Palmitoylethanolamide (PEA) Induces an Increase in Spleen Regulatory T Cells, Reduces CD8+ Cells and TNF-α Levels in Target Organs, and Protects Mice From Graft-Versus-Host Disease-Related Mortality Through PPAR Activation Without Compromising the Graft-Versus-Tumour Response.

IF 4.9 3区 医学 Q2 IMMUNOLOGY
Immunology Pub Date : 2025-06-25 DOI:10.1111/imm.70010
Bárbara Betônico Berg, Zara Desiree Tonidandel Campos, Gioconda Muniz Fiorenza Ruggio, Ana Flávia Santos Linhares, Bárbara Maximino Rezende, Stêfany Bruno de Assis Cau, Thiago Roberto Lima Romero, Mauro Martins Teixeira, Vanessa Pinho, Marina Gomes Miranda Castor
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Abstract

Graft-versus-host disease (GVHD), a secondary complication of bone marrow transplantation, leads to the development of a systemic inflammatory illness in the host, resulting in high mortality and morbidity. Current therapies lack prophylactic effectiveness and often fail to achieve an optimal immunological balance between inflammation and immunosuppression. In this study, we investigated the effects of palmitoylethanolamide (PEA), an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory, and neuroprotective effects, on the complex pathology of GVHD. Treatment with PEA reduced clinical disease severity in GVHD mice, leading to an 80% increase in survival rates. Additionally, PEA created an immunoregulatory environment in the spleen by reducing the activation of CD3+CD4+ cells. In the intestine, PEA protected against damage, reduced the number of CD3+CD4+ and CD3+CD8+ cells, and suppressed the activation of CD3+CD8+ cells. PEA also decreased the levels of TNF-α in the intestine and increased IL-10 production. Furthermore, in the liver, PEA treatment reduced the number of CD8+ cells, the activation of CD3+CD4+ and CD3+CD8+ cells, and TNF-α levels. The effect of PEA on survival was dependent on Peroxisome Proliferator-activated receptor gamma (PPAR-γ) activation but did not rely on cannabinoid (CB) receptors activation. In addition to GVHD protection, PEA treatment did not interfere in the graft-versus-tumour response. These results demonstrate the therapeutic potential of PEA as a promising option for the treatment of GVHD, balancing inflammation and immunosuppression, and improving both survival and clinical outcomes.

棕榈酰乙醇酰胺(PEA)诱导脾脏调节性T细胞增加,降低靶器官中CD8+细胞和TNF-α水平,并通过PPAR激活保护小鼠免于移植物抗宿主病相关的死亡,而不影响移植物抗肿瘤反应。
移植物抗宿主病(GVHD)是骨髓移植的继发性并发症,可导致宿主发生全身性炎症性疾病,导致高死亡率和发病率。目前的治疗方法缺乏预防效果,往往不能达到炎症和免疫抑制之间的最佳免疫平衡。在这项研究中,我们研究了棕榈酰乙醇酰胺(PEA)对GVHD复杂病理的影响,PEA是一种内源性大麻素样脂质介质,具有广泛的抗炎、镇痛、抗菌、免疫调节和神经保护作用。PEA治疗降低了GVHD小鼠的临床疾病严重程度,导致存活率提高80%。此外,PEA通过降低CD3+CD4+细胞的激活,在脾脏中创造了一个免疫调节环境。在肠道中,PEA保护机体免受损伤,减少CD3+CD4+和CD3+CD8+细胞的数量,抑制CD3+CD8+细胞的活化。PEA还降低了肠道中TNF-α的水平,增加了IL-10的产生。此外,在肝脏中,PEA治疗减少了CD8+细胞的数量、CD3+CD4+和CD3+CD8+细胞的活化以及TNF-α水平。PEA对生存的影响依赖于过氧化物酶体增殖物激活受体γ (PPAR-γ)的激活,而不依赖于大麻素(CB)受体的激活。除了GVHD保护外,PEA治疗不会干扰移植物抗肿瘤反应。这些结果表明,PEA作为一种治疗GVHD的有希望的选择,具有治疗潜力,可以平衡炎症和免疫抑制,并提高生存率和临床结果。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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