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

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.