Intralipid ® attenuates acute cardiac allograft rejection in relation to promoting CD4 + CD25 + Foxp3 + regulatory T-cells and inhibiting toll-like receptor 4 expression

Abstract Background Cardiac allograft rejection is known to have a profound impact on graft survival and mortality after heart transplant. Previous data on the efficacy of extracorporeal photopheresis (ECP) in the management of cardiac allograft rejection is encouraging. Though, clear evidence on the exact indication and data regarding its effect on distinct lymphocyte subtypes are still lacking. Based on their cytokine production, both helper and cytotoxic T cells can differentiate into either regulatory cells participating in the suppression of rejection or into effector cells responsible for its maintenance. Regulatory T cells are essential for the termination of rejection, while B lymphocytes and natural killer (NK) cells contribute to it. Purpose We aimed to investigate the anti-rejection efficacy and the impact of ECP on peripheral blood lymphocyte subclasses in adult heart transplant recipients. Methods In a retrospective analysis of 12 consecutive patients treated with ECP for cardiac allograft rejection between 2013 and 2019, we examined the grade of rejection in endomyocardial biopsies (EMB) based on the International Society for Heart and Lung Transplantation classification. We analysed the absolute counts and the percentages of helper, cytotoxic and regulatory T cells, B lymphocytes and NK cells with fluorescence activated cell sorting. Measurements were performed both before and after the ECP treatment period. Data values were given as either mean±standard deviation or median [min–max]. Results The patients underwent 26 [2–39] ECP treatments in addition to standard immunosuppressant therapy. Whereas grade 2R cellular rejection was detected in 83% of the cases prior to initiating ECP, none of the examined EMB specimen revealed rejection greater than grade 1R cellular rejection post ECP therapy. The average grade of cellular rejection improved significantly (1.25±0.45 vs. 0.50±0.53; p=0.022). The absolute count and the percentage of helper T cells increased significantly post ECP therapy (0.34 G/l±0.26 G/l vs. 0.51 G/l±0.39 G/l; p=0.018 and 3.43%±2.24% vs. 5.98%±3.64%; p=0.017, respectively). There was also a significant rise in the percentage of cytotoxic T cells (2.33%±1.46% vs. 4.16±2.98%; p=0.027). We noticed an almost significant twofold increase in the percentage of regulatory T cells on completion of the ECP therapy (0.20%±0.22% vs. 0.37%±0.20%; p=0.060). Neither B lymphocyte nor NK cell counts revealed any significant changes. Conclusion ECP was effective in reducing the severity of cardiac allograft rejection episodes. The significant decrease in rejection rates might be indicative of the predominance of anti-inflammatory helper and cytotoxic T cell subpopulations and the increase of regulatory T cell count post ECP therapy. However, discussion of the results are limited by small sample size and the effect of medical therapy on the lymphocytes.

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Faculty Opinions recommendation of Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4+CD25+Foxp3+ regulatory T cells and down-regulates cardiac allograft rejection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3052958.2735061 ◽

2010 ◽

Author(s):

Robert Knobler

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Ultraviolet A ◽

Cardiac Allograft Rejection ◽

Donor Lymphocytes

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Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2008.01.004 ◽

2008 ◽

Vol 27 (4) ◽

pp. 362-371 ◽

Cited By ~ 21

Author(s):

Yusuke Kitazawa ◽

Masayuki Fujino ◽

Takatoshi Sakai ◽

Haruhito Azuma ◽

Hiromitsu Kimura ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Cardiac Allograft Rejection

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Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4+CD25+Foxp3+ regulatory T cells and down-regulates cardiac allograft rejection

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2010.04.062 ◽

2010 ◽

Vol 395 (4) ◽

pp. 540-546 ◽

Cited By ~ 10

Author(s):

De-Hua Zheng ◽

Li-Ping Dou ◽

Yu-Xiang Wei ◽

Guo-Sheng Du ◽

Yi-Ping Zou ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Ultraviolet A ◽

Cardiac Allograft Rejection ◽

Donor Lymphocytes

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Combined treatment with simvastatin and rapamycin attenuates cardiac allograft rejection through the regulation of T helper 17 and regulatory T cells

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.5635 ◽

2017 ◽

Author(s):

Yingjie Liu ◽

Lu Sun ◽

Wei Chen ◽

Junbo Chuai ◽

Yu Shang ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Allograft Rejection ◽

Combined Treatment ◽

Cardiac Allograft ◽

T Helper ◽

T Helper 17 ◽

Cardiac Allograft Rejection

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CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

Journal of International Medical Research ◽

10.1177/0300060520980940 ◽

2020 ◽

Vol 48 (12) ◽

pp. 030006052098094

Author(s):

Shuang Qin ◽

Li Li ◽

Jia Liu ◽

Jinrui Zhang ◽

Qing Xiao ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Response ◽

Mouse Model ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Unexplained Recurrent Spontaneous Abortion ◽

Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

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Induction of CD4+CD25+ T Cells and Control of Cardiac Allograft Rejection by CD40/CD40L Costimulatory Pathway Blockade in Mice

Transplantation Proceedings ◽

10.1016/j.transproceed.2012.10.044 ◽

2013 ◽

Vol 45 (2) ◽

pp. 611-617 ◽

Cited By ~ 7

Author(s):

W. Fu ◽

J. Zhu ◽

Y. Qiu ◽

W. Li

Keyword(s):

T Cells ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Cardiac Allograft Rejection ◽

And Control ◽

Costimulatory Pathway

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Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival

Journal of Experimental Medicine ◽

10.1084/jem.20012088 ◽

2002 ◽

Vol 195 (6) ◽

pp. 795-800 ◽

Cited By ~ 94

Author(s):

Qunrui Ye ◽

Christopher C. Fraser ◽

Wei Gao ◽

Liqing Wang ◽

Samantha J. Busfield ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Allograft Rejection ◽

Cell Activation ◽

Cardiac Allograft ◽

Allograft Survival ◽

Activated T Cells ◽

Cardiac Allograft Rejection ◽

Ifn Γ

LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT−/− mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT−/− mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT+/+ mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT+/+ mice (7 days). However, mean allograft survival in CsA-treated LIGHT−/− allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT−/− mice or CsA-treated LIGHT+/+ controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-γ, plus IFN-γ–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT+/+ allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection.

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