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S. Cordes et al.
aGvHD therapies aiming at reducing vascular permeabil- ity and stabilization of vascular tight-junctions as well as adherence-junctions. Vestweber and colleagues have gen- erated mice with stabilized endothelial junctions; these mice had strongly reduced neutrophil and lymphocyte recruitment into inflamed tissues.56 Examples for a thera- peutic approach derive from the field of sepsis where reduction of vascular permeability with the αVb3 antag- onist cilengitide57 or with an antibody binding to angiopoietin 2 and TIE258 which led to substantial biolog- ical benefits.
Recent clinical studies suggest a role of endothelial pathology particularly in SR-aGvHD13,14,17,28,29,31 and a high medical need for development of respective therapies. We now demonstrate in two independent clinical cohorts as well as in experimental models that inflammatory infil- tration in target organs is considerably reduced compared to aGvHD at diagnosis. Consequently, we found that dexamethasone treatment did not significantly reduce the severity of endothelial damage during SR-aGvHD. Pavan Reddy’s group recently published the results of extensive experiments in murine models of SR-GvHD. In line with our findings, their results point towards the existence of T-cell independent mechanisms in the pathophysiology of SR-GvHD.23 This may explain the historically disap- pointing clinical results of immunosuppressive treatments for SR-aGvHD. The low inflammatory status in connec- tion with considerable endothelial pathology provides a rationale for therapies protecting the endothelium during SR-aGvHD. Based on previous encouraging data on nor- malization of endothelial dysfunction,32-39 we used the PDE5 inhibitor sildenafil as a first attempt to treat SR- aGvHD by an ‘endothelium-protective’ approach. Sildenafil treatment ameliorated aGvHD and the effect was more pronounced in case of SR-aGvHD compared with previously untreated aGvHD. The latter observation may be explained by the high level of tissue inflammation in non-glucocorticoid treated aGvHD mice superimpos- ing the beneficial effects of sildenafil on EC. However, we cannot exclude the possibility of a synergistic effect of sildenafil with steroids in our models.
The direct mechanisms of sildenafil treatment on the course of SR-aGvHD remain unclear. However, improve- ment of vascular barrier function and reduction of EC apoptosis probably contribute to the beneficial effects of sildenafil. During aGvHD we found increased vascular permeability in target organs and alterations of Rho GTPases, who are critical regulators of endothelial barrier function.59 Sildenafil-mediated stabilization of endothelial barrier function60,61 as well as impact of sildenafil on regu- lation of Rho GTPases62 have been described previously. We found that apoptosis and expression of relevant genes,
such as nitric oxide synthase (Nos3) and BCL-2, was increased in target organ EC during aGvHD. Sildenafil has been shown to have cyto-protective effects by regulation of nitric oxide synthase 3 signaling and BCL-2 expres- sion.63 In addition, sildenafil may have positive effects by stabilizing vessel surrounding pericytes and thereby vas- cular integrity: PDE5 targets cGMP, which has been demonstrated to inhibit the proliferation of smooth mus-
In conclusion, our results demonstrate extensive dam- age, structural changes, and dysfunction of the vascula- ture during aGvHD, and our findings suggest a novel con- cept of therapeutic intervention by endothelium-protect- ing agents as an attractive treatment approach for SR- aGvHD. A likely future perspective is to test endotheli- um-targeting approaches complementing treatment options with proven efficacy in SR-aGvHD, such as JAK- 2 inhibition.65
Disclosures
No conflicts of interest to disclose.
Contributions
SC, AB, EC, MD-R, JM, LB, CPS and OP designed the study; SC, ZM, MB, YS, SM, KR, JM, MK, AM, JS, MP and GB performed experiments and analyzed results; SC and OP wrote the manuscript. All authors read, edited and approved the manuscript.
Acknowledgments
This work was supported by the José Carreras Leukämie- Stiftung (11R2016, 03R\2019), Deutsche Krebshilfe (70113519), Deutsche Forschungsgemeinschaft (PE 1450/7-1), Monika-Kutzner-Stiftung, and Wilhelm-Sander-Stiftung (2014.150.1).
Funding
MB was funded by the European Training and Research in Peritoneal Dialysis Program, funded by the European Union within the Marie Curie Scheme (287813). AB received funding from the German Research Foundation (DFG), collaborative research center TRR221 (B11, Z02) and ZM was funded by the DFG collaborative research center TRR225 (B08).
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cle cells by causing a delay in G
cycle.64 Interestingly, we detected differentially regulated cell cycle genes in EC during aGvHD. Of note, we found that sildenafil treatment led to reduction of aGvHD-asso- ciated expression of co-stimulatory molecules on target organ EC. However, our finding that sildenafil had no sig- nificant effects on in vivo proliferation of allogeneic donor T cells in irradiated hosts argue against the biologic signif- icance of the observed impact of sildenafil on EC co-stim- ulatory molecule expression during aGvHD.
/S transition in the cell 1
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