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1.
Respir Res ; 25(1): 262, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38951782

ABSTRACT

BACKGROUND: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.


Subject(s)
Graft Rejection , Lung Transplantation , Pseudomonas Infections , Pseudomonas aeruginosa , Lung Transplantation/adverse effects , Lung Transplantation/mortality , Humans , Female , Male , Middle Aged , Pseudomonas Infections/immunology , Pseudomonas Infections/diagnosis , Pseudomonas Infections/mortality , Adult , Pseudomonas aeruginosa/immunology , Graft Rejection/immunology , Graft Rejection/diagnosis , Tissue Donors , Retrospective Studies , Graft Survival , Cohort Studies , Isoantibodies/blood , Aged
2.
J Immunol ; 203(7): 1857-1866, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31484731

ABSTRACT

Multiple sclerosis is an inflammatory disease of the CNS characterized by neurologic impairment resulting from primary demyelination and axonal damage. The pathogenic mechanisms of disease development include Ag-specific T cell activation and Th1 differentiation, followed by T cell and macrophage migration into the CNS. CCL2 is a chemokine that induces migration of monocytes, memory T cells, and dendritic cells. We previously demonstrated that picomolar levels of CCL2 strongly restrict the development of inflammation in models of inflammatory bowel disease. Moreover, CCR2 deficiency in T cells promotes a program inducing the accumulation of Foxp3+ regulatory T cells while decreasing the levels of Th17 cells in vivo. In the current study, the effect of picomolar levels of CCL2 on the autoimmune inflammatory response associated with a multiple sclerosis-like disease in mice was analyzed. We found that low dosages of CCL2 were effective in suppressing MOG-induced experimental autoimmune encephalomyelitis (EAE), and they downregulated chronic EAE. The modulation of EAE by CCL2 was associated with downregulation of Th1/Th17 cells and upregulation of TGF-ß and induction of regulatory CD4+Foxp3 T cells. Most strikingly, these low levels of CCL2 induced formation of highly functional regulatory T cells. Thus, this study strongly supports the potential use of CCL2 as a regulatory mediator for treating inflammatory autoimmune diseases.


Subject(s)
Chemokine CCL2/immunology , Down-Regulation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunologic Memory , Multiple Sclerosis/immunology , Th17 Cells/immunology , Animals , Chronic Disease , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice , Multiple Sclerosis/pathology , T-Lymphocytes, Regulatory/pathology , Th17 Cells/pathology , Transforming Growth Factor beta/immunology
3.
J Immunol ; 199(8): 2745-2757, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28904129

ABSTRACT

The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, proliferation, and apoptosis. In this study, we focused on the role of T cells in the maintenance/survival of the mature naive peripheral B cell population. We show that naive B and T cells interact via the signaling lymphocyte activation molecule (SLAM) family receptor, SLAMF6. This interaction induces cell type-specific signals in both cell types, mediated by the SLAM-associated protein (SAP) family of adaptors. This signaling results in an upregulation of the expression of the cytokine migration inhibitory factor in the T cells and augmented expression of its receptor CD74 on the B cell counterparts, consequently enhancing B cell survival. Furthermore, in X-linked lymphoproliferative disease patients, SAP deficiency reduces CD74 expression, resulting in the perturbation of B cell maintenance from the naive stage. Thus, naive T cells regulate B cell survival in a SLAMF6- and SAP-dependent manner.


Subject(s)
B-Lymphocyte Subsets/physiology , B-Lymphocytes/physiology , Blood Cells/physiology , Lymphoproliferative Disorders/immunology , Signaling Lymphocytic Activation Molecule Associated Protein/metabolism , Signaling Lymphocytic Activation Molecule Family/metabolism , T-Lymphocytes/physiology , Animals , Antibodies, Blocking/administration & dosage , Cell Communication , Cell Differentiation , Cell Proliferation , Cell Survival , Cells, Cultured , Homeostasis , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Small Interfering/genetics , Signaling Lymphocytic Activation Molecule Associated Protein/genetics , Signaling Lymphocytic Activation Molecule Family/genetics
4.
J Immunol ; 198(12): 4659-4671, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28507030

ABSTRACT

Chemokines and chemokine receptors establish a complex network modulating immune cell migration and localization. These molecules were also suggested to mediate the differentiation of leukocytes; however, their intrinsic, direct regulation of lymphocyte fate remained unclear. CCR2 is the main chemokine receptor inducing macrophage and monocyte recruitment to sites of inflammation, and it is also expressed on T cells. To assess whether CCR2 directly regulates T cell responses, we followed the fates of CCR2-/- T cells in T cell-specific inflammatory models. Our in vitro and in vivo results show that CCR2 intrinsically mediates the expression of inflammatory T cell cytokines, and its absence on T cells results in attenuated colitis progression. Moreover, CCR2 deficiency in T cells promoted a program inducing the accumulation of Foxp3+ regulatory T cells, while decreasing the levels of Th17 cells in vivo, indicating that CCR2 regulates the immune response by modulating the effector/regulatory T ratio.


Subject(s)
Immunity, Cellular , Receptors, CCR2/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Cell Movement , Colitis/immunology , Cytokines/genetics , Cytokines/immunology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation , Macrophages/immunology , Mice , Receptors, CCR2/deficiency , Receptors, CCR2/genetics , Receptors, CCR2/immunology , Receptors, CCR5/immunology , Receptors, CCR5/metabolism , Th17 Cells/immunology , Th17 Cells/physiology
5.
Inflamm Bowel Dis ; 22(2): 257-67, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26529559

ABSTRACT

The continuous recirculation of mature lymphocytes and their entry into the peripheral lymph nodes are crucial for the development of an immune response to foreign antigens. Occasionally, the entry and the subsequent response of T lymphocytes in these sites lead to severe inflammation and pathological conditions. Here, we characterized the tetraspanin molecule, CD151, as a regulator of T cell motility in health and in models of inflammatory bowel disease. CD151 formed a cell surface complex with VLA-4 and LFA-1 integrins, and its activation led to enhanced migration of T cells. Picomolar levels of CCL2 that were previously shown to inhibit T-cell migration to lymph nodes suppressed CD151 expression and dissociated CD151-integrin complexes in T lymphocytes, resulting in attenuated migration toward T-cell attractant chemokines. To directly inhibit CD151 function, a truncated CD151 peptide fragment mimicking of the CD151 extracellular loop was designed. CD151 extracellular loop inhibited T-cell migration in vitro and in vivo and attenuated the development of dextrane sulfate sodium-induced colitis. Thus, CD151 is a key orchestrator of T cell motility; interference with its proper function results in attenuated progression of inflammatory bowel disease.


Subject(s)
Cell Movement/immunology , Colitis, Ulcerative/immunology , Crohn Disease/immunology , Inflammation/immunology , T-Lymphocytes/immunology , Tetraspanin 24/physiology , Animals , Case-Control Studies , Cell Movement/physiology , Follow-Up Studies , Homeodomain Proteins/physiology , Humans , Leukocyte Common Antigens/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Prognosis , Receptors, CCR2/physiology
6.
Cancer Res ; 73(18): 5754-63, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-24008320

ABSTRACT

The transmembrane neural cell adhesion receptor L1 is a Wnt/ß-catenin target gene expressed in many tumor types. In human colorectal cancer, L1 localizes preferentially to the invasive front of tumors and when overexpressed in colorectal cancer cells, it facilitates their metastasis to the liver. In this study, we investigated genes that are regulated in human colorectal cancer and by the L1-NF-κB pathway that has been implicated in liver metastasis. c-Kit was the most highly suppressed gene in both colorectal cancer tissue and the L1-NF-κB pathway. c-Kit suppression that resulted from L1-mediated signaling relied upon NF-κB, which directly inhibited the transcription of SP1, a major activator of the c-Kit gene promoter. Reconstituting c-Kit expression in L1-transfected cells blocked the biological effects conferred by L1 overexpression in driving motility and liver metastasis. We found that c-Kit expression in colorectal cancer cells is associated with a more pronounced epithelial morphology, along with increased expression of E-cadherin and decreased expression of Slug. Although c-Kit overexpression inhibited the motility and metastasis of L1-expressing colorectal cancer cells, it enhanced colorectal cancer cell proliferation and tumorigenesis, arguing that separate pathways mediate tumorigenicity and metastasis by c-Kit. Our findings provide insights into how colorectal cancer metastasizes to the liver, the most common site of dissemination in this cancer.


Subject(s)
Biomarkers, Tumor/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Liver Neoplasms/secondary , Neural Cell Adhesion Molecule L1/metabolism , Proto-Oncogene Proteins c-kit/genetics , Animals , Apoptosis , Biomarkers, Tumor/metabolism , Blotting, Western , Cadherins/genetics , Cadherins/metabolism , Cell Adhesion , Cell Movement , Cell Proliferation , Chromatin Immunoprecipitation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Fluorescent Antibody Technique , Gene Expression Profiling , Humans , Immunoenzyme Techniques , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice , Mice, Nude , NF-kappa B/genetics , NF-kappa B/metabolism , Neural Cell Adhesion Molecule L1/genetics , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins c-kit/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , beta Catenin/genetics , beta Catenin/metabolism
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