A Novel Diagnostic Assay for Pulmonary Antibody Mediated Rejection - Detection of Circulating Donor Tissue-Specific B Cells

2014 ◽  
Vol 33 (4) ◽  
pp. S69
Author(s):  
S. Yerkovich ◽  
M. Tan ◽  
C. Smith ◽  
L. Samson ◽  
A. Fiene ◽  
...  
Keyword(s):  
B Cells ◽  
Diagnostic Assay ◽  
Tissue Specific ◽  
Donor Tissue ◽  
Antibody Mediated Rejection

scholarly journals Short-Term Immunopathological Changes Associated with Pulse Steroids/IVIG/Rituximab Therapy in Late Kidney Allograft Antibody Mediated Rejection

Kidney360 ◽  
2020 ◽  
Vol 1 (5) ◽  
pp. 389-398
Author(s):  
Kenna R. Degner ◽  
Nancy A. Wilson ◽  
Shannon R. Reese ◽  
Sandesh Parajuli ◽  
Fahad Aziz ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
B Cell Depletion ◽  
Short Term ◽  
Antibody Mediated Rejection ◽  
Pulse Steroids

BackgroundB cell depletion is a common treatment of antibody-mediated rejection (ABMR). We sought to determine the specific immunopathologic effects of this therapeutic approach in kidney transplantation.MethodsThis was a prospective observational study of recipients of kidney transplants diagnosed with late ABMR (>3 months after transplant). Patients received treatment with pulse steroids, IVIG, and rituximab. Donor-specific HLA antibodies (DSA), kidney allograft pathology, renal function, immune cell phenotypes, and 47 circulating cytokines were assessed at baseline and at 3 months.ResultsWe enrolled 23 patients in this study between April 2015 and March 2019. The majority of patients were male (74%) and white (78%) with an average age of 45.6±13.8 years. ABMR was diagnosed at 6.8±5.9 years (4 months to 25 years) post-transplant. Treatment was associated with a significant decline in circulating HLA class I (P=0.003) and class II DSA (P=0.002) and peritubular capillaritis (ptc; P=0.04) compared to baseline. Serum creatinine, BUN, eGFR, and proteinuria (UPC) remained stable. Circulating B cells were depleted to barely detectable levels (P≤0.001), whereas BAFF (P=0.0001), APRIL (P<0.001), and IL-10 (P=0.02) levels increased significantly post-treatment. Notably, there was a significant rise in circulating CD4+ (P=0.02) and CD8+ T cells (P=0.003). We also noted a significant correlation between circulating cytotoxic CD8+ T cells and BAFF (P=0.05), regulatory T cells and IL-10 (P=0.002), and regulatory T cells and HLA class I DSA (P=0.005).ConclusionsShort-term pulse steroids/IVIG/rituximab therapy was associated with inhibition of ABMR (DSA and ptc), stabilization of kidney function, and increased regulatory B cell and T cell survival cytokines. Additional studies are needed to understand the implications of B cell depletion on the crosstalk between T cells and B cells, and humoral components that regulate ABMR.

scholarly journals Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells

Cell Cycle ◽  
2014 ◽  
Vol 13 (10) ◽  
pp. 1583-1589 ◽  
Author(s):  
Claire Leduc ◽  
Guillaume Chemin ◽  
Nadine Puget ◽  
Carla Sawan ◽  
Mohammed Moutahir ◽  
...  
Keyword(s):  
B Cells ◽  
Essential Role ◽  
Tissue Specific

scholarly journals The Pu.1 Locus Is Differentially Regulated at the Level of Chromatin Structure and Noncoding Transcription by Alternate Mechanisms at Distinct Developmental Stages of Hematopoiesis

2007 ◽  
Vol 27 (21) ◽  
pp. 7425-7438 ◽  
Author(s):  
Maarten Hoogenkamp ◽  
Hanna Krysinska ◽  
Richard Ingram ◽  
Gang Huang ◽  
Rachael Barlow ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
B Cells ◽  
Regulatory Element ◽  
Precursor Cells ◽  
Hematopoietic Stem ◽  
Tissue Specific ◽  
Specific Regulation

ABSTRACT The Ets family transcription factor PU.1 is crucial for the regulation of hematopoietic development. Pu.1 is activated in hematopoietic stem cells and is expressed in mast cells, B cells, granulocytes, and macrophages but is switched off in T cells. Many of the transcription factors regulating Pu.1 have been identified, but little is known about how they organize Pu.1 chromatin in development. We analyzed the Pu.1 promoter and the upstream regulatory element (URE) using in vivo footprinting and chromatin immunoprecipitation assays. In B cells, Pu.1 was bound by a set of transcription factors different from that in myeloid cells and adopted alternative chromatin architectures. In T cells, Pu.1 chromatin at the URE was open and the same transcription factor binding sites were occupied as in B cells. The transcription factor RUNX1 was bound to the URE in precursor cells, but binding was down-regulated in maturing cells. In PU.1 knockout precursor cells, the Ets factor Fli-1 compensated for the lack of PU.1, and both proteins could occupy a subset of Pu.1 cis elements in PU.1-expressing cells. In addition, we identified novel URE-derived noncoding transcripts subject to tissue-specific regulation. Our results provide important insights into how overlapping, but different, sets of transcription factors program tissue-specific chromatin structures in the hematopoietic system.

scholarly journals Combinatorial determinants of tissue-specific transcription in B cells and macrophages.

1997 ◽  
Vol 17 (7) ◽  
pp. 3527-3535 ◽  
Author(s):  
B S Nikolajczyk ◽  
M Cortes ◽  
R Feinman ◽  
R Sen
Keyword(s):  
B Cells ◽  
Protein Binding ◽  
Binding Sites ◽  
Leucine Zipper ◽  
Chain Gene ◽  
Tissue Specific ◽  
Protein Binding Sites ◽  
Helix Loop Helix ◽  
Heavy Chain Gene Enhancer ◽  
Immunoglobulin Mu

A tripartite domain of the immunoglobulin mu heavy-chain gene enhancer that activates transcription in B cells contains binding sites for PU.1, Ets-1, and a leucine zipper-containing basic helix-loop-helix factor. Because PU.1 is expressed only in B cells and macrophages, we tested the activity of a minimal mu enhancer fragment in macrophages by transient transfections. The minimal mu enhancer activated transcription in macrophages, and the activity was dependent on all three sites. Analysis of mutated enhancers, in which spacing and orientation of the ETS protein binding sites had been changed, suggested that the mechanisms of enhancer activation were different in B cells and macrophages. Thus, ETS protein binding sites may be combined in different ways to generate tissue-specific transcription activators. Despite the activity of the minimal enhancer in macrophages, a larger mu enhancer fragment was inactive in these cells. We propose that formation of the nucleoprotein complex that is formed on the minimal enhancer in macrophages cannot be helped by the neighboring muE elements that are essential for activity of the monomeric enhancer.

The peritoneal micromilieu commits B cells to home to body cavities and the small intestine

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4627-4634 ◽  
Author(s):  
Simon Berberich ◽  
Reinhold Förster ◽  
Oliver Pabst
Keyword(s):  
Small Intestine ◽  
B Cells ◽  
Peritoneal Cavity ◽  
Chemokine Receptors ◽  
Migration Pattern ◽  
The Body ◽  
Tissue Specific ◽  
Class Switch ◽  
Migratory Capacity ◽  
Follicular B Cells

Abstract The distinct combination of homing receptors such as selectins, chemokine receptors, and integrins directs the migration of lymphocytes throughout the body. Upon activation lymphocytes irreversibly switch their set of homing receptors, now guiding them to entirely different destinations. Here we report that exposure of naive B cells to the microenvironment of the peritoneal cavity modulates their migration propensities in the absence of antigenic stimulation. B1 and B2 cells isolated from the peritoneal cavity reenter this compartment more efficiently compared with splenic follicular B cells. Moreover, when kept in the peritoneal cavity splenic follicular B cells gain such increased capability to reenter this compartment. These altered migratory capacities are reflected by an up-regulation of the chemokine receptors CXCR4 and CXCR5 and β7 integrin by the peritoneum-experienced splenic B cells, among which CXCR5 is instrumental in directing B cells into the peritoneal cavity. Moreover, intraperitoneal transfer of plasma blasts favors their migration into the small intestine presumably before class switch recombination occurs, demonstrating that a reconfigured transient migration pattern is not restricted to naive cells. In conclusion, these data demonstrate a hitherto unrecognized role for tissue-specific cues, altering the migratory capacity of B1, naive B2, as well as antigen-experienced B2 cells.

scholarly journals Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Maolin Ma ◽  
Qipeng Sun ◽  
Xiujie Li ◽  
Gengguo Deng ◽  
Yannan Zhang ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
Immune Cells ◽  
Cardiac Transplantation ◽  
Inflammatory Cytokine ◽  
Cardiac Allograft ◽  
Effective Strategies ◽  
Antibody Mediated Rejection ◽  
Specific Antibody Production ◽  
Transplantation Model

Acute antibody-mediated rejection (AAMR) is an important cause of cardiac allograft dysfunction, and more effective strategies need to be explored to improve allograft prognosis. Interleukin (IL)-6/IL-6R signaling plays a key role in the activation of immune cells including B cells, T cells and macrophages, which participate in the progression of AAMR. In this study, we investigated the effect of IL-6/IL-6R signaling blockade on the prevention of AAMR in a mouse model. We established a mouse model of AAMR for cardiac transplantation via presensitization of skin grafts and addition of cyclosporin A, and sequentially analyzed its features. Tocilizumab, anti-IL-6R antibody, and recipient IL-6 knockout were used to block IL-6/IL-6R signaling. We demonstrated that blockade of IL-6/IL-6R signaling significantly attenuated allograft injury and improved survival. Further mechanistic research revealed that signaling blockade decreased B cells in circulation, spleens, and allografts, thus inhibiting donor-specific antibody production and complement activation. Moreover, macrophage, T cell, and pro-inflammatory cytokine infiltration in allografts was also reduced. Collectively, we provided a highly practical mouse model of AAMR and demonstrated that blockade of IL-6/IL-6R signaling markedly alleviated AAMR, which is expected to provide a superior option for the treatment of AAMR in clinic.

scholarly journals Artemisinin Attenuates Transplant Rejection by Inhibiting Multiple Lymphocytes and Prolongs Cardiac Allograft Survival

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhe Yang ◽  
Fei Han ◽  
Tao Liao ◽  
Haofeng Zheng ◽  
Zihuan Luo ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Transplant Rejection ◽  
Cell Infiltration ◽  
Therapeutic Effects ◽  
Antibody Mediated Rejection ◽  
T Cell Infiltration ◽  
Cytokine Levels ◽  
Immunological Rejection

Immunological rejection is an important factor resulting in allograft dysfunction, and more valid therapeutic methods need to be explored to improve allograft outcomes. Many researches have indicated that artemisinin and its derivative exhibits immunosuppressive functions, apart from serving as a traditional anti-malarial drug. In this assay, we further explored the therapeutic effects of artemisinin for transplant rejection in a rat cardiac transplantation model. We found that it markedly attenuated allograft rejection and histological injury and significantly prolonged the survival of allograft. Upon further exploring the mechanism, we demonstrated that artemisinin not only attenuated T cell-mediated rejection (TCMR) by reducing effector T cell infiltration and inflammatory cytokine secretion and increasing regulatory T cell infiltration and immunoregulatory cytokine levels, but also attenuated antibody-mediated rejection (ABMR) through inhibition of B cells activation and antibody production. Furthermore, artemisinin also reduced macrophage infiltration in allografts, which was determined to be important for TCMR and ABMR. Moreover, we demonstrated that artemisinin significantly inhibited the function of pure T cells, B cells, and macrophages in vitro. All in all, this study provide evidence that artemisinin significantly attenuates TCMR and ABMR by targeting multiple effectors. Therefore, this agent might have potential for use in clinical settings to protect against transplant rejection.

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