Introduction:
Hematopoietic stem cell transplantation (HSCT) is the last therapeutic approach among the various medical treatments that can cure complicated hematological malignancies, improve dysfunctional hematopoietic stem cells and induce the tolerance in solid organ transplantation. Over past 4 decades, more than one million patients have been treated with HSCT and have benefited from a return to a healthy and effective life. Every day new solutions are applied to the use of HSCT until basic science concepts are fully visualized in the clinic. Despite these successes, many challenges remain, such as understanding the biology of immune cells and their ability to detect malignancies. The valuable findings in this area have led to advances in the use of acquired immune cells such as natural killer cells, T cells, regulatory cells and the application of new therapeutic approaches for serious hematological malignancies and other disorders(1). GvHD is the main cause of allogeneic stem cell transplant related mortality and occurs when donor’s T cells do not show tolerance against specific proteins on host cells(2). There are two kinds of GvHD. Acute form (aGvHD) that usually occurs before 100 days of transplantation. If it occurs 100 days after bone marrow transplantation, it is considered as a chronic GvHD(3) Of course this classification is not accurate and it is said that it should be confirmed by assessing the biopsy of the affected organ. On the other hand, there are some other disorders that occur in the skin, Gastro intestinal tract or liver that are not related to GvHD such as CMV related diarrhea(4). Based on the source of the donor and the similarity of the patient with the donor in terms of HLA, aGvHD occurs in between 30 and 80% of hosts (5). There are several methods for prevention and control of GVHD, including corticosteroids (especially prednisolone) as the first line therapeutic approach. But drug resistance to immunosuppressive drugs in some patients on one hand, and infection due to overuse of them on the other hand, has failed this treatment in 30-40% of transplanted patients(6).It is now believed that substituting preventive methods for GVHD rather than treating it is more reliable. Mesenchymal Stem Cell (MSC) Therapy as a new therapeutic approach has been used for reducing the risk of GvHD(7).
Specific features of MSCs such as, low MHCI expression and non-MHCII expression, presence of co-stimulatory molecules CD80, CD86 and CD40(8, 9), inducing the down regulation of IFNγ by Th1 and increasing the secretion of IL12 BY Th17, inducing the secretion of IL4 by Th2, increasing the regulatory T cells, induction of peripheral tolerance and inhibition of proinflammatory immune response(10-12) have made these cells as a great candidate for bone marrow transplantation. These cells co-localize with HSCs in normal bone marrow and produce factors that recruit and regulate stem cells(13). It has been shown that co-transplantation of MSCs and HSCT reduce the risk of GvHD and is also effective in the treatment of GvHD. Numerous studies have shown different results and even 100% efficacy has been reported(14). And also it is reported that in the case of using these cells from day zero (day of HSCT) to 30th day, they can have a role of prophylaxis for GvHD and from day 30 onwards play the role of treatment for graft-versus-host disease(2). In a study, 4 biomarkers 1L2Ra, TNFR1, HGF, and IL8 were identified with increased expression in the serum of patients with GvHD(15). Another study showed that high concentrations of these cytokine receptors at days 14 and 21 were significantly correlated with the likelihood of GvHD(16). Soluble IL-2R has also been shown on day 7 be to a predictive factor for GvHD(17). Approximately 60% of patients develop acute gastrointestinal GvHD after Alo-HSCT. REG3a (regenerating islet-derived 3-alpha) is a type C lectin secreted from paneth cells and its plasma concentration is associated with disease activity in inflammatory bowel disease, and some studies have suggested that as a biomarker for gastrointestinal GvHD (18, 19).TNF-α (tumor necrosis factor α) induces GVHD by enhancing the amplification of donor immune responses against host tissues and direct toxicity to target organs. Studies have shown that changes in plasma TNFR1 levels are associated with the severity and incidence of GVHD and survival of patients. It has also been suggested that if the three markers sIL-2R, sCD8 and sTNFR1 be examined simultaneously, it will be possible to detect aGVHD before the appearance of symptoms(20, 21). It is noteworthy that REG3α, which is secreted from paneth cells, has a regulatory effect for Gram-positive gastrointestinal bacteria and can differentiate between GVHD-induced diarrhea from non-GVHD one. REG3α is one of the most important biomarkers confirmed for aGVHD(22). TNFR1 is a receptor for the inflammatory cytokine TNFα that can change to the soluble form after binding to its ligand. Although this biomarker is not specific for aGVHD, its level is strongly correlated with the severity of GVHD, response to treatment, mortality from any factor except of relapse and patient survival(20). ST2 is a receptor against IL33 and is secreted in response to inflammatory stimuli and induces an inflammatory phenotype in T lymphocytes(23). The sDNAM1 molecule (sCD226) (An activating immunoreceptor) is a member of the super immunoglobulin family that is expressed on the surface of T, NK cells and large number of hematopoietic and non-hematopoietic cells. The soluble form of this molecule is also available in plasma. Recently, sDNAM1 has been implicated in the pathogenesis of aGVHD(24). Since sDNAM1 is a potential biomarker for predicting aGVHD on day 7 (7 days before transplant), we have planned to measure the concentration of that in patients’ serum prior to HSCT and afterwards to confirm the effect of co-injection of MSC with HSCT. By examining the panel of TNFR1, REG3α and ST2, we can assess the risk of GVHD-induced NRM, and by monitoring the serum level of sDNAM1, we can evaluate the probability of aGVHD occurrence and finally evaluate the effect of MSC injection on outcome of transplantation.
Given that co-injection of MSC with HSCT has a significant role in modulating the immune system and may possibly prevent GVHD as the deadliest complication of hematopoietic stem cell transplantation, The aim of this study was to evaluate the effect of simultaneous injection of MSC with HSCT and to monitor its efficacy through serial examination (days 7 +, + 14 +, + 21 + and + 28) of TNFR1, REG3α, ST2 and sDNAM1.