high expression. Co-expression was observed in 33 (28.9%) patients. In addition, a positive correlation was found between VEGFC and PD-L1 (P = 0.0398, r = 0.1937). In a univariate analysis, both progression-free survival (PFS) and overall survival (OS) were significantly worse in the VEGFC high expression group and the PD-L1 high expression group, respectively. Furthermore, VEGFC/PD-L1 co-expression showed a worse OS (P = 0.03) and PFS survival (P = 0.01) than the other groups. Conclusions: Taken together, these results indicate that VEGFC/PD-L1 coexpression can forecast both poor OS and PFS in patients with resected lung adenocarcinoma. Co-expression of VEGFC and PD-L1 may serve as a significant prognostic factor for patients with lung adenocarcinoma. Key pointsVEGFC/PD-L1 co-expression forecasts poor survival in patients with resected lung adenocarcinoma. VEGFC/PD-L1 co-expression may be used as a prognostic indicator and provide the theoretical possibility to screen the optimal population with a combination of anti-VEGFC and anti-PD-L1 therapy in the clinical treatment.

show abstract

Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function

Cited by 74 publications

References 46 publications

The Unresolved Pathophysiology of Lymphedema

The Unresolved Pathophysiology of Lymphedema

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Clinical importance of VEGFC and PD‐L1 co‐expression in lung adenocarcinoma patients

Contact Info

Product

Resources

About