Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial

Crocchiolo, Roberto; Cesana, Clara; Girgenti, Debora; Bertani, Giambattista; Barba, Claudia; Liga, Giuseppa; Ferri, Ursula; Crucitti, Lara; Grillo, Giovanni; Rossini, Silvano; Cairoli, Roberto

doi:10.1186/s40164-021-00210-9

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…In different cytokine environments, CD4 + T cells can differentiate into different subpopulations, including Th1, Th2, Th17 and Treg cells. Th1 and Th17 cells can contribute to aGVHD development, while Tregs can protect against aGVHD [51]. Interestingly, hUC-EVs-ATO reduced the frequency of Th1 and Th17 cells while increasing the Treg cell frequency in vivo but not in vitro.…”

Section: Discussionmentioning

confidence: 95%

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Sun

Liu

et al. 2022

J Hematol Oncol

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Background Both extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Methods An aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4+ were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect. Results The clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4+ T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment. Conclusions hUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT.

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Section: Discussionmentioning

confidence: 95%

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Sun

Liu

et al. 2022

J Hematol Oncol

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“…ECP has exhibited therapeutic efficacy in the management of T cell-mediated diseases, particularly among the patients with GVHD, transplant rejections, and various autoimmune diseases. In murine models of GVHD, as well as in a majority of patients with GVHD, Tregs have been observed to proliferate in response to ECP [ 12 , 49 ]. On the other hand, in some clinical trials focusing on systemic sclerosis undergoing ECP, in addition to the increase of Tregs in the peripheral blood of the patients, it was also observed that Th17 cells, which had a surge at the beginning of the disease, were decreased after ECP treatment and positively correlated with the improvement of skin symptoms [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…ECP has demonstrated effective and safe therapeutic outcomes in the clinical management of various T cell-mediated disorders [ 10 , 11 ]. For instance, in patients with graft-versus-host disease (GVHD) or solid organ transplant rejection, the prophylactic or therapeutic use of ECP has shown specific and long-term immunosuppressive effects [ 12 – 15 ]. Moreover, prospective studies conducted on ECP treatment for other autoimmune disease like systemic sclerosis, Crohn’s disease, and type 1 diabetes, pemphigus vulgaris and other autoimmune diseases, have also revealed promising results [ 16 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

Extracorporeal photopheresis reduces inflammation and joint damage in a rheumatoid arthritis murine model

Lin,

Cheng,

Zhong

et al. 2024

J Transl Med

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Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory reactions and tissue damage in the joints. Long-term drug use in clinical practice is often accompanied by adverse reactions. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy with few side effects, offering a potential and safe therapeutic alternative for RA through the induction of immune tolerance. This study aimed to investigate the therapeutic effects of ECP on RA using a collagen-induced arthritis (CIA) murine model, as well as to explore its immunomodulatory effects in vivo. Additionally, particular attention was given to the significant role of monocytes during the ECP process. Methods A murine model of rheumatoid arthritis was established by administering two injections of bovine type II collagen to DBA/1J mice. ECP, ECP-MD (mononuclear cells were depleted during the ECP), MTX, and PBS treatment were applied to the CIA mice. During the treatment process, clinical scores and body weight changes of CIA mice were closely monitored. After six treatment sessions, micro-CT images of the hind paws from live mice were captured. Ankle joints and paws of the mice were collected and processed for histological evaluation. Spleen samples were collected to measure the Th17/Treg cells ratio, and serum samples were collected to assess cytokine and anti-type II collagen IgG levels. Monocytes and dendritic cells populations before and after ECP in vitro were detected by flow cytometry. Result ECP therapy significantly attenuated the progression of CIA, alleviated the severity of clinical symptoms in CIA mice and effectively suppressed synovial hyperplasia, inflammation, and cartilage damage. There was an expansion in the percentage of CD3 + CD4 + CD25 + FoxP3 + Tregs and a decrease in CD3 + CD4 + IL17A + Th17 cells in vivo. Furthermore, ECP reduced the serum levels of pro-inflammatory cytokines IL-6 (53.47 ± 7.074 pg/mL vs 5.142 ± 1.779 pg/mL, P < 0.05) and IL-17A (3.077 ± 0.401 pg/mL vs 0.238 ± 0.082 pg/mlL, P < 0.0001) compared with PBS. Interestingly, the depletion of monocytes during the ECP process did not lead to any improvement in clinical symptoms or histological scores in CIA mice. Moreover, the imbalance in the Th17/Treg cells ratio became even more pronounced, accompanied by an augmented secretion of pro-inflammatory cytokines IL-6 and IL-17A. In vitro, compared with cells without ECP treatment, the proportion of CD11b + cells were significantly reduced (P < 0.01), the proportion of CD11c + cells were significantly elevated (P < 0.001) 24 h after ECP treatment. Additionally, the expression of MHC II (P < 0.0001), CD80 (P < 0.01), and CD86 (P < 0.001) was downregulated in CD11c + cells 24 h after ECP treatment. Conclusion Our study demonstrates that ECP exhibits a therapeutic effect comparable to conventional therapy in CIA mice, and the protective mechanisms of ECP against RA involve Th17/Treg cells ratio, which result in decreased IL-6 and IL-17A. Notably, monocytes derived from CIA mice are an indispensable part to the efficacy of ECP treatment, and the proportion of monocytes decreased and the proportion of tolerogenic dendritic cells increased after ECP treatment in vitro.

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“…While the type of apoptosis induced in leukemic malignant T cells has not been further evaluated, in 8-MOP treated melanoma cell lines, photoactivation induced an immunogenic cell death ( 176 ). While ECP has been shown to eliminate alloreactive T cells in GVHD, it has also been reported to induce the generation of Tregs, a potentially unfavorable immune response in CTCL ( 177 ). Understanding the effect of ECP on Treg populations in CTCL in the past has been challenging given the difficulty of distinguishing malignant T cells expressing Treg markers from benign Tregs ( 178 ).…”

Section: Radiationmentioning

confidence: 99%

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

et al. 2023

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Cutaneous T cell lymphomas are a rare subset of non-Hodgkin’s lymphomas with predilection for the skin with immunosuppressive effects that drive morbidity and mortality. We are now appreciating that suppression of the immune system is an important step in the progression of disease. It should come as no surprise that therapies historically and currently being used to treat these cancers have immune modulating functions that impact disease outcomes. By understanding the immune effects of our therapies, we may better develop new agents that target the immune system and improve combinatorial treatment strategies to limit morbidity and mortality of these cancers. The immune modulating effect of therapeutic drugs in use and under development for cutaneous T cell lymphomas will be reviewed.

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Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial

Cited by 9 publications

References 12 publications

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Extracorporeal photopheresis reduces inflammation and joint damage in a rheumatoid arthritis murine model

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

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