scholarly journals Statin Modulation of Human T-Cell Proliferation, IL-1 and IL-17 Production, and IFN- T Cell Expression: Synergy with Conventional Immunosuppressive Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ashmal Jameel ◽  
Kenneth G.-J. Ooi ◽  
Natasha R. Jeffs ◽  
Grazyna Galatowicz ◽  
Susan L. Lightman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Immunosuppressive Agents ◽  
Experimental Models ◽  
T Cell Proliferation ◽  
Reductase Inhibitors ◽  
Human T Cell ◽  
Human Immune ◽  
Cell Expression

HMG-CoA reductase inhibitors (statins) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models. The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responsesin vitrowith those of conventional immunosuppressives (dexamethasone, cyclosporin A (CsA), mycophenolate, and rapamycin). Statins (atorvastatin, lovastatin, and simvastatin) were investigated for their modulatory effects on human PBMC viability, cytokine profiles, and T-cell proliferation. At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation (), simvastatin significantly decreased intracellular CD4+T-cell expression of IFN- () to levels similar to those induced by conventional immunosuppressives. Atorvastatin and lovastatin also decreased IFN- expression, although to a lesser degree (). All three statins reduced levels of IL-17 production (). However, in response to anti-CD3/28 stimulation, simvastatin significantly upregulated IL-1 production (). The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone, suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines. This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells.

scholarly journals Hapalindoles from the Cyanobacterium Hapalosiphon sp. Inhibit T Cell Proliferation

Planta Medica ◽  
2019 ◽  
Vol 86 (02) ◽  
pp. 96-103 ◽  
Author(s):  
Tomasz Chilczuk ◽  
Carmen Steinborn ◽  
Steffen Breinlinger ◽  
Amy Marisa Zimmermann-Klemd ◽  
Roman Huber ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Annexin V ◽  
T Cell Proliferation ◽  
Immunomodulatory Activity ◽  
Human Immune ◽  
Apoptosis And Necrosis ◽  
Apoptotic Effects ◽  
First Time

AbstractNovel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts. Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.

scholarly journals T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD

Blood ◽  
2017 ◽  
Vol 130 (3) ◽  
pp. 348-359 ◽  
Author(s):  
Trisha A. Dant ◽  
Kaifeng L. Lin ◽  
Danny W. Bruce ◽  
Stephanie A. Montgomery ◽  
Oleg V. Kolupaev ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Acute Gvhd ◽  
T Cell Proliferation ◽  
Donor Cells ◽  
Key Points ◽  
Donor T Cells ◽  
Cell Expression

Key Points Donor T cells lacking AhR demonstrate decreased aGVHD because of reduced donor T-cell proliferation early after transplant. Absence of AhR on donor cells increased pTreg cells in the colon; in vitro blockade increased the number of human iTreg from CD4+ T cells.

scholarly journals Repurposing a novel anti-cancer RXR agonist to attenuate acute GVHD and maintain graft-versus-leukemia responses

Blood ◽  
2020 ◽  
Author(s):  
Govindarajan Thangavelu ◽  
Chao Wang ◽  
Michael Loschi ◽  
Asim Saha ◽  
Mark Osborn ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Acute Gvhd ◽  
Transcriptional Analysis ◽  
T Cell Proliferation ◽  
Graft Versus Leukemia ◽  
Human T Cell

The nuclear receptors (NR) retinoid X receptors (RXRs) exert immunomodulatory functions to control inflammation and metabolism via homodimers and heterodimers with several other NRs including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers but not heterodimers. Here, we show that in vivo IRX4204 was compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T cell proliferation, reducing T helper 1 differentiation and promoting regulatory T cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating pro-inflammatory pathways. In vitro, inducible Treg differentiation from naïve CD4+ T cells was enhanced by IRX4204; in vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrate that IRX4204 supported Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be used as a novel approach to prevent acute GVHD in the clinic.

scholarly journals Keratinocytes Regulate the Threshold of Inflammation by Inhibiting T Cell Effector Functions

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1606
Author(s):  
Peter Seiringer ◽  
Stefanie Eyerich ◽  
Kilian Eyerich ◽  
Daniela Dittlein ◽  
Anna Caroline Pilz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cytokine Production ◽  
Nickel Sulfate ◽  
Human Keratinocytes ◽  
T Cell Proliferation ◽  
Effector Functions ◽  
The Impact ◽  
Cell Effector

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.

scholarly journals Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

2020 ◽  
Vol 11 ◽  
Author(s):  
Christian Binder ◽  
Felix Sellberg ◽  
Filip Cvetkovski ◽  
Erik Berglund ◽  
David Berglund
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
T Cell Proliferation ◽  
Allogeneic Mixed Lymphocyte Reaction ◽  
Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

scholarly journals IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3101
Author(s):  
Cuiping Zhang ◽  
Mina Delawary ◽  
Peng Huang ◽  
Jennifer A. Korchak ◽  
Koji Suda ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Therapeutic Potential ◽  
Immune Dysregulation ◽  
T Cell Proliferation ◽  
Immunomodulatory Effects ◽  
Freezing And Thawing ◽  
Mrna Transfection ◽  
Clinical Conditions

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.

In Vitro Effects of Cyclosporine A and Tacrolimus on Regulatory T-Cell Proliferation and Function

2012 ◽  
Vol 94 (2) ◽  
pp. 123-131 ◽  
Author(s):  
Céline Miroux ◽  
Olivier Morales ◽  
Khaldoun Ghazal ◽  
Samia Ben Othman ◽  
Yvan de Launoit ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cyclosporine A ◽  
Regulatory T Cell ◽  
T Cell Proliferation ◽  
In Vitro Effects ◽  
And Function
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