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.