LAUSR

January 21, 2020 e35 *Drs Wang, Yang, and Bi contributed equally. Daxin Wang, MD* Xinquan Yang, MD* Keying Bi, MD* To the Editor: We read with great interest the recent publication by Magee et al,1 highlighting the novel effects of the Notch-1 signaling pathway on the modulation of alloimmunity after transplantation based on these elegant data that inhibiting Notch-1 signaling could prolong allograft survival and immune tolerance in multiple transplant models in a regulatory T-cell(Treg)-dependent manner. Because the results of Magee and colleagues show that Notch-1low Tregs exhibited more potent suppressive capacity than Notch-1high Tregs in human peripheral blood, we wondered whether (1) monitoring the change of these 2 different types of human Treg in allogeneic graft-versus-host disease might provide the association between the expression of Notch-1 in human Treg and patients prognosis; (2) Notch-1low Tregs could be a positive indicator of responsiveness to anti-Notch-1 therapy in the long term; and (3) this immune therapy would be also effective for treating other autoimmune diseases characterized by accumulation of proinflammatory phenotype Tregs such as multiple sclerosis and type 1 diabetes mellitus. Hoare et al2 reported that dynamic alteration of Notch-1 activity during senescence regulated 2 distinct secretomes, TGF-β-rich secretome and proinflammatory cytokines, such as Notch-1 inhibition mediating the upregulation of proinflammatory cytokines and promotion of both lymphocyte recruitment and senescence surveillance, highlighting the important effects of Notch-1 activity on the temporospatial controller of secretome composition. In addition, Kageyama et al3 discovered the protective role of Notch-1 signaling in liver transplant through serial evidences that both murine and human liver, defined by high activity of Notch-1 intracellular domain, were relatively resistant to the liver ischemia-reperfusion injury. Hence, we considered differences in transplanted organs, systemic state of senescence, intervention window of Notch-1 inhibition and allograft duration should be taken into deep consideration for comprehensively evaluating the feasibility and contraindication of anti-Notch-1 therapy in extended study. Previous study demonstrated that inhibiting Notch-1 signaling could worsens hypoxia-induced pulmonary hypertension and impaired endothelial cell regenerative function associated with loss of precapillary arteries, emphasizing the crucial role of Notch-1 in the contact between endothelial cells and smooth muscle cells and maintaining monolayer integrity and vascular homeostasis.4 Similarly, Mack et al5 found loss of Notch-1 in adult endothelium could increase hypercholesterolemia-induced atherosclerosis in the descending aorta, supporting the atheroprotective function of Notch-1 in adult arteries. In light of these findings, we thought further study should also focus on causal link between anti-Notch-1 therapy, disease susceptibility, and epigenetic changes, especially under the condition of some pathogenic factors, for understating the mechanisms of the potential adverse response and improving its clinical utilization in transplantation. © 2020 American Heart Association, Inc. LETTER TO THE EDITOR