Publications by authors named "Hao Wei Li"

28 Publications

  • Page 1 of 1

Mixed xenogeneic porcine chimerism tolerizes human anti-pig natural antibody-producing cells in a humanized mouse model.

Xenotransplantation 2021 07 26;28(4):e12691. Epub 2021 Apr 26.

Department of Medicine, Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig-reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown.

Methods: We investigated this question using a humanized mouse model in which durable mixed (pig-human) xenogeneic chimerism can be established.

Results: Human natural anti-pig cytotoxic antibodies, predominantly IgM, are detectable in non-chimeric humanized mouse serum, and pig-reactive antibodies were reduced in mixed chimeric versus non-chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti-pig antibodies when stimulated in vitro compared with those from non-chimeric mice.

Conclusions: Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.
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http://dx.doi.org/10.1111/xen.12691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376778PMC
July 2021

Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.

Cancer Discov 2021 05 28;11(5):1212-1227. Epub 2020 Dec 28.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102348PMC
May 2021

Negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen in the human thymus.

J Transl Autoimmun 2020 9;3:100061. Epub 2020 Aug 9.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA.

During T cell development in mice, thymic negative selection deletes cells with the potential to recognize and react to self-antigens. In human T cell-dependent autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, T cells reactive to autoantigens are thought to escape negative selection, traffic to the periphery and attack self-tissues. However, physiological thymic negative selection of autoreactive human T cells has not been previously studied. We now describe a human T-cell receptor-transgenic humanized mouse model that permits the study of autoreactive T-cell development in a human thymus. Our studies demonstrate that thymocytes expressing the autoreactive Clone 5 TCR, which recognizes insulin B:9-23 presented by HLA-DQ8, are efficiently negatively selected at the double and single positive stage in human immune systems derived from HLA-DQ8 HSCs. In the absence of hematopoietic expression of the HLA restriction element, negative selection of Clone 5 is less efficient and restricted to the single positive stage. To our knowledge, these data provide the first demonstration of negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen. Intrathymic antigen presenting cells are required to delete less mature thymocytes, while presentation by medullary thymic epithelial cells may be sufficient to delete more mature single positive cells. These observations set the stage for investigation of putative defects in negative selection in human autoimmune diseases.
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http://dx.doi.org/10.1016/j.jtauto.2020.100061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451786PMC
August 2020

Cerebral arterial infundibula are preaneurysmal lesions caused by direct flow impact.

World Neurosurg 2020 Jan 16. Epub 2020 Jan 16.

The First Hospital of Hebei Medical University.

Purpose: To investigate whether arterial infundibular widening is a preaneurysmal lesion or not.

Methods: Two hundred and nine patients with cerebral angiography were enrolled. The morphology, size and location of infundibula and cerebral aneurysms were studied in two-dimensional angiography and three-dimensional software space. Computational fluid dynamics (CFD) analysis was performed.

Results: 234 infundibula and 129 infundibulum-like aneurysms (IFAs) were detected. In two-dimensional space, the typical morphology of an infundibulum was a symmetric dilatation at the arterial branch origin with a small vessel branch emanating from the tip and a wide base connecting the parent artery. In three-dimensional space, the infundibulum was dissymmetric with always one side longer than the other side. Furthermore, the infundibulum tilted upstream rather than downstream, with the longer side located downstream and the shorter side upstream in all cases. All the 129 IFAs occurred on the distal wall of the vessel branch origin, and no IFAs grew from the proximal wall of the branch origin. The possible development process of an infundibulum to an IFA was described in four development stages. The CFD analysis revealed that these lesions were associated with direct flow impingement in all cases. All the hemodynamic parameters on the distal wall of infundibula and IFAs were significantly (P<0.0001 or P<0.05) decreased compared with on the distal wall after virtual lesion removal.

Conclusion: The infundibulum is a preaneurysmal lesion associated with high total pressure and high wall shear stress resulted from direct flow impingement and will progress to an aneurysm with time.
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http://dx.doi.org/10.1016/j.wneu.2019.12.183DOI Listing
January 2020

Asymmetrical than symmetrical cerebral arterial bifurcations are more vulnerable to aneurysm presence.

Sci Rep 2019 11 20;9(1):17144. Epub 2019 Nov 20.

Department of Medical Research, Shijiazhuang First Hospital, Shijiazhuang, China.

In order to investigate the role of lateral angle ratio (LA ratio) and daughter artery ratio (DA ratio) for predicting aneurysmal presence in main cerebral arterial bifurcations, three-dimensional cerebral angiographic data of major cerebral artery bifurcations were used for measurement of artery diameters and bifurcation angles including 115 middle cerebral arteries (MCAs), 59 basilar arteries (BAs), 35 internal carotid arteries (ICAs) and 115 anterior cerebral arteries (ACAs) with bifurcation aneurysms and control subjects of 1921 bifurcations with no aneurysms. The LA ratio (larger lateral angle/smaller lateral angle) and DA ratio (larger branch diameter/smaller branch diameter) were calculated, and ROC curve analysis of LA and DA ratios between normal and aneurysmal cases was performed. The LA and DA ratios of MCA bifurcations and the LA ratios of BA and ICA bifurcations with aneurysms were all significantly larger than normal bifurcations (P < 0.05), and the DA ratio of ACA bifurcations with aneurysms was significantly smaller than normal cases (P < 0.01). Moreover, the LA ratio or DA ratio between the normal and aneurysm cases in MCA, BA and ACA bifurcations demonstrated significant differences by ROC analysis (P < 0.01) except in the ICA bifurcations. No significant difference was observed (P > 0.05) between ruptured and unruptured aneurysms in MCA, BA, ICA and ACA bifurcations. In summary, normal MCA, BA and ICA bifurcations show symmetrical morphology in the lateral angles and daughter branches, whereas aneurysmal bifurcations show asymmetrical morphology. Normal ACA bifurcations have asymmetrical bilateral daughter branches while symmetrical branches are associated with ACA bifurcation aneurysm presence.
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http://dx.doi.org/10.1038/s41598-019-53715-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868127PMC
November 2019

Asymmetrical middle cerebral artery bifurcations are more vulnerable to aneurysm formation.

Sci Rep 2019 10 24;9(1):15255. Epub 2019 Oct 24.

Department of Medical Research, Shijiazhuang First Hospital, Hebei Medical University, 36 Fanxi Road, Shijiazhuang, Hebei Province, 050011, China.

The objective of this study was to elucidate possible relationship between middle cerebral artery (MCA) bifurcation aneurysms and bifurcation morphology. In the present study, 799 patients with three-dimensional angiography were enrolled, including 115 patients with MCA bifurcation aneurysms and 684 subjects without aneurysms. The MCA bifurcation geometry, including angles formed between two M2 segments (φ1) and between M1 and M2 segments, vessel diameters and aneurysm sizes were measured. DA ratio (larger/smaller M2 in diameter) and LA ratio (larger/smaller lateral angle) were also analyzed. The LA and DA ratios and angle φ1 were significantly (P < 0.0001) greater in patients harboring MCA bifurcation aneurysms than in the control, whereas lateral angles and bifurcation branch diameters were significantly smaller (P < 0.01) in patients with than without bifurcation aneurysms. Angle φ1 was significantly increased (P < 0.0001) while both lateral angles significantly decreased (P < 0.0001 and P = 0.0005, respectively) with increase of patients' age. The size of MCA bifurcation aneurysms was significantly (P < 0.05) positively correlated with the bifurcation vascular diameter and aneurysm neck at the MCA bifurcation. A significantly positive correlation existed between aneurysm neck and DA ratio (P = 0.0075), whereas an inverse correlation between aneurysm neck and LA ratio (P = 0.0219). MCA bifurcation aneurysms were mostly deviated toward the smaller lateral angles and smaller M2 branch. In conclusion, aneurysmal MCA bifurcations have asymmetrical bifurcation structures with widened bifurcation angles, narrowed lateral angles, decreased M1 diameter, imbalanced lateral angles and M2 segments, with the cutoff bifurcation angle of 125.0° and cutoff lateral angle ratio of 1.57 for predicting MCA bifurcation aneurysms, whereas normal MCA bifurcations show close to symmetrical structures in the lateral angles and M2 branches.
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http://dx.doi.org/10.1038/s41598-019-51734-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813347PMC
October 2019

Rapid thymectomy of NSG mice to analyze the role of native and grafted thymi in humanized mice.

Eur J Immunol 2020 01 28;50(1):138-141. Epub 2019 Nov 28.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.

We developed a rapid method to remove the native mouse thymus from NSG mice, which allowed us to compare the behavior of human immune cells in the presence or absence of human T cells in human immune system mice. Removing the native mouse thymus is critical for studies of human thymopiesis in grafted thymic tissue in humanized mice.
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http://dx.doi.org/10.1002/eji.201948205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940512PMC
January 2020

Reduced positive selection of a human TCR in a swine thymus using a humanized mouse model for xenotolerance induction.

Xenotransplantation 2020 01 29;27(1):e12558. Epub 2019 Sep 29.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY, USA.

Background: Tolerance-inducing approaches to xenotransplantation would be optimal and may be necessary for long-term survival of transplanted pig organs in human patients. The ideal approach would generate donor-specific unresponsiveness to the pig organ without suppressing the patient's normal immune function. Porcine thymus transplantation has shown efficacy in promoting xenotolerance in humanized mice and large animal models. However, murine studies demonstrate that T cells selected in a swine thymus are positively selected only by swine thymic epithelial cells, and therefore, cells expressing human HLA-restricted TCRs may not be selected efficiently in a transplanted pig thymus. This may lead to suboptimal patient immune function.

Methods: To assess human thymocyte selection in a pig thymus, we used a TCR transgenic humanized mouse model to study positive selection of cells expressing the MART1 TCR, a well-characterized human HLA-A2-restricted TCR, in a grafted pig thymus.

Results: Positive selection of T cells expressing the MART1 TCR was inefficient in both a non-selecting human HLA-A2 or swine thymus compared with an HLA-A2 thymus. Additionally, CD8 MART1 TCR T cells were detected in the spleens of mice transplanted with HLA-A2 thymi but were significantly reduced in the spleens of mice transplanted with swine or HLA-A2 thymi. [Correction added on October 15, 2019, after first online publication: The missing superscript values +, -, and bright have been included in the Results section.] CONCLUSIONS: Positive selection of cells expressing a human-restricted TCR in a transplanted pig thymus is inefficient, suggesting that modifications to improve positive selection of cells expressing human-restricted TCRs in a pig thymus may be necessary to support development of a protective human T-cell pool in future patients.
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http://dx.doi.org/10.1111/xen.12558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007369PMC
January 2020

Author Correction: Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice.

Acta Pharmacol Sin 2020 04;41(4):581-582

Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.

During re-read of our previously article Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of micepublished in Acta Pharmacologica Sinica, we were regretted to point out a mistake shown in Fig. 2a. The representative figure chosen to indicate the inhibitory effect of 4 mg/kg of plumbagin treatment at 1 week against MDA-MB-231SArfp cells localization within bone environment was incorrect due to the mishandling in manuscript preparation. Although this correction does not affect the results and conclusion of the paper, all the authors agree on the correction of our negligence as providing the corrected Fig. 2a presented below. We feel sorry and apologize for all the inconvenience it caused.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41401-019-0252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470846PMC
April 2020

Correction to: Suppressive effects of plumbagin on invasion and migration of breast cancer cells via the inhibition of STAT3 signaling and down-regulation of inflammatory cytokine expressions.

Bone Res 2019 22;7:16. Epub 2019 May 22.

1Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011 China.

[This corrects the article DOI: 10.4248/BR201304007.].
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http://dx.doi.org/10.1038/s41413-019-0052-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531459PMC
May 2019

[Slit/Robo pathway participates in luteal cells apoptosis].

Sheng Li Xue Bao 2019 Apr;71(2):287-293

Department of Scientific Research Center, Shijiazhuang First Hospital, Shijiazhuang 050011, China.

This study was aimed to examine the expression and function of Slit/Robo family members in mouse ovary. Real-time PCR was used to assess the mRNA expression levels of Slit/Robo family members, and immunohistochemistry was used to examine the location of Slit2 and Robo1 in the ovary. The mRNA and protein expression levels of Slit2 and Robo1 in early-, middle- and late-phase corpus luteum (CL) were examined by real-time PCR and immunohistochemistry, respectively. Blocking agent ROBO1/Fc chimera was used in the luteal cells in vitro to examine the function of Slit/Robo signaling pathway in mouse CL. The results showed that, among the Slit/Robo family members, the expression levels of ligand Slit2 and receptor Robo1 were the highest in mouse ovarian tissue. Moreover, both of them were specifically expressed in mouse luteal cells. Compared with proestrus ovaries, the expression levels of Slit2 and Robo1 mRNA in the ovaries during diestrus were significantly up-regulated (P < 0.01, P < 0.001). The mRNA expression levels of Slit2 and Robo1 in late-phase CL were significantly increased when compared with pregnant CL. Furthermore, blocking Slit/Robo signaling pathway with ROBO1/Fc chimera in the luteal cells in vitro significantly decreased the apoptotic rate of late luteal cells. These results suggest that Slit/Robo family members are mainly expressed in the late-phase CL of ovary and participate in luteal cells apoptosis.
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April 2019

Dual IFN-γ/hypoxia priming enhances immunosuppression of mesenchymal stromal cells through regulatory proteins and metabolic mechanisms.

J Immunol Regen Med 2018 Mar 25;1:45-56. Epub 2018 Apr 25.

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration.
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http://dx.doi.org/10.1016/j.regen.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197483PMC
March 2018

The Optimality Principle Decreases Hemodynamic Stresses for Aneurysm Initiation at Anterior Cerebral Artery Bifurcations.

World Neurosurg 2019 Jan 26;121:e379-e388. Epub 2018 Sep 26.

Department of Neurosurgery, The First Hospital, Hebei Medical University, Shijiazhuang, China; Department of Medical Research, Shijiazhuang First Hospital, Hebei Medical University, Shijiazhuang, China. Electronic address:

Objective: To investigate hemodynamic stresses on anterior cerebral artery bifurcation apex and possible mechanism of the optimality principle in protecting bifurcation wall from supercharged hemodynamic stresses.

Methods: Three-dimensional angiographic datasets of 122 patients with anterior communicating artery (Acom) aneurysms, 21 patients with non-Acom aneurysms, and 220 control subjects with no aneurysms were used. Radii of parent (r) and daughter branches (r and r) were measured, and bifurcations obeying the optimality principle required optimal caliber control of r = r + r, with the junction exponent n approximating 3. Radius ratio = r/(r + r) and n were compared between aneurysmal and control bifurcations. Blood flow was simulated for analysis of hemodynamic stresses.

Results: Acom bifurcations in subjects without Acom aneurysms displayed optimal caliber radius, with mean radius ratio of 0.99 and n of 3.25, whereas Acom aneurysmal bifurcations had significantly lower radius ratio, 0.62 (P < 0.05), but higher n, 4.23 (P < 0.05). Peak wall shear stress and corresponding total pressure were significantly smaller for bifurcations obeying than disobeying the optimality principle (P < 0.001 and P < 0.05, respectively). Total pressures in the direct impinging center, peak wall shear stress distance, and anterior cerebral artery bifurcation angle all were significantly smaller for bifurcations obeying than disobeying the optimality principle (P < 0.05 and P < 0.001, respectively).

Conclusions: Normal anterior cerebral artery bifurcations obey the optimality principle whereas bifurcations with Acom aneurysms do not. Disobeying the optimality principle presents significantly enhanced hemodynamic stresses to possibly damage the bifurcation wall for aneurysm initiation.
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http://dx.doi.org/10.1016/j.wneu.2018.09.112DOI Listing
January 2019

Enlarged Anterior Cerebral Artery Bifurcation Angles May Induce Abnormally Enhanced Hemodynamic Stresses to Initiate Aneurysms.

World Neurosurg 2018 Dec 31;120:e783-e791. Epub 2018 Aug 31.

Department of Neurosurgery, The First Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, China; Department of Medical Research, Shijiazhuang First Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, China. Electronic address:

Objective: To investigate the relationship of anterior cerebral artery (ACA) bifurcation angles with hemodynamic stresses for aneurysm initiation.

Methods: Forty patients with or without anterior communicating artery aneurysms were enrolled, and 3 patients with ACA bifurcation angles of 169.0°, 136.9°, and 73.2°, respectively, were entered into computational fluid dynamics analysis for hemodynamic stresses.

Results: Larger bifurcation angles had a larger direct flow impinging zone and larger peak pressure area. In the direct flow impinging center, the total pressure was the highest, whereas the other stresses were the lowest. As blood flowed distally, the total pressure decreased rapidly, whereas all other parameters increased quickly to their peaks. The hemodynamic peak distance was decreased as the bifurcation angle became narrower. The total pressure summit and the peak hemodynamic stresses all decreased with the decrease of bifurcation angles. The distance between the hemodynamic peaks was the smallest at 73.2° compared with larger angles. A significant (P < 0.01) positive linear correlation existed in the ACA bifurcation angle with the distance between hemodynamic stress peaks or in the ACA branch diameter with the distance from the direct impinging center to the ipsilateral hemodynamic stress peak. The hemodynamic stresses on the aneurysm dome were significantly (P < 0.001) smaller than at the aneurysm initiation site.

Conclusions: Larger bifurcation angles may lead to abnormally enhanced hemodynamic stresses, enlarged zones of direct flow impingement, and increased distance between hemodynamic stress peaks to damage the vascular wall for aneurysm initiation on the bifurcation apex wall.
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http://dx.doi.org/10.1016/j.wneu.2018.08.167DOI Listing
December 2018

Association of Basilar Bifurcation Aneurysms With Age, Sex, and Bifurcation Geometry.

Stroke 2018 06 3;49(6):1371-1376. Epub 2018 May 3.

Henan Balance Medical Laboratory, Henan Balance Medical Corporation, Ltd, China (D.-H.Z.).

Background And Purpose: Basilar artery (BA) bifurcation aneurysms are common, but the correlation between BA bifurcation morphology and aneurysm formation remains to be established. Our purpose was to determine the association of BA bifurcation aneurysms with patient age, sex, bifurcation angle, and branch diameter.

Methods: Three-dimensional angiographic data of 195 patients were used, including 59 patients with BA bifurcation aneurysms and 136 control subjects. The angles formed between left and right posterior cerebral arteries (φ1) and between posterior cerebral artery and BA (the smaller angle defined as φ2 and the larger one as φ3), arterial diameters, and BA bifurcation aneurysm geometric characters were examined.

Results: Women of 40 to 70 years of age are more vulnerable to BA bifurcation aneurysm formation than men. The φ1 bifurcation angle significantly increased (<0.0001), whereas both φ2 and φ3 angles significantly decreased (<0.0001 and =0.09, respectively) with increase of patients' age. Statistically significant (<0.0001 and =0.0002, respectively) positive correlations were observed between BA bifurcation branch diameter and aneurysm size. The φ1 angle was significantly (<0.0001) wider in patients harboring BA bifurcation aneurysms than the control, whereas φ2 and φ3 angles in aneurysm group were significantly smaller than those in the control group (<0.0001). The BA bifurcation aneurysms were mostly deviated toward the smaller φ2 angle side between φ2 and φ3 angles and deviated toward the smaller-diameter daughter posterior cerebral artery branch.

Conclusions: BA bifurcation aneurysms are significantly associated with patients' age, female sex, wider bifurcation angles, and smaller vascular diameter at the BA bifurcation.
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http://dx.doi.org/10.1161/STROKEAHA.118.020829DOI Listing
June 2018

CD150 Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine.

Cell Stem Cell 2018 03 15;22(3):445-453.e5. Epub 2018 Feb 15.

Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Department of Pediatrics, Division of Hematology and Oncology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address:

A crucial player in immune regulation, FoxP3 regulatory T cells (Tregs) are drawing attention for their heterogeneity and noncanonical functions. Here, we describe a Treg subpopulation that controls hematopoietic stem cell (HSC) quiescence and engraftment. These Tregs highly expressed an HSC marker, CD150, and localized within the HSC niche in the bone marrow (BM). Specific reduction of BM Tregs achieved by conditional deletion of CXCR4 in Tregs increased HSC numbers in the BM. Adenosine generated via the CD39 cell surface ectoenzyme on niche Tregs protected HSCs from oxidative stress and maintained HSC quiescence. In transplantation settings, niche Tregs prevented allogeneic (allo-) HSC rejection through adenosine and facilitated allo-HSC engraftment. Furthermore, transfer of niche Tregs promoted allo-HSC engraftment to a much greater extent than transfer of other Tregs. These results identify a unique niche-associated Treg subset and adenosine as regulators of HSC quiescence, abundance, and engraftment, further highlighting their therapeutic utility.
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http://dx.doi.org/10.1016/j.stem.2018.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534147PMC
March 2018

Presence of Anterior Communicating Artery Aneurysm Is Associated With Age, Bifurcation Angle, and Vessel Diameter.

Stroke 2018 02 4;49(2):341-347. Epub 2018 Jan 4.

From the Department of Interventional Therapy, Henan Provincial People's Hospital, Zhengzhou, Henan Province, China (X.-J.Z., B.-L.G., W.-L.H., S.-S.W.); Department of Medical Research, Shijiazhuang First Hospital, Hebei Medical University, Hebei Province, China (X.-J.Z., B.-L.G., W.-L. H., S.-S. W.); and Henan Balance Medical Laboratory, Zhengzhou, Henan Province, China (D.-H.Z.).

Background And Purpose: The anterior communicating artery (Acom) aneurysm is the most complex in all cerebral aneurysms, and wider vascular bifurcation angles are considered to be associated with aneurysm formation. The objective of this study was to investigate association of the Acom aneurysm formation with patient age and vascular bifurcation morphology.

Methods: Three-dimensional angiographic data of 665 patients were used in this study, including 160 patients with Acom aneurysms, 66 with non-Acom aneurysms, and 439 control subjects with no aneurysms. The anterior cerebral artery bifurcation angle (Acom/A2 angle), arterial diameters, and Acom aneurysm geometric characters were examined.

Results: Women of 50 to 70 years were more vulnerable to Acom aneurysm formation than men. The Acom/A2 bifurcation angle was significantly increased (0.0001) with increase of patient age. The size of the Acom aneurysm dome and neck was statistically positively correlated with the diameter of the Acom, A1 and A2 segments (0.0001). The Acom/A2 bifurcation angle was significantly (0.0001) wider in patients with than without Acom aneurysms, whereas the A1/A2 angle was significantly smaller in patients with than without Acom aneurysms (0.0001). The Acom aneurysms at the bifurcation apex mostly deviated toward the smaller angle formed between the parent A1 and branches and toward the daughter artery with a smaller diameter. The Acom aneurysms were located mostly on the dominant anterior cerebral artery.

Conclusions: The presence of Acom aneurysm is significantly associated with patient age, wider angles of the anterior cerebral artery bifurcation, and smaller vascular diameter of the anterior communicating complex.
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http://dx.doi.org/10.1161/STROKEAHA.117.019701DOI Listing
February 2018

mTOR Inhibition for Transplantation: More May Not Be Better.

Authors:
Hao Wei Li

Transplantation 2017 12;101(12):2816-2817

Columbia Center for Translational Immunology, Columbia University, New York, NY.

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http://dx.doi.org/10.1097/TP.0000000000001946DOI Listing
December 2017

Construction of an in vivo carotid siphon model for testing endovascular devices for neuro-interventions.

Interv Neuroradiol 2017 Jun 2;23(3):325-329. Epub 2017 Feb 2.

3 Henan Balance Medical Laboratory, China.

Objective The aim of this study was to construct an in vivo carotid siphon model for testing neurovascular devices for endovascular interventions. Methods A model of a human carotid siphon was pre-shaped using a glass tube from a human cadaver and used to confine a segment of one side of the common carotid artery (CCA) in canines. This segment of CCA with the glass carotid siphon on was interposed end-to-end onto the contralateral CCA so as to simulate a human carotid artery siphon in vivo. Two weeks later, the siphon model was evaluated using computed tomography angiography and digital subtraction angiography, and the covered stent specially designed for intracranial vasculature was navigated through the siphon model for a longitudinal flexibility test. Results All dogs tolerated the procedures well, and the artificial siphon model in vivo provided realistic conditions for device testing. Two weeks later, the in vivo carotid siphon model remained patent with no thrombosis. Five covered stents were navigated to pass through five siphon models successfully, with vasospasm occurring in two siphons. Conclusion Construction of an in vivo siphon model in dogs with a glass tube is feasible and useful for the test of endovascular devices for treating neurovascular diseases.
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http://dx.doi.org/10.1177/1591019916688649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490852PMC
June 2017

MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice.

PLoS One 2015 6;10(11):e0141785. Epub 2015 Nov 6.

Columbia Center for Translational Immunology, Department of Medicine, Surgery and Microbiology/Immunology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.

NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141785PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636372PMC
June 2016

Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation.

J Immunol 2015 Aug 17;195(3):1282-92. Epub 2015 Jun 17.

Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032; Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129;

Inflammation in the priming host environment has critical effects on the graft-versus-host (GVH) responses mediated by naive donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show in this article that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared with naive T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation, and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared with freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-γ dependent. TLR stimulation after transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for graft-versus-host disease and T cell-mediated immunotherapies.
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http://dx.doi.org/10.4049/jimmunol.1401511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506852PMC
August 2015

Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts.

J Immunol 2014 Apr 3;192(7):3442-50. Epub 2014 Mar 3.

Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.

Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support the generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate that SW THY generates all human T cell subsets, including regulatory T cells (Tregs), in similar numbers as fetal human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34(+) cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to nondonor human and pig Ags. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naive-type Tregs compared with HU THY-generated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8(+) T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells, and reduced responses to protein Ags. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.
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http://dx.doi.org/10.4049/jimmunol.1302886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983999PMC
April 2014

Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice.

Acta Pharmacol Sin 2014 Jan;35(1):124-34

Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Aim: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice.

Methods: Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses.

Results: Plumbagin (2.5-20 μmol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 μmol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2-3 weeks and reduced the tumor volume by 44%-74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts.

Conclusion: Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells.
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http://dx.doi.org/10.1038/aps.2013.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075744PMC
January 2014

Suppressive Effects of Plumbagin on Invasion and Migration of Breast Cancer Cells via the Inhibition of STAT3 Signaling and Down-regulation of Inflammatory Cytokine Expressions.

Bone Res 2013 Dec 31;1(4):362-70. Epub 2013 Dec 31.

Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, China.

Objective: The aim of this study was to investigate the effects of plumbagin (PL), a naphthoquinone derived from the medicinal plant plumbago zeylanica, on the invasion and migration of human breast cancer cells.

Methods: Human breast cancer MDA-MB-231SArfp cells were treated with different concentrations of plumbagin for 24 h. The effects of plumbagin on the migration and invasion were observed by a transwell method. The expressions of IL-1α, IL-1β, IL-6, IL-8, TGF-β, TNFα, MMP-2 and MMP-9 mRNA in MDA-MB-231SArfp cells were detected using Real-Time PCR. MDA-MB-231SArfp cells were treated with plumbagin at different concentrations for 45 minutes. The activation of STAT3 was detected by western blot. Following this analysis, STAT3 in MDA-MB-231SArfp cells was knocked out using specific siRNA. mRNA levels of IL-1α, TGF-β, MMP-2 and MMP-9 were then detected. Consequently, MDA-MB-231SArfp cells were injected intracardially into BALB/c nude mice to construct a breast cancer bone metastatic model. The mice were injected intraperitoneally with plumbagin. Non-invasive in vivo monitoring, X-ray imaging and histological staining were performed to investigate the effects of plumbagin on the invasion and migration of breast cancer cells in vivo.

Results: The in vitro results showed that plumbagin could suppress the migration and invasion of breast cancer cells and down-regulate mRNA expressions of IL-1α, TGF-β, MMP-2 and MMP-9. Western blotting demonstrated that plumbagin inhibited the activation of STAT3 signaling in MDA-MB-231SArfp cells. The inactivation of STAT3 was found to have an inhibitory effect on the expressions of IL-1α, TGF-β, MMP-2 and MMP-9. In vivo studies showed that plumbagin inhibited the metastasis of breast cancer cells and decreased osteolytic bone metastases, as well as the secretion of MMP-2 and MMP-9 by tumor cells at metastatic lesions.

Conclusions: Plumbagin can suppress the invasion and migration of breast cancer cells via the inhibition of STAT3 signaling and by downregulation of IL-1α, TGF-β, MMP-2 and MMP-9.
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http://dx.doi.org/10.4248/BR201304007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472116PMC
December 2013

Nonalloreactive T cells prevent donor lymphocyte infusion-induced graft-versus-host disease by controlling microbial stimuli.

J Immunol 2012 Dec 7;189(12):5572-81. Epub 2012 Nov 7.

Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.

In mice, graft-versus-host reactions, associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras. However, GVHD sometimes occurs after DLI in established mixed chimeric patients. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell-depleted hematopoietic cell transplantation is slow, resulting in lymphopenia at the time of DLI. We demonstrate in this study that T cell lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of nonalloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a regulatory T cell-independent mechanism. GVHD was not inhibited by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by regulatory T cell-depleted, nonalloreactive T cells. Finally, thymectomized mixed chimeras showed increased GVHD following delayed DLI. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, T cell lymphopenia is a risk factor for GVHD in mixed chimeras receiving delayed DLI. Our data suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of T cells to control microbial infections.
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http://dx.doi.org/10.4049/jimmunol.1200045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524834PMC
December 2012

Emerging concepts in haematopoietic cell transplantation.

Nat Rev Immunol 2012 May 25;12(6):403-16. Epub 2012 May 25.

Columbia Center for Translational Immunology, Columbia University Medical Center, 650 West 168th Street, BB 15-02, New York, New York 10032, USA.

Haematopoietic cell transplantation (HCT) is the most widely used form of cellular therapy. It is the only known cure for some haematological malignancies and has recently been used in additional clinical settings, such as allograft tolerance induction and treatment of autoimmune diseases. Recent advances have enabled HCT in a wider range of patients with improved outcomes. This Review summarizes the latest developments in this therapy, focusing on issues that will affect future advancement.
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http://dx.doi.org/10.1038/nri3226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006975PMC
May 2012

Invariant NKT cells are required for antitumor responses induced by host-versus-graft responses.

J Immunol 2010 Aug 14;185(4):2099-105. Epub 2010 Jul 14.

Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.

Based on clinical observations, we have previously shown in a murine model that recipient leukocyte infusion (RLI) induces a host-versus-graft reaction in mixed bone marrow chimeras and that rejection of donor cells leads to a specific antitumor response against recipient malignancies. This response is dependent on T cells and IFN-gamma. We investigated the role of NKT cells (NKTs) in this phenomenon. Depletion of recipient NK1.1(+) cells led to loss of an anti-tumor effect induced by RLI in mixed bone marrow chimeras. In recipients specifically lacking host invariant NKT cells (iNKTs), RLI did not induce an antitumor effect, indicating a critical role for recipient iNKTs. Conversely, specific activation of iNKTs enhanced the anti-tumor effect induced by RLI. Following RLI, recipient iNKTs, NK cells, dendritic cells (DCs), and CD8 T cells were activated. CD8 T cells were the major producers of IFN-gamma. Lack of recipient iNKTs resulted in failure of activation of NK cells and DCs by RLI. Our studies demonstrate a central role for iNKTs in promoting RLI-induced anti-tumor effects and suggest that this pathway involved promotion of the activation of recipient NK cells and DCs.
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http://dx.doi.org/10.4049/jimmunol.0901985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111022PMC
August 2010

[Study of reducing graft-versus-host disease by in vitro blockade of CD40-CD40 ligand co-stimulatory pathway in allogeneic bone marrow transplantation mouse model].

Zhonghua Xue Ye Xue Za Zhi 2003 Jun;24(6):290-4

Department of Pediatrics, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China.

Objective: To investigate the effect and its mechanism of reducing graft-versus-host disease (GVHD) by in vitro blockade of CD(40)-CD(40)L pathway in vitro, the donor T lymphocytes cultured in vitro with anti-CD(40)L mAb were transfused in bone marrow transplantation (BMT) GVHD mouse model.

Methods: C57BL/6(H-2b) spleen T cells were isolated as responder cells, and BALB/c(H-2d) spleen cells as stimulator cells. They were cocultured with or without Anti-CD(40)L mAb as anti-CD(40)L mAb group and control group, respectively. At day 5, the mixed lymphocyte response (MLR)-culture cells mixed with bone marrow cells and transfused respectively into the TBI conditioned recipient mice. The mice were divided into two groups: group A, bone marrow cells (2 x 10(6)) and spleen T lymphocytes (2 x 10(6)) from MLR control group; group B, bone marrow cells (2 x 10(6)) and spleen T lymphocytes (2 x 10(6)) from MLR anti-CD(40)L mAb group. The GVHD incidence and hematopoietic reconstitution were observed. Peripheral blood sera and spleen cells of the recipients mice were harvested at scheduled time points for the measurement of cytokines and T cell immunophenotyping with flow cytometry.

Results: The incidence of GVHD in group A was 100% (10/10), and in group B was 20% (2/10). The percentage of H-2D(b) positive cells in group B (n = 8) was (93.54 +/- 2.32)% at day 40 after transplantation. The levels of cytokines in serum from group B were significantly lower than those from group A (P < 0.05). The expressions of CD(4)(+), CD(8)(+), CD(4)(+)CD(25)(+), CD(8)(+)CD(25)(+), CD(4)(+)CD(69)(+), CD(8)(+)CD(69)(+) and CD(4)(+)CD(40)L(+) were lower in group B than in group A (P < 0.05). The expressions of CD(8)(+)CD(40)L(+) and CD(4)(+)CD(45)RA(+) were similar in the two groups (P > 0.05).

Conclusion: Blockade of CD(40)-CD(40)L interaction in vitro could induce immune tolerance in vivo, reduce aGVHD in aGVHD mice model and form chimerism, which was mediated by inhibiting the Th1 and Th2 cytokines production, inducing tolerance of CD(4)(+) and CD(8)(+) cells to alloantigens. The obstruction of T cells activation after tolerance happened mainly at the early and mature phase of T cells activation. These provided the experimental basis for the use of anti-CD(40)L mAb in the clinical transplantation to prevent aGVHD.
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June 2003
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