Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice

Abstract

Mesenchymal stem cells (MSCs) have emerged as a therapeutic approach in a range of medical fields, including regenerative medicine, cancer, autoimmune diseases, and inflammatory diseases, because of their unique properties of tissue repair and major histocompatibility complex-unmatched immunosuppression. Because both in vitro and in vivo findings demonstrate that MSCs possess potent immunoregulatory functions, there has been increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation, especially in the prevention and treatment of graft-versus-host disease (GVHD). GVHD is a major cause of transplantation-related mortality, and conventional immunosuppressants frequently fail to treat patients suffering from GVHD. Following Ringden's pilot study that used third-party MSCs to treat a steroid-refractory GVHD patient, MSCs have created growing interest as a therapeutic agent for GVHD. There have been further studies which demonstrated the potentials of MSC treatment in steroid-refractory GVHD, de novo GVHD, and also GVHD prevention. However, MSCs still present limitations. The need for MSCs to be "licensed" in a pro-inflammatory environment, especially in the presence of interferon gamma, allows only a narrow window for their administration. Thus, their effects have been less clear as a preventive measure before the inflammatory environment of GVHD is established and also when administered during a chronic setting where MSCs may be alternatively licensed. In this review, we focus on the immunomodulatory properties of MSCs and their effects in relation to GVHD. Given the efficacy of MSCs in murine models of GVHD and their safety in clinical trials, it is crucial that larger clinical trials are conducted and further modifications are investigated.

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

“…The results however, remain controversial, with some groups reporting beneficial effects of MSCs treatments and other groups finding no difference in the success rates between patients that received the treatments and controls (Kim et al 2013). …”

“…RFC-1 is a component of the BRCA1-associated genome surveillance complex (BASC) that scans the genomic DNA for the presence of structural damage in DNA, activates damageresponse pathways and recruits DNA repair machinery to the damage site (Wang et al 2000). Recipient carriership of the 2351insT (rs41376448) allele of the HMGB1 gene (coding for a master transcription regulator protein tightly linked with DNA repair) was found to reduce the risk of moderate-to-severe acute GVHD, whereas homozygous carriership of the same allele in the donor cells was associated with chronic GVHD (Kornblit et al 2010). Unlike acute GVHD, chronic GVHD (provided that it is kept under control) may be associated with increased survival after transplantations of allogeneic HSCs.…”

“…Carriership of these two polymorphisms has already been identified as a risk factor for development of leukaemia, increasing the risk > 2-fold for XPD Lys751Gln and > 3.5 fold for XRCC3 Thr241Met, respectively (Hamdy et al 2011, Bănescu et al 2014). Additional research is required in order to confirm the report of Diamond et al 2011, but it could be expected that some of the polymorphisms in other genes responsible for identification and repair of DNA damage and maintenance of genomic integrity that have been already implicated in the pathogenesis of leukaemia, such as TP53 Pro72Arg, MDM2 SNP309 (rs2279744), XRCC1 Arg194Trp (rs1799782), hOGG1 Ser326Cys (rs1052134), CCNH Val270Ala (rs2230641) (Enjuanes et al 2008, Batar et al 2009, Do et al 2009, Li et al 2011) and polymorphisms that have been associated with differential outcomes after haematological disease and HSC transplantations (the above mentioned TP53 Pro72Arg and also HMGB1 3814 C-to-G (rs2249825); XPC Lys939Gln (rs2228001) and XPF C673T (Kornblit et al 2010, McGraw et al 2015, Bănescu et al 2016) and potentially, others may modulate the risk for development of donor-cell leukaemia in patients with HSC transplantations. Carriership of the variant (deletion) allele of the -1377delA (rs41369348) polymorphism in the HMGB1 gene was associated with 2-fold increased risk of relapse of the primary haematological malignancy (Kornblit et al 2010).…”

Pediatric small bowel transplantation: A single-center experience from Turkey

“…It is used as a new stem cell therapy for autoimmune diseases, solid organ transplantation, and treatment of graft-versus-host disease (13)(14)(15). For reducing ACR, BMSC treatment was used in three patients.…”

Mesenchymal Stromal Cells Prevent Allostimulation In Vivo and Control Checkpoints of Th1 Priming: Migration of Human DC to Lymph Nodes and NK Cell Activation

“…In addition to their potential for tissue repair, MSC display immunomodulatory properties and regulate both adaptive and innate immune cells [3][4][5]. In particular, MSC have been used in preclinical and clinical studies for the treatment of immune-related disorders including autoimmune diseases, transplant rejection, and graft-versus-host disease [6][7][8][9][10]. Since autologous MSC often display disease-and age-related impairments [11,12] and as their preparation is logistically challenging, cost and time consuming, the use of off-the-shelf major histocompatibility complex (MHC)-unmatched MSC would be of great advantage, provided they do not elicitate an a Berlin-Brandenburg Center for Regenerative Therapies (BCRT), b Berlin-Brandenburgimmune response.…”