miRNA in Graft-Versus-Host-Disease

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1		Martina Pitea	--	2313	2023-09-26 09:41:38	\|
2	format layout	Fanny Huang	+ 1 word(s)	2314	2023-10-07 05:15:44	\|

This entry is adapted from the peer-reviewed paper 10.3390/genes14091796

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a clinically challenging modality for the treatment of many hematologic diseases such as leukemia, lymphoma, and myeloma. Graft-versus-host disease (GVHD) is a common complication after allo-HSCT and remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. Several microRNAs (miRNAs) have recently been shown to impact the biology of GVHD. They are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation, and contribute to the pathological function of T-cells during GvHD.

miRNAs GVHD graft-versus-host disease

1. Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for various hematological malignancies and non-malignant diseases. One of the most frequent complications of allo-HSCT is graft-versus-host disease (GVHD), a clinical syndrome in which the graft recognizes the transplant recipient as foreign. GVHD is the most serious complication of allogeneic hematopoietic cell transplantation; it can cause damage to organs and systems and can lead to death. The term graft-versus-host disease (GVHD) to define this disorder is due to Morton Simonsen and was first described in 1959 ^[1].

Billingham defines three crucial requirements for the development of GVHD, which are: (1) the graft must contain immunocompetent cells, (2) the host must possess allo-antigens that can be recognized as foreign by the immunocompetent cells in the graft, and (3) the host must be unable to mount an appropriate immune response against the graft ^[2]. Risk factors for GVHD include incompatible HLA match, advanced age of recipient/donor, multiparous female donor to male recipient, use of peripheral blood stem cell grafts rather than bone marrow, intensity of regimen conditioning, and CMV serological status ^[3]. GVHD has classically been divided into acute (aGVHD) or chronic (cGVHD) subtypes based on the time of onset before or after posttransplant day 100. Acute GVHD has several grades (grade 0–4), depending on the number and extent of organ involvement. Patients with grade 3 or 4 GVHD have a poor prognosis ^[4].

Thanks to the recently developed prophylactic strategies ^[5], incidences of aGvHD grades 2–4 decreased from 40% to 28% and the overall survival (OS) of patients experiencing GVHD has improved ^[6], but there is still a need for further progress. On the other hand, cGvHD remains the prevailing cause of non-relapse mortality (NRM) in patients surviving longer than two years after allo-HCT. New insight into the pathogenesis of GVHD could be the basis for the development of novel immunosuppressive therapies for the treatment of GvHD which are more effective and therefore able to decrease the administration of corticosteroids and lower the NRM of patients following allogeneic HSCT.

2. miRNA Involved in aGVHD

Although miRNA studies in relation to GVHD are still in their infancy, miRNA-155 was the first miRNA to be associated with aGVHD ^[7]. In 2013, Xiao’s group identified a group of plasma miRNAs as potential biomarkers for aGVHD. They drew their attention to 6 miRNAs (miRNA-423, miRNA-199a-3p, miRNA-93*, miRNA-377, miRNA-155, and miRNA-30a) that were significantly upregulated in the plasma of aGVHD patients compared to non-GVHD patients after allo-HSCT. In vivo experiments showed that miRNA-155 expression was upregulated in the T cells of mice with severe aGVHD after allo-HSCT and instead a reduction in miRNA-155 results in decreased aGVHD severity and prolonged survival in mice ^[8]. The researchers focused their attention on miRNA-155 because it is encoded within the integration cluster of B cells and is important for the regulation of acute inflammation and innate immunity. miR-NA-155 expression can be activated by inflammatory mediators, such as IFN-α/γ and TNF-α ^[9], and Ceppi et al. ^[10] proposed that it functions as part of the negative feedback loop that controls inflammatory cytokine secretion by LPS-induced DC activation. Xiao’s research team identified 6 miRNAs, those mentioned at the beginning of this paragraph, that were present in the plasma of aGVHD patients involved in inflammation, tissue damage, regulation of cell proliferation, and tissue repair. In particular, miRNA-155 plays a key role in the regulation of inflammation and immune responses ^[11]. Indeed, it appears this miRNA is upregulated in the effector T cells of aGVHD mice and that miR-155 expression in lymphocytes is essential for lethal aGVHD in mice ^[7]. This result has been confirmed by other researchers over the years, for example Lin-Na Xie’s group in 2014 showed that miRNA-155 expression was upregulated in the T cells of mice developing aGVHD after allo-HSCT and the blockade of miRNA-155 expression indicated aGVHD severity, which decreased after allo-HSCT and survival was prolonged in mice ^[12]. This study highlighted that miRNA-155 level correlates with aGVHD severity; miR-155 expression was upregulated in patients with third and fourth stage aGVHD, i.e., severe stages. Furthermore, in patients with intestinal GVHD, the expression of miRNA-155 was particularly higher than that of the hepatic GVHD group. In 2016, the Atarod’s group started to investigate whether the expression of two miRNAs (miRNA-155 and miRNA-146a) could be used to predict aGVHD before the onset of the disease. This knowledge could make clinical interventions possible before the onset of the disease and, therefore, prevent the complications associated with aGVHD ^[13]. This study showed that the statistical interaction of miR-146a and miRNA-155 expression levels at day +28 post-transplant was significant in predicting aGVHD incidence, and investigation of the data revealed the conditional regulation mechanism wherein when both miRNAs were expressed at lower levels, there was a higher incidence of aGVHD. This observed statistical interaction is related to the “checkpoint” differential mechanism shown by Schulte et al. ^[14], in which by using various immune system stimulators, such as lipopolysaccharides (LPS), that trigger the expression of miRNA-146a ^[8] the authors showed that miRNA-146a was upregulated first, thus initiating the inflammatory response. This underscores the concept hypothesized that there is a time to onset of miRNA circulation. miRNA-155 expression was only altered when miRNA-146a levels of inflammatory tolerance were exceeded ^[15].

This may explain why higher miRNA-155 expression levels have been observed in both the serum and gut of patients at the time of aGVHD onset, which is the effector phase of the GVHD cycle ^[16]. Their results support the mice aGVHD study which showed that miRNA-146a expression levels were lower in severe aGVHD cases ^[17]. This may suggest that the overexpression of miRNA-146a prevents an inflammatory response and may have a protective role in innate immunity, the negative regulation of T-cells from donors by targeting TNF receptor associated factor 6 (TRAF6), and the subsequent TNF transcription inhibition ^[18]. The pathophysiology of GVHD is very complex and the study of this pathology is even more complex because most of the studies in the literature focus on animal models, which cannot fully mimic the pathophysiology of human GVHD. A clinical analysis of blood levels of specific miRNAs in patients with GVHD could be related to the development, diagnosis, and prognosis of GVHD.

In recent years, specifically in 2021, Crossland’s research team conducted a study by performing a comprehensive expression profile of miRNA-146a, miRNA-155, and miR-NA-155* expression in the target tissue and biofluids of patients with aGVHD and its post-HSCT expression ^[19]. Their findings are consistent with previously published observations that miRNA-155 and miRNA-146a play opposite roles during inflammation. In a transplant setting, as previously described, both miRNA-155 and miRNA-146a can be induced by LPS, which is a central component in triggering aGVHD pathology. These studies demonstrated that the expression of miRNA-155 and miRNA-146a is elevated in gastrointestinal aGVHD (gastrointestinal tract) compared with patients without gastrointestinal GVHD; expression was also elevated in the skin of patients with cutaneous GVHD compared with normal control skin (only the miRNA-155) and compared to pre-HSCT patients and patients without cutaneous GVHD (only the miRNA-146a). Furthermore, both miRNA-146a and miRNA-155 expression were elevated in the serum and urine of patients with generalized aGVHD at day 14 before the onset of symptomatic disease and also at aGVHD diagnosis. These results further support an important role obtained by the combination of miRNA-155 and miRNA-146a in aGVHD patients; however, the link between their involvement in generalized inflammation and specific organ pathophysiology requires further systemic investigations to confirm this correlation ^[20]^[21].

3. miRNA Involved in cGVHD

Chronic graft versus host disease (cGVHD) remains a leading cause of mortality and morbidity after allogeneic hematopoietic cell transplantation (allo-HCT). cGVHD is characterized by systemic inflammation, multiorgan fibrosis, and increased risk of infection ^[22]. Thus, cGVHD can be said to be a pleiotropic multiorgan syndrome involving tissue inflammation and the development of fibrosis, ultimately leading to organ dysfunction ^[23]. The role of miRNAs has also been studied in GVHD; however, most of these studies have been performed in aGVHD and researchers' knowledge of miRNAs in cGVHD is generally limited and lacking due to the complexity of this disease, especially as it involves several organs simultaneously. There is a time window much studied by researchers, namely the one that exists between the appearance of symptoms and the beginning of the “circulation” of biomarkers. In fact, the primary objective of most studies is to study the time of onset of the disease, i.e., the window that allows for early diagnosis of cGVHD rather than an already advanced stage with very serious symptoms already evident, and it is precisely in this stage that miRNAs are of vital importance. Reikvam’s group, in 2022 ^[24], found that miRNA analysis was feasible in frozen serum samples and that the quality controls for the samples were satisfactory even after several years of freezing. They identified a heterogeneous miRNA pattern among allo-HSCT recipients, and a large amount of miRNA was detected in the majority of patients. Hence, their study highlighted the possibility of identifying large miRNA profiles among allo-HSCT recipients 1 year after transplantation. Initially looking for discriminatory miRNAs differentially expressed between patients who developed cGVHD and those who did not develop cGVHD, given the pleiotropic effects of miRNAs, the authors investigated miRNA profiles rather than individual miRNAs. Using bioinformatics tools to study miRNA profiles in allo-HSCT recipients, they identified different patient groups classified according to miRNA profiles. Most of the identified miRNAs were upregulated among cGVHD patients; indeed, the investigators focused their attention on miRNA-365a-3p as it was the most significantly altered miRNA among patients with and without cGVHD. This miRNA has aroused great interest as a previous study demonstrated that miR-365a is associated with nuclear factor κ-B (NF-κB) and the induced expression of the NF-κB subunit induces an upregulation of the promoter activity of the miRNA-365 ^[25]. NF-κB is involved in the stimulation of the expression of several inflammatory mediators and is thought to be crucial in the pathophysiology of GVHD ^[26]. The second identified miRNA, miR-148a-3p was also one of the miRNAs highly associated with cGVHD; it was also previously found to be significantly increased in GVHD patients ^[27]. Furthermore, miR-148a appears to activate Th1 cells, and the induced expression of miRNA-148a is believed to be crucial for chronic inflammation ^[28], concurrently, however, miRNA-148a downregulates the expression of the proapoptotic gene Bim, resulting in the survival of T cells that generate inflammation. Another miRNA associated with cGVHD in their study, miRNA-378a-3p, was previously found to be differentially expressed in patients with primary Sjogren’s syndrome compared with healthy controls. This chronic autoimmune syndrome has several common features with cGVHD, particularly symptoms from glands similar to cGVHD, and thus may indicate a potential role of miRNA-378a-3p in this process ^[29].

A very recent study by Lacina’s group in 2022 ^[30] sought to establish a panel of human EV miRNAs isolated from the plasma of a group of post-HSCT patients. They identified a potentially upregulated miRNA in cGVHD, miRNA-29c-3p, which has been extensively studied in various other diseases. It is reported in the literature in which it appears to be downregulated in acute lymphoblastic leukemia ^[31]. Furthermore, many studies have established that miRNA-29c-3p suppresses tumor cell proliferation and migration ^[32]^[33]. This study compared a group of only three patients who developed cGVHD with a group of four patients without cGVHD, with samples collected 3 months after transplantation. The number of patients studied was rather low as was the study time; therefore, the results presented should be treated with caution and are subject to validation in larger patient cohorts.

There are many studies concerning cGVHD and they are not very detailed, this is because this disease involves different organs and it is difficult to identify the upstream mechanism. It is of fundamental importance, precisely for this reason, to identify a miRNA, or a cluster of miRNAs, or more generally a biomarker that can help clinical researchers with the diagnosis and monitoring of such a complex disease. So, although there are several pathways that have identified the potential miRNAs involved in cGVHD, they still need to continue to be studied.

4. Conclusions

Acute and chronic GVHD represent the main specific post-transplant complications affecting a patient’s life. The crucial point that distinguishes acute from chronic is the time of onset, followed by different clinical features, and above all the immunopathological mechanisms ^[34]. Acute GVHD (aGVHD) develops within the first 100 days posttransplant and affects the gastrointestinal tract, liver, skin, eyes, and oral mucosa as target organs ^[35]. Chronic GVHD (cGVHD) represents a delayed complication associated with transplantation and significantly reduced quality of life because it is a complicated multiorgan inflammatory syndrome ^[36]. Thus, timely diagnosis of GVHD is very important for patient outcomes as it is the main question that researchers seek to answer, and for this reason early biomarkers must be discovered for the prevention of transplant-associated morbid complications ^[37].

The discovery of miRNAs has triggered intense research to determine their role in normal and malignant haematopoiesis. The altered miRNA levels in cancer and healthy cells allow for the potential use of circulating miRNAs as diagnostic biomarkers. Researchers wanted to highlight the advances reported in the literature regarding circulating miRNA levels in plasma or EVs, which represent a promising tool not only for aGVHD but also for the diagnosis, prognosis, and prediction of cGVHD. Therefore, miRNAs represent the future of diagnostics and monitoring of many diseases and studying them and getting to know this world is essential for scientific progress.

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Subjects: Transplantation

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Martina Pitea

Filippo Antonio Canale

Gaetana Porto

Chiara Verduci

Giovanna Utano

Giorgia Policastro

Caterina Alati

Ludovica Santoro

Lucrezia Imbalzano

Massimo Martino

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Update Date: 07 Oct 2023

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