scholarly journals 19 F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells

2011 ◽  
Vol 65 (4) ◽  
pp. 1144-1153 ◽  
Author(s):  
T. Kevin Hitchens ◽  
Qing Ye ◽  
Danielle F. Eytan ◽  
Jelena M. Janjic ◽  
Eric T. Ahrens ◽  
...  
Keyword(s):  
Immune Cells ◽  
Allograft Rejection ◽  
Acute Allograft Rejection

IN VIVO IMMUNOSUPPRESSIVE EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN ON INNATE AND ADAPTIVE IMMUNE CELLS INVOLVED IN ALLOGRAFT REJECTION

2010 ◽  
Vol 90 ◽  
pp. 395
Author(s):  
A. S. Tjon ◽  
T. Tha-In ◽  
H. J. Metselaar ◽  
L. V.D. Laan ◽  
Z. M. Groothuismink ◽  
...  
Keyword(s):  
Intravenous Immunoglobulin ◽  
Immune Cells ◽  
Allograft Rejection ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract 34: Statins Directly Activate Erk5 and Reduce Endothelial Dysfunction and Acute Allograft Rejection

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yuichiro Takei ◽  
Nhat-Tu Le ◽  
Hakjoo Lee ◽  
Kyung-Sun Heo ◽  
Cheryl Hurley ◽  
...  
Keyword(s):  
Allograft Rejection ◽  
High Throughput Screening ◽  
Transcriptional Activity ◽  
Vascular Reactivity ◽  
Pleiotropic Effects ◽  
Protective Effects ◽  
Acute Allograft Rejection

Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are principal therapeutic agents for the treatment of hypercholesteremia. Statins, however, appear to also exert cholesterol-independent pleiotropic effects, such as improvement of endothelial (EC) function, stabilization of fibrous plaques, and decrease vascular inflammation. It is now well established that statins are beneficial in the prevention of cardiovascular disease and also widely used for suppressing cardiac allograft rejection. Previously, we have reported anti-inflammatory effect of ERK5 kinase in ECs. Methods and Results: In this study, we screened small molecules that activate ERK5 using high throughput screening, and identified statins as strong activators of the transcriptional activity of ERK5. In particular, we have found that pitavastatin increases ERK5 transcriptional activity, KLF2 promoter activity, and eNOS mRNA expression in ECs. These effects are abolished by the depletion of ERK5, but not its direct upstream kinase, MEK5. In addition, pitavastatin directly and dose-dependently activates ERK5 kinase activity in an in vitro kinase reaction assay, suggesting that ERK5 is a direct target of this statin. To examine the functional role of EC ERK5 activation by the statin in vivo, we utilized inducible endothelial ERK5 knock out (EC-ERK5-KO) mice and evaluated the effect of pitavastatin on EC function and acute allograft rejection. Depletion of ERK5 in ECs resulted in significant EC inflammation and dysfunction in vivo. Although pitavastatin reduced leukocyte rolling and vascular reactivity in mesebteruc microvessels of diabetic mice and prolonged allograft survival in a full allomismatch combination model, these protective effects were lost in EC-ERK5-KO mice. Conclusion: These data suggest the crucial role of ERK5 in pleiotropic effects of statins on EC dysfunction and allograft rejection in vivo.

scholarly journals A20 is an immune tolerance factor that can determine islet transplant outcomes

2019 ◽  
Author(s):  
Nathan W. Zammit ◽  
Stacey N. Walters ◽  
Karen L. Seeberger ◽  
Gregory S. Korbutt ◽  
Shane T. Grey
Keyword(s):  
Immune Cells ◽  
Allograft Rejection ◽  
Inflammatory Factors ◽  
Acute Allograft Rejection ◽  
Allograft Survival ◽  
Editing Domain ◽  
Neonatal Porcine Islets ◽  
Editing Enzyme ◽  
Therapeutic Administration

AbstractIslet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is restricted in its clinical application by limiting supplies of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-κB signalling thresholds. Here we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45 % of recipients, and >80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon regulatory T cells, was antigen-specific and grafts showed reduced expression of inflammatory factors, but increased TGFβ and IL-10. By analysing islets expressing an A20 coding mutation (I325N) that cripples A20’s OTU ubiquitin editing domain, we found that A20 regulates intra-graft RIPK1 levels to modulate NF-κB signalling. Transplantation of I325N islets resulted in increased NF-κB signalling, graft hyper-inflammation and acute allograft rejection. Neonatal porcine islets (NPI) represent a clinical alternative islet source but are readily rejected. However, forced A20 expression reduced NPI inflammation and increased their function after transplantation. Therapeutic administration of A20 raises NF-κB signalling thresholds and promotes islet allogeneic survival. Clinically this would allow for reduced immunosuppression supporting the use of alternate islet sources.

Increased Circulatory Extrarenal 1α,25-Dihydroxyvitamin D3 in Bilaterally Nephrectomized Rats

2020 ◽  
Vol 20 (9) ◽  
pp. 1523-1530
Author(s):  
Murat Dabak ◽  
Durrin O. Dabak ◽  
Tuncay Kuloglu ◽  
Ersoy Baydar ◽  
Hakan Bulut ◽  
...  
Keyword(s):  
Immune Cells ◽  
Low Dose ◽  
Systemic Circulation ◽  
Bilateral Nephrectomy ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Inflammatory Conditions ◽  
Calcium Phosphorus ◽  
25 Hydroxyvitamin D

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusions: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

scholarly journals A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubin Michalon ◽  
Andreas Hagenbuch ◽  
Christian Huy ◽  
Evita Varela ◽  
Benoit Combaluzier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Ex Vivo ◽  
Phase 1 ◽  
Hereditary Disease ◽  
Elderly Subjects ◽  
Human Antibody ◽  
Cardiac Amyloid ◽  
Healthy Elderly ◽  
Ongoing Phase

AbstractTransthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

scholarly journals FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo

2021 ◽  
Vol 22 (14) ◽  
pp. 7666
Author(s):  
Sara C. Credendino ◽  
Marta De Menna ◽  
Irene Cantone ◽  
Carmen Moccia ◽  
Matteo Esposito ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Immune Cells ◽  
Cancer Susceptibility ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Thyroid Cells ◽  
Transcriptional Alterations ◽  
Cancer Phenotypes

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

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