作者: Tasker, Carley ; Lu, Wuyuan ; Fitzgerald-Bocarsly, Patricia ; Heller, Debra ; Chang, Theresa Li-Yun ; Ding, Jian ; Dai, Jihong ; Lespinasse, Pierre

BACKGROUNDCD4 T cells are crucial for the establishment and dissemination of HIV in mucosal tissues during acute infection. Studies indicate that integrin α4β7 CD4 T cells are preferentially infected by HIV in vitro and during acute SIV infection. The integrin α4β7 is thought to promote HIV capture by target cells; however, the role of integrin α4β7 in HIV transmission remains controversial. In this study, we characterized immune phenotypes of human cervical T cells and examined HIV preference in integrin α4β7 CD4 T cells. In vitro all-trans retinoic acid-differentiated peripheral CD4 T cells (atRA-differentiated cells) were included as a comparison.RESULTSIn both peripheral and cervical cells, the majority of HIV p24 cells were activated CD4 T cells expressing integrin α4β7. Among infected atRA-differentiated cells, the frequency of CCR5 expression was higher in HIV p24 cells than in HIV p24 cells; no such difference was observed in cervical cells. Neither the cyclic hexapeptide CWLDVC nor a monoclonal antibody against integrin α4β7 blocked HIV attachment or gp120 binding to target cells regardless of the presence of CD4, indicating that integrin α4β7 did not facilitate HIV capture by target cells.CONCLUSIONSIntegrin α4β7 expression increases HIV susceptibility, but the mechanism is not through promoting HIV binding to target cells.

2002-08-01·Journal of Biological Chemistry

JAM2 Interacts with α4β1

Article

作者: Rodriguez, Jose M. ; Cunningham, Sonia A. ; Brock, Tommy A. ; Tran, Tuan M. ; Arrate, M. Pia

We have previously reported that junctional adhesion molecule 2 (JAM2) adheres to T cells through heterotypic interactions with JAM3. An examination of the cation dependence of JAM2 adhesion to HSB cells revealed a Mn(2+)-enhanced binding component indicative of integrin involvement. Using neutralizing integrin antibodies, we have defined an interaction between JAM2 and alpha(4)beta(1) in T cells. The interaction is readily amenable to drug intervention as demonstrated by the ability of TBC 772, an alpha(4)-specific inhibitor, to attenuate the Mn(2+)-enhanced component. Intriguingly, the engagement of alpha(4)beta(1) by JAM2 is only enabled following prior adhesion of JAM2 with JAM3 and is not detectable in cells where JAM3 expression is absent. Supporting this observation, we show that neutralizing JAM3 serum and soluble JAM3 ectodomain inhibit not only JAM2 binding to JAM3 but also prevent JAM2/alpha(4)beta(1) interactions in T cells. We further define the first Ig-like fold of JAM2 as being competent in binding both JAM3 and alpha(4)beta(1) counter-receptors. Mutagenesis of the only acidic residue in the C-D loop of this Ig fold, namely Asp-82, has no bearing on alpha(4)beta(1) interactions, and thus JAM2 deviates somewhat from the mechanism used by other immunoglobulin superfamily cell adhesion molecules to engage integrin.

2002-01-01·Current Eye Research4区 · 医学

Mechanisms for sickle red blood cell retention in choroid

4区 · 医学

Article

作者: Gerard A. Lutty ; Sandra Suzuka ; Sahng Yeon Kim ; D. Scott McLeod ; Mary E. Fabry ; Carol Merges ; Ronald L. Nagel ; Peter Vanderslice ; Tsuyoshi Otsuji ; Makoto Taomoto

PURPOSEAlthough sickle (SS) red cell-mediated vaso-occlusion in retina and resultant retinopathy is well documented, the effects of SS red cells on choroidal vasculature are poorly understood. The intent of this study was to determine, using a rat model, the conditions under which retention of sickle erythrocytes in choroid occur and if that retention can be inhibited.METHODSSickle red cells were density separated into high density (SS4) or normal density, reticulocyte-enriched fractions (SS2). Red cells were labeled with FITC and administered IV to anesthetized Sprague Dawley rats. Rats were made either hypoxic or were given TNF-alpha intraperitoneally 5 hours before intravenous administration of red cells. Five minutes after administration of red cells, rats were exsanguinated, the retinas removed, and choroids prepared as flatmounts. The number of red cells retained in five high power fields of choroid was then determined. In other experiments, SS red cells were preincubated with the cyclic peptide TBC772 [inhibits binding of alpha4beta1 (VLA-4) and alpha4beta7 to their ligands], a control peptide TBC1194, or a VLA-4 neutralizing antibody before administration to the rat or antibodies against VLA-4 ligands were delivered IV before administration of SS red cells.RESULTSHypoxic conditions before administration of SS red cells significantly stimulated retention of SS4 cells (P = 0.0003), but did not significantly increase retention of SS2 cells. Administration of TNF-alpha significantly increased retention of all types of SS red cells (P < 0.001). Preincubation of cells with anti-VLA-4 or TBC 772 inhibited retention of SS red cells in choriocapillaris of TNF-alpha-treated rats (P < 0.0001). Complete inhibition of cytokine-stimulated retention was also accomplished by IV administration of monoclonal antibodies against fibronectin or its CS-1 domain, a ligand for VLA-4.CONCLUSIONSThe mechanisms for retention of SS red cells in retina and choroid appear identical: hypoxia-mediated retention of dense red cells and adherence of red cells in reticulocyte-rich fractions after cytokine stimulation. TNF-alpha-stimulated retention of SS red cells in choroid appears to be mediated by VLA-4, presumably on the surface of some reticulocytes. This increased retention was inhibited by a VLA-4 antagonist (TBC772), a VLA-4 neutralizing antibody or by blocking one of VLA-4's ligands, the CS-1 portion of fibronectin.

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适应症	最高研发状态	国家/地区	公司	日期
动脉硬化	临床前	美国	Encysive Pharmaceuticals, Inc.	-
哮喘	临床前	美国	Encysive Pharmaceuticals, Inc.	-
多发性硬化症	临床前	美国	Encysive Pharmaceuticals, Inc.	-
类风湿关节炎	临床前	美国	Encysive Pharmaceuticals, Inc.	-