scholarly journals MiR-146a regulates regulatory T cells to suppress heart transplant rejection in mice

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jian Lu ◽  
Weiwei Wang ◽  
Peiyuan Li ◽  
Xiaodong Wang ◽  
Chao Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Heart Transplant ◽  
Transplant Rejection ◽  
Mouse Heart ◽  
Allograft Survival ◽  
Treg Function ◽  
Ifn Γ ◽  
Heart Transplant Rejection

AbstractRegulatory T cells (Tregs), which characteristically express forkhead box protein 3 (Foxp3), are essential for the induction of immune tolerance. Here, we investigated microRNA-146a (miR-146a), a miRNA that is widely expressed in Tregs and closely related to their homeostasis and function, with the aim of enhancing the function of Tregs by regulating miR-146a and then suppressing transplant rejection. The effect of the absence of miR-146a on Treg function in the presence or absence of rapamycin was detected in both a mouse heart transplantation model and cell co-cultures in vitro. The absence of miR-146a exerted a mild tissue-protective effect by transiently prolonging allograft survival and reducing the infiltration of CD4+ and CD8+ T cells into the allografts. Meanwhile, the absence of miR-146a increased Treg expansion but impaired the ability of Tregs to restrict T helper cell type 1 (Th1) responses. A miR-146a deficiency combined with interferon (IFN)-γ blockade repaired the impaired Treg function, further prolonged allograft survival, and alleviated rejection. Importantly, miR-146a regulated Tregs mainly through the IFN-γ/signal transducer and activator of transcription (STAT) 1 pathway, which is implicated in Treg function to inhibit Th1 responses. Our data suggest miR-146a controls a specific aspect of Treg function, and modulation of miR-146a may enhance Treg efficacy in alleviating heart transplant rejection in mice.

Unique roles of Schistosoma japonicum protein Sj16 to induce IFN-γ and IL-10 producing CD4+CD25+ regulatory T cells in vitro and in vivo

2012 ◽  
Vol 34 (8-9) ◽  
pp. 430-439 ◽  
Author(s):  
X. J. SUN ◽  
R. LI ◽  
X. SUN ◽  
Y. ZHOU ◽  
Y. WANG ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Schistosoma Japonicum ◽  
Ifn Γ

Orthotopic Heart Transplant Rejection and Immunosuppression

2020 ◽  
pp. 247-256
Author(s):  
Kevin J. Clerkin ◽  
Maryjane A. Farr
Keyword(s):  
T Cells ◽  
Heart Transplant ◽  
Transplant Rejection ◽  
Early Period ◽  
Human Leukocyte ◽  
Cardiac Allograft ◽  
Routine Practice ◽  
Post Transplantation ◽  
Orthotopic Heart Transplant ◽  
Heart Transplant Rejection

This chapter focuses on orthotopic heart transplant rejection. Hyperacute rejection is a catastrophic complication that occurs early post-transplantation. This type of rejection is most often due to pre-formed donor-specific anti–human leukocyte antigen antibodies or an ABO blood type mismatch and is rarely seen in the current era because pre-transplant virtual and prospective crossmatch has become routine practice. Meanwhile, immune activation of recipient T cells against the cardiac allograft causes acute cellular rejection (ACR). Treatment of ACR will vary depending on the grade of rejection, symptoms, and hemodynamic significance. On the other hand, antibody-mediated rejection (AMR), previously known as humoral or vascular rejection, is primarily mediated by antibodies and not T cells, as in ACR. AMR is difficult to treat because it may persist or be recurrent and is associated with an increased risk of cardiac allograft vasculopathy and mortality. The chapter then discusses the management of acute rejection. Induction therapy is augmented immunosuppression in the early period following heart transplantation, when the recipient is at the greatest risk of rejection. Maintenance immunosuppression includes calcineurin inhibitors, anti-metabolites, glucocorticoids, and proliferation signal inhibitors.

The In Vivo Impact of Human Regulatory T Cells on the Graft Versus Tumor Effect.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 349-349 ◽  
Author(s):  
Tuna Mutis ◽  
Henk Rozemuller ◽  
Maarten E. Emmelot ◽  
Tineke Aarts-Riemens ◽  
Vivienne Verweij ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Cells ◽  
Cell Reactivity ◽  
Human Pbmc ◽  
Ifn Γ ◽  
T Cell Reactivity ◽  
The Impact

Abstract The curative Graft-vs-Tumor effect (GvT) of allogeneic Stem cell transplantation (SCT) is frequently complicated with life threatening Graft-vs-Host Disease (GvHD). In mice, prevention of GvHD, without abrogation of GvT is possible by co-transplantation of naturally occurring regulatory T cells (Tregs) with SC grafts. Consistent with these murine studies, we recently demonstrated that also human Tregs possess potent GvHD-downregulatory capacities in a xenogeneic(x) model, where x-GvHD is induced by infusion of autologous human T cells in RAG2−/−γc−/− mice (Mutis et al. Clin. Cancer Res.2006, 12: 5520–5525). Towards clinical application of Tregs, we now explored the impact of human Treg-administration on GvT in a bioluminescence imaging (BLI) based human-GvT model in the RAG2−/−γc−/− mice. In this model, mice inoculated with luciferase (LUC)-transduced human myeloma (MM) cell lines developed BLI-detectable, progressive, MM-like multifocal tumors exclusively in the bone marrow (BM). Full blown tumors were effectively eliminated by infusion of allogeneic human PBMC. This treatment also caused lethal x-GvHD as expected. In this setting, co-infusion of human PBMC with autologous, in vitro cultured Tregs at a 1:1 Treg: T effector cell ratio had no adverse effects on the development of GvT while significantly reducing the lethality of x-GvHD. In vitro analyses of sacrificed mice at day 21 revealed that administered Tregs homed to BM and spleen, significantly downregulated the total numbers of IFN-γ-producing CD4+ and CD8+ T cells responding to CD3 mediated signals, but had no downregulatory effect on the frequencies of IFN-γ-producing T cells responding to tumor cells. There was also no downregulation of cytotoxic activity against tumor cells in Treg-treated mice. Conclusively, these results showed that Tregs, at doses which are inhibitory for x-GvHD-inducing T cells, could maintain the GvT effect by allowing T cell reactivity against tumor cells. Human Tregs thus still hold promise as attractive cellular tools for separating GvT from GvHD.

scholarly journals Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2356 ◽  
Author(s):  
Andreas von Knethen ◽  
Ulrike Heinicke ◽  
Andreas Weigert ◽  
Kai Zacharowski ◽  
Bernhard Brüne
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lupus Erythematosus ◽  
Target Genes ◽  
Transplant Rejection ◽  
Histone Deacetylation ◽  
Promoter Regions ◽  
Therapy Regimen

Regulatory T cells (Tregs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4+Forkhead box protein3+ (CD4+FOXP3+), these cells are a subset of CD4+ T lymphocytes and can originate from the thymus (tTregs) or from the periphery (pTregs). The malfunction of CD4+ Tregs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional Tregs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking Treg differentiation might be favorable in sepsis patients. It has been shown that Tregs can be generated from conventional naïve T cells, called iTregs, due to their induced differentiation. Moreover, Tregs can be effectively expanded in vitro based on blood-derived tTregs. Taking into consideration that the suppressive role of Tregs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of Tregs in this review in detail.

scholarly journals Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or –sufficient conditions

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246967
Author(s):  
Ju Hee Hwang ◽  
Honglin Piao ◽  
Joon Young Jang ◽  
Sun-Kyung Lee ◽  
Dongkyu Han ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Vitamin C ◽  
Allograft Rejection ◽  
Sufficient Conditions ◽  
High Dose ◽  
Allograft Survival ◽  
Heart Allograft

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.

scholarly journals Immunosuppressive PLGA TGF-β1 Microparticles Induce Polyclonal and Antigen-Specific Regulatory T Cells for Local Immunomodulation of Allogeneic Islet Transplants

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Li ◽  
Anthony W. Frei ◽  
Irayme M. Labrada ◽  
Yanan Rong ◽  
Jia-Pu Liang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Transplant Rejection ◽  
Host Immune System ◽  
Cell Based Therapy ◽  
Mouse Islets ◽  
Islet Transplants ◽  
Tgf Β1

Allogeneic islet transplantation is a promising cell-based therapy for Type 1 Diabetes (T1D). The long-term efficacy of this approach, however, is impaired by allorejection. Current clinical practice relies on long-term systemic immunosuppression, leading to severe adverse events. To avoid these detrimental effects, poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) were engineered for the localized and controlled release of immunomodulatory TGF-β1. The in vitro co-incubation of TGF-β1 releasing PLGA MPs with naïve CD4+ T cells resulted in the efficient generation of both polyclonal and antigen-specific induced regulatory T cells (iTregs) with robust immunosuppressive function. The co-transplantation of TGF-β1 releasing PLGA MPs and Balb/c mouse islets within the extrahepatic epididymal fat pad (EFP) of diabetic C57BL/6J mice resulted in the prompt engraftment of the allogenic implants, supporting the compatibility of PLGA MPs and local TGF-β1 release. The presence of the TGF-β1-PLGA MPs, however, did not confer significant graft protection when compared to untreated controls, despite measurement of preserved insulin expression, reduced intra-islet CD3+ cells invasion, and elevated CD3+Foxp3+ T cells at the peri-transplantation site in long-term functioning grafts. Examination of the broader impacts of TGF-β1/PLGA MPs on the host immune system implicated a localized nature of the immunomodulation with no observed systemic impacts. In summary, this approach establishes the feasibility of a local and modular microparticle delivery system for the immunomodulation of an extrahepatic implant site. This approach can be easily adapted to deliver larger doses or other agents, as well as multi-drug approaches, within the local graft microenvironment to prevent transplant rejection.

scholarly journals THE PROBLEM OF HEART TRANSPLANT REJECTION AND WAYS OF OPTIMIZING THE ASSESSMENT OF ENDOMYOCARDIAL BIOPSY RESULTS

2017 ◽  
Vol 8 (3) ◽  
pp. 28-33
Author(s):  
T V Stavenchuk ◽  
E D Kosmachova ◽  
I A Shelestova ◽  
A A Slavinsky ◽  
E A Terman ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Transplantation ◽  
International Society ◽  
Heart Transplant ◽  
Endomyocardial Biopsy ◽  
Rejection Episode ◽  
Transplant Rejection ◽  
Morphometric Study ◽  
Cd 68 ◽  
Heart Transplant Rejection

The following article describes tactics of recipient management when a rejection episode of a heart transplant is being suspected. We have discovered some new figures to assess biopsy samples through computerised morphometric study, which can both improve and clarify biopsy results. CD3+ (T-cells) and CD 68+ (macrophages) figures make it possible to determine the extent of transplant rejection in accordance with the International Society for Heart and Lung Transplantation diagnostic criteria (sensitivity 91%, specificity 91%).

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