Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Route of lymphocyte migration through the high endothelial venule (HEV) in human palatine tonsil

Eleven palatine tonsils were collected from subjects who underwent tonsillectomy in Christian Medical College Hospital and the route of migration of lymphocytes through the high endothelial vessel was studied under EM. In the interendothelial route, migration of a lymphocyte through HEV wall began with the adhesion of a lymphocyte to the surface of endothelial cells by means of a short cytoplasmic projection in the vicinity of intercellular space. The projection extended into the cleft between adjacent endothelial cells. The lymphocyte migrated through HEV by diapedesis. After the lymphocyte had traversed the interendothelial space, it occupied the subendothelial space. In the transendothelial route, migration of a lymphocyte through HEV was initiated by adherence of the lymphocyte to the endothelial cell. The adherent lymphocyte compressed or invaginated into the cytoplasm of the endothelial cell, entered the endothelial cell, was completely enclosed within the endothelial cell cytoplasm, and emerged from the endothelial cell to occupy the subendothelial space. Evidence is presented from static transmission electron microscopic pictures for the migration of lymphocytes by both interendothelial and transendothelial routes through the high endothelial venule.     

大鼠肠系膜淋巴结高内皮微静脉与淋巴迷路之间的网状纤维支架的研究

目的 研究大鼠肠系膜淋巴结内高内皮微静脉与淋巴迷路之间淋巴细胞归巢的通路.方法 用镀银染色光镜观察法和冻裂割断扫描电镜观察法观察健康、成熟Wistar大鼠肠系膜淋巴结的基质网状结构.结果 位于高内皮微静脉和淋巴迷路周围有网状纤维支架,在二者相临近部位有密集交织的网状纤维网.结论 淋巴结内高内皮微静脉和淋巴迷路之间密集交织的网状纤维网,为细胞的居留和迁移提供结构支持和适宜的微环境,可能是淋巴细胞归巢的重要通路.     

Activation of CD44 induces ICAM-1/LFA-1-independent,Ca2+, Mg2+, —independent adhesion pathway in lymphocyte-endothelial cell interaction

We have established an endothelial cell line KOP2.16 from pooled mouse lymph nodes. Resting lymphocytes avidly bound to KOP2.16 and migrated underneath the cytoplasm. The binding was partly mediated by VLA-4 and VCAM-1, but apparently independent of CD44 since anti-CD44 antibody examined failed to inhibit the binding. However, pretreatment of lymphocytes with anti-CD44 resulted in the rapid appearance of Ca²⁺-, Mg²⁺-independent, LFA-1/ICAM-1-, CD2/LFA-3,VLA-4/VCAM-l-independent lymphocyte binding, indicating that a novel adhesion pathway was induced by the anti-CD44 treatment. Interestingly, the elicited adhesion was observed only when anti-CD44 that block hyaluronate recognition of CD44 were used for lymphocyte pretreatment. Neither hyaluronate itself nor non-blocking anti-CD44 up-regulated the adhesion. Fab fragment of the blocking anti-CD44 did not induce the up-regulation unless cross-linked with a second antibody, indicating that cross-linking of surface CD44 is necessary for induction of a novel adhesion pathway. We propose that the agonistic anti-CD44 antibodies induce a novel adhesion pathway by mimicking ligand binding to CD44 on the lymphocyte surface and that non-hyaluronate ligand(s) is involved in regulation of adhesive function of CD44. Potential involvement of such a regulatory mechanism in lymphocyte homing is discussed.     

肾上腺髓质微血管构筑

本文以树脂铸型扫描电镜法,观察大鼠和小鼠肾上腺髓质的微血管构筑,并特别注意髓质血管和皮质血管的相互关系;此外切片观察测量了肾上腺髓质两种嗜铬细胞的分布。肾上腺皮质集合小静脉发出侧支,分布于髓质,构成了门静脉循环特点。小鼠的肾上腺髓质,主要由这种侧支供应;而大鼠的髓质,还有多支髓质动脉供应。从血管铸型上表现出的明显局部环形缩窄推测,肾上腺髓质血液循环有若干括约装置控制。大、小鼠两种嗜铬细胞在肾上腺髓质内的分布不同,大鼠的呈随机分布;小鼠的 NA 细胞多靠近皮质,而 A 细胞多远离皮质。     

Differential coronary microvascular exchange responses to adenosine: roles of receptor and microvessel subtypes

OBJECTIVE: To assess the role of adenosine receptors in the regulation of coronary microvascular permeability to porcine serum albumin (P(s)(PSA)). METHODS: Solute flux was measured in single perfused arterioles and venules isolated from pig hearts using fluorescent dye-labeled probes by microspectro-fluorometry. Messenger RNA, protein, and cellular distribution of adenosine receptors in arterioles and venules were analyzed by RT-PCR, immunoblot, and immunofluorescence. RESULTS: Control venule P(s)(PSA) (10.7 +/- 4.8 x 10(- 7) cm x s(- 1)) was greater than that of arterioles (6.4+/- 2.8 x 10(-7) cm . s(-1); p < .05). Arteriolar P(s)(PSA) decreased (p < .05) with adenosine suffusion over the range from 10(- 8) to 10(-5) M, while venular P(s)(PSA) did not change. The nonselective A(1) and A(2) receptor antagonist, 8-(p-sulfophenyl) theophylline, blocked the adenosine-induced decrease in arteriolar P(s)(PSA). Messenger RNA for adenosine A(1), A(2A), A(2B), and A(3) receptors was expressed in arterioles and venules. Protein for A(1), A(2A), and A(2B), but not A(3), was detected in both microvessel types and was further demonstrated on vascular endothelial cells. CONCLUSION: Arteriolar P(s)(PSA) decreases with adenosine suffusion but not venular P(s)(PSA). Adenosine A(1), A(2A), and A(2B) receptors are expressed in both arterioles and venules. Selective receptor-linked cellular signaling mechanisms underlying the regulation of permeability remain to be determined.     

Lymphocyte ‘homing’ and chronic inflammation

Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV‐like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV‐like vessel‐mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others.     

Microvascular remodelling in chronic airway inflammation in mice

1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasmapulmonis and the tracheal vessels treatment also decreased the immunoreactivity for P-selectin and the number of adherent leucocytes (595 +/- 203 vs 2,024 +/- 393 cells/ mm2 in treated and non-treated infected mice, respectively). 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease.