Treatment of graft-versus-host disease and hemophagocytic syndrome
Graft-versus-host disease (GvHD) is a systemic syndrome that can occur following a hematopoietic stem cell transplantation (HSCT) (165). This disease results from the activation of donor-derived T lymphocytes by histocompatibility antigens from host tissues and leads to the attack of the host's body cells by these activated donor-derived T cells (166). The therapeutic potential of the administration of hMSCs for the treatment of graft-versus-host disease was investigated in 40 (33–72) out of the 132 articles (33–164) analyzed. Among them, 29 were conducted in humans (42–47, 49–71) and 11 used mice as the experimental model (33, 34, 35–41, 48, 72). Regarding the source of the hMSCs used, in 28 studies hMSCs were isolated from the bone marrow (35, 37, 42–47, 49–71, 72), in seven studies (36, 38, 39, 41, 46, 61, 65) they were isolated from the umbilical cord and in two (40, 59) from the adipose tissue. The menstrual blood (72), dental pulp (33), placenta (48) and fetal membrane (34) was used as a source of hMSCs in only one study each.
Based on timing of onset after HSCT and according to the clinical manifestations observed, GvHD can be classified as acute or chronic. Acute GvHD usually affects the skin, liver and gastrointestinal tract of the patients affected by the disease (167). On the other hand, chronic GvHD can affect any organ (168). Clinical effects commonly observed after the administration of hMSCs included an increase in the survival rates (35, 36, 39–41, 44, 45, 48, 49, 51, 56–62, 65–68, 71, 72), a decrease in the severity of the symptoms of the disease (33–36, 38–46, 52–59, 61–64, 66–68, 71) and a reduction in the incidence of acute and chronic GvHD (51, 53, 54, 65) in patients submitted to hematopoietic stem cell transplantation. Among the studies conducted in mice, the cumulative survival rate, the clinical score of the disease and the rate of change in body weight were the outcomes used by most animal studies selected in this systematic review to assess the potential of hMSCs administration for the treatment of GvHD. Among the human clinical trials selected, the primary endpoints used by most studies to assess the effectiveness of the treatment with hMSCs were: the overall survival rate; the disease-free survival rate; the progression-free survival rate; the non-relapse mortality rate; and the relapse incidence. We propose that both the disease-free survival rate and the progression-free survival rate are the most appropriate endpoints for future clinical trials when evaluating the effectiveness of hMSCs administration for the treatment of GvHD. While the disease-free survival rate should be used for patients in remission at time of HSCT, the progression-free survival rate should be used for patients that were not in remission at time of HSCT. These two primary endpoints were chosen because they are more likely to not be affected by bias, are detected earlier than the overall survival rate, include all clinically important events evaluated, and are more likely to reflect the real benefits of the treatment. Furthermore, additional endpoints such as the cumulative incidence of grade II-IV acute GVHD, the cumulative incidence of grade III-IV acute GVHD, and the cumulative incidence of moderate or severe chronic GVHD can also be used in combination with the primary endpoints selected in order to answer to other important questions about the benefits of the treatment.
In addition to the amelioration of symptoms and decrease in mortality, many studies observed a significant decrease in the pathology of the gut (35, 36, 39, 41, 48, 56, 59, 64, 67, 72), liver (35, 36, 39, 41, 48, 56, 59, 67), skin (36, 48, 56, 59, 64, 67), lungs (41, 65), and kidneys (41) of patients treated with hMSCs. In conjunction with this reduction in the pathological state, some studies also described a decrease in the serum concentration of local tissue damage biomarkers such as the markers of epithelial damage elafin (71), ccK18 (50), and K18 (50) and the markers of gastrointestinal damage sCK18f (66), Reg3α (71), and CK18 (66, 71). On the other hand, adverse effects observed after the administration of hMSCs included an increase in the rates of pneumonia (47) and infection-related death (49). Additionally, the occurrence of fatal embolism was also found to be significantly associated with the administration of hMSCs in one study (33) and, in another study (70), the reconstitution of both T and B cell function was found to be worsened after hMSCs administration. However, a study conducted by Guo et al. (43) showed that CD3−CD16+56+(NK) and CD3+CD16+56+(NKT) cells and CD3+CD8+ T cells were upregulated in 1–3 months after transplantation when hMSCs were administered, showing that the administration of hMSCs may be important in reducing leukemia relapse after HSCT.
While the development of acute GvHD is related to the activation of alloreactive T lymphocytes of the graft, the development of chronic GvHD involves both alloreactive and autoreactive mechanisms (169). The immune response of acute GvHD occurs in two phases, one afferent and one efferent. In the afferent phase, CD4+ and CD8+ T cells react to the host's class I and II alloantigens present on the surface of antigen-presenting cells (APCs) (166). This phase starts when the conditioning regimen initiates an immune response due to the damage to host tissues, such as the intestinal mucosa and liver, which results in the induction of cytokine secretion, especially IL-1 and tumor necrosis TNF-α (170). After HSCT, donor's T cells are stimulated by the IL-1 and by the costimulatory signals present, producing IL-2. Under the influence of IL-2, CD4+ and CD8+ T cells clonally expand and differentiate into effector cells, which induce the graft response against the host (170). These effector cells are activated by costimulatory molecules and proinflammatory cytokines such as IFN-γ and IL-12, giving rise to T helper 1 (Th1) effector cells, which direct even more the graft response against the host (171). In the efferent phase of GvHD, activated T cells secrete a storm of cytokines such as IL-2, IL-4, IL-3, and IFN-γ. These mediators recruit and activate effector cells, including additional lymphocytes, macrophages, and natural killer (NK) cells, which attack both donor and host tissues (170). The mechanisms of action of the hMSCs administered included effects in the proliferation and differentiation of immune cells and changes in the expression pattern of growth factors, cytokines, enzymes, prostaglandins and surface receptors and ligands. While some studies reported an increase in the levels of growth factors such as HGF (34, 72), IGF-1 (34), VEGF (34, 72), bFGF (34, 71), TGF-β (39, 41), activin A (72), and NGF (71), others demonstrated an increase in the levels of the prostaglandin E2 (34, 41, 72) (PGE2) and the enzymes IDO (39, 72), Cox-2 (72), and granzyme B (71). Generally, an increase in levels of immunomodulatory cytokines such as IL-10 (36, 58, 71) and IL-23 (71) and a decrease in the levels of pro-inflammatory cytokines such as TNF-α (35, 36, 55, 64), IFN-γ (36, 41, 55, 64), IL-1β (64), IL-2 (36), IL-8 (71), CCL2 (71), CXCL9 (71), and CXCL10 (71) following treatment with hMSCs was observed by most studies. In addition, some studies reported an increase in the serum levels of IL-6 (50, 72), a cytokine with both pro-inflammatory and anti-inflammatory properties, after administration of hMSCs while another study reported an increase in the levels of GM-CSF (71), a cytokine usually employed to stimulate the production of leukocytes in order to prevent neutropenia after chemotherapy. A change in the expression of cell surface receptors and ligands following the administration of hMSCs for the treatment of GvHD was also demonstrated by some studies. For instance, a decrease in the expression of PPAR-γ (51), IL-2 (49, 66, 71), and TNF-α (66, 71) receptors and in the CD40 ligand (71) (CD40L) was observed in some articles while an increase in the expression of the protein receptor CTLA-4 (58) and NRP-1 (72) and in the PD-ligand 1 (72) (PD-L1) and CCR2 (71) ligand (CCL7) was demonstrated by other studies.
Many of the studies selected reported an inhibitory effect in the proliferation of both B (55) and T (35, 36, 69, 72) cells after treatment with hMSCs. Some of the studies selected described a decrease in the proliferation of both CD8+ (50, 72) and CD4+ (38, 39, 50, 59) T cells after treatment of GvHD with hMSCs. However, an increase in the CD4+/CD8+ T cell ratio was also commonly observed (36, 50, 53). Specifically, some studies reported that the administration of hMSCs suppressed the clonal expansion of CD4+IFN-γ+ Th1 (40, 72) and CD4+IL-17+ Th17 (40, 50, 59, 72) cells while exhibiting an opposite effect on CD4+IL-4+ Th2 (40) and CD4+CD25+Foxp3+ Treg (40, 50, 53, 55, 58, 59, 65, 72) cells. In addition, a study conducted by Weng et al. (42) demonstrated that the administration of hMSCs stimulated the generation of CD8+CD28− T cells, which may regulate the balance between Th1 and Th2 responses. Regarding the effects of hMSCs administration in the proliferation and differentiation of B cells, a study conducted by Zhang et al. (55) demonstrated that the treatment with hMSCs inhibited the proliferation of CD19+ B cells and increased the proportion of CD5+IL-10+Breg cells within the CD19+ B cell population. On the other hand, Gao et al. (65) reported an increase in the proliferation of CD27+ memory B lymphocytes after the administration of hMSCs. Effects in the proliferation of NK cells following the administration of hMSCs were also observed in some studies. For instance, a study conducted by Jitschin et al. (50) found that the proportion of activated CD56bright NK-cells was significantly lower in patients treated with hMSCs compared to untreated patients while Gao et al. (65) described a decrease in the total number of NK cells following hMSCs administration. Some studies also reported effects in the infiltration of immune cells in organs typically affected by GvHD after treatment with hMSCs. For instance, Gregoire-Gauthier et al. (38) described that the infiltration of CD4+ T helper cells was found to be decreased in the liver and increased in spleen of acute GvHD mice after hMSCs administration. On the other hand, in a study conducted by Luz-Crawford et al. (72), infiltration of CD8+ cytotoxic T cells in spleen was found to be either decreased or increased after hMSCs administration, depending on the source of hMSCs used. Furthermore, according to Girdlestone et al. (61), administration of hMSCs previously treated with rapamycin significantly inhibited the infiltration of CD45+ cells in the spleen of acute GvHD mice.
It is possible that the secretion of immunomodulatory cytokines and growth factors by hMSCs strongly influences this inhibitory effect observed in the proliferation of B and T cells after hMSCs administration. For instance, secretion of IL-4, IL-10, TGF-β, HGF, PGE2, and PDL-1 may act on donor T cells and inhibit their activation, proliferation and differentiation into Th1 cells and stimulates their differentiation into Th2 lymphocytes and antiinflammatory Treg lymphocytes. As a consequence, the secretion of pro-inflammatory cytokines such as IL-2, IL-3, IL-12, and IFN-γ by donor T cells is also inhibited, which decreases the trafficking of reactive T cells, the recruitment of B cells, monocytes, neutrophils and NK cells and the secretion of granzymes, perforin, IFN-γ, TNF-α and antibodies by these cells. In addition, secretion of immunomodulatory cytokines and growth factors by hMSCs may act on the cells recruited by donor T cells, inhibiting their proliferation and stimulating their differentiation into immunomodulatory cells such regulatory dendritic cells, Breg cells and M2 macrophages. Therefore, the damage to organs such as lungs, spleen, gut, skin and liver would also be decreased. As a result of this reduction in the damage to host tissues, the induction of cytokine secretion in these tissues is also inhibited, further inhibiting the occurrence of the pathological process of GvHD. The mechanisms proposed by this systematic review concerning the inhibition in the progression of the pathological process of GvHD mediated by hMSCs are represented in Figure 5.
Figure 5  hMSCs inhibit the pathological course of GvHD through several mechanisms. hMSC-produced IL-4, IL-10, HGF, PGE2, PDL-1, and TGF-β inhibit the proliferation and activation of T and B cells and stimulate the generation of Breg, Treg, and Th2 lymphocytes. hMSCs inhibit the activation of dendritic cells and stimulate the generation of regulatory dendritic cells. hMSC-produced IL-6, IDO, PGE2, and TGF-β suppresses neutrophil respiratory burst, NK cell activation and macrophage polarization to M1, though favors M2 polarization. Hemophagocytic syndrome is an autoimmune disease characterized by the activation and proliferation of macrophages, T CD8+ lymphocytes and NK cells in the bone marrow and in other endothelial reticular systems (172), leading to the phagocytosis of erythrocytes, leukocytes, platelets, and their precursors and to the exacerbated production of several inflammatory cytokines, including IL-1β, IL-2, IL-6, TNF-α, and IFN-γ (173). The hemophagocytic syndrome may be primary when triggered by genetic factors or secondary when occurs due to infections, neoplasms, rheumatic diseases, HSCT or other autoimmune disorders. The clinical manifestations of the hemophagocytic syndrome include hyperferritinemia, fever, hepatosplenomegaly and cytopenias (174). In this systematic review, hMSCs were used for the treatment of the hemophagocytic syndrome in only two studies (52, 73); both of which had the bone marrow as the source of hMSCs and were conducted in humans. Both the studies selected were single case reports and used the platelet, leukocyte and reticulocyte number, the amount of hemophagocytosis of erythroblasts and myeloid cells and the serum levels of ferritin and lactate dehydrogenase as primary study endpoints. The serum levels of pro-inflammatory and immunomodulatory cytokines such as IL-1β, IL-6, IL-8, IL-10, IL-17, and IL-15 were used as secondary study endpoints as they provide a strong evidence of the efficacy of the hMSCs administration inmodulating autoimmunity. Due to the fact that the hemophagocytic syndrome is a universally fatal disease if untreated, we recommend the use of a primary endpoint that is able to reflect a change in lethality following hMSCs administration, such as the cumulative survival rate. Other outcomes such as neutropenia, occurrence of relapses and serum levels of cytokines should be used in conjunction with the primary endpoint to correctly assess the potential of hMSCs administration for the treatment of hemophagocytic syndrome. After hMSCs administration, a decrease in the severity of the disease was observed in both studies following the administration of hMSCs. Mougiakakos et al. (73) described that this decrease in the severity of the disease was accompanied by a reduction in the serum levels of lactate dehydrogenase, ferritin and triglycerides. This study also described an increase in the levels of the immunomodulatory cytokine IL-10 and a decrease in the levels of the inflammatory cytokines IL-8, IL-6, IL-15, IL-17, and TNF-α after treatment with hMSCs. Table 1 summarizes the methodology employed and the results obtained in the studies selected in this systematic review regarding the effects of the administration of hMSCs for the treatment of GvHD and hemophagocytic syndrome.
Table 1  List of in vivo studies in which the therapeutic potential of the administration of hMSCs for the treatment of GvHD and hemophagocytic syndrome was evaluated and the results obtained.
References   Autoimmune disease   Source of hMSC   Variables   Experimental model   Clinical and laboratory effects   Proposed mechanisms for the in vivo action of MSCs
(33)  GVHD  Dental pulp  Administration of MSCs alone Administration of MSCs transduced with immunosuppressive genes  Mice  ↓Clinical score↑Fatal embolism Effectiveness MSC transduced with immunosuppressive genes = effectiveness of MSCs alone  ↓Mouse splenocyte proliferation
(34)  GVHD  Fetal membrane  Administration of MSCs from amnion membrane  Mice  ↓Weight loss Effectiveness MSC from amnion membrane > effectiveness of MSCs from from chorion membrane  ↑HGF secretion↑IGF-1 secretion↑VEGF secretion↑bFGF secretion↑PGE2 secretion↓T-cell proliferation
Administration of MSCs from chorion membrane   None
(35)  GVHD  Bone marrow  Infusion of MSCs on day 0  Mice  None  ↓Donor T cell proliferation↓TNF-α
Infusion of MSCs on day 7   ↓Weight loss↑Survival rates↓Acute GvHD score↓Gut and liver pathology
Stimulation of MSCs with IFN-γ for 48 h prior to administration on day 0   ↓Weight loss↑Survival rates↓Clinical score↓Gut and liver pathology
(36)  GVHD  Umbilical cord stroma  None  Mice  ↓Clinical score↓Weight loss↑Survival rates↓Gut, skin and liver pathology  ↓CD3+CD8+ T cells↑CD4+/CD8+ ratio↓TNF-α↓IL-2↓IFN- γ↑IL-10
(37)  GVHD  Bone marrow  None  Mice  None  ↓T-cell proliferation↓IFN- γ secretion
(38)  GVHD  Umbilical cord blood  Presence of radiation-induced damage  Mice  ↓Weight loss  ↓Human/mice CD45+ cells ratio↑Human CD45+ cells total number↓Human CD3+ cells in the liver↓Human CD4+ cells in the liver
Absence of radiation-induced damage   ↓Clinical score↑Survival rates  ↓Human/mice CD45+ cells ratio↓Human CD45+ cells total number↓Human CD3+ cells in the liver↓Human CD4+ cells in the liver
(39)  GVHD  Umbilical cord stroma  Stimulation of MSCs with IFN-γ for 24 h  Mice  Not assessed  ↓CD4+ T-cell proliferation↑IDO gene expression↑TGF-β gene expression
Absence of stimulation of MSCs with IFN-γ for 24 h   ↓Clinical score↓Weight loss↑Survival rates↓Gut and liver pathology  ↑TGF-β gene expression
(40)  GVHD  Adipose tissue  Absence of stimulation of MSCs with rapamycin prior to administration Stimulation of MSCs with rapamycin prior to administration  Mice  ↓Clinical score↑Survival rates↓Weight loss Effectiveness MSCs + rapamycin > effectiveness MSCs alone  ↓CD4+IFN-γ+ Th1 cells↓CD4+IL-17+ Th17 cells↑CD4+IL-4+ Th2 cells↑CD4+CD25+Foxp3+ Treg cells
(41)  GVHD  Umbilical cord blood  Prevention study for GVHDTreatment study for GVHD  Mice  ↑Survival rates↓Weight loss↓Clinical score↓Kidney, lungs, liver and gut pathology Multiple MSCs administrations > single MSCs administration at day 0.  ↑PGE2↑TGF-β1↓IFN-γ
(48)  GVHD  Placenta  None  Mice  ↑Survival rates↓Weight loss↓Gut, skin and liver pathology  None
(59)  GVHD  Adipose tissue  Co-infusion of MSCs and Tregs Administration of MSCs alone  Mice  ↑Survival rates↓Weight loss↓Clinical score↓Gut, skin and liver pathology Effectiveness MSCs + Tregs > effectiveness MSCs alone  ↓CD3+CD4+ T-cells↓Th17 cells↑Foxp3+ Tregs cells
(61)  GVHD  Umbilical cord blood  Infusion of MSCs previously treated with rapamycinAdministration of MSCs aloneMSCs from pooled bone marrow mononuclear cells of eight “3rd-party” donors (MSCs end-products)  Mice  ↑Survival rates↓Weight loss Effectiveness MSCs + rapamycin > effectiveness MSCs alone  ↓Infiltration of human CD45+ cells in the spleen (MSCs pre-treated with rapamycin)
(72)  GVHD  Bone marrow Menstrual blood  None  Mice  ↑Survival rates↓Weight loss↓Gut and liver pathology Effectiveness MSCs from menstrual blood > effectiveness MSCs from bone marrow  ↓CD8+IFN-γ+ cells↓CD4+IFN-γ+ Th1 cells↓Th17 cells↑CD4+IL4+IL10+ T cells↑Tregs cells↑IDO↑PD-L1↑PGE2↑Activin A↑Cox-2↑IFN-γ (menstrual blood MSCs)↓Foxp3+ expression in splenocytes (menstrual blood MSCs)↑IL-6 expression↑NRP-1 expression↑HGF expression in the liver (menstrual blood MSCs)↑VEGF expression in the liver (menstrual blood MSCs)
↑CXCR4+ cells (in the menstrual blood MSCs population)↓Human CD45+ cells in spleen (bone marrow MSCs)↓Human CD45+CD8+ T cells in spleen (bone marrow MSCs)↑ Human CD45+CD8+ T cells in spleen (menstrual blood MSCs)↑ Human CD45+CD4+ T cells in spleen (menstrual blood and bone marrow MSCs)
(42)  GVHD  Bone marrow  None  Humans  ↓Dry eye symptoms↓GvHD clinical score  ↑CD8+CD28− T cells↑IL-2↑IFN-γ↓IL-10↓IL-4
(43)  GVHD  Bone marrow  None  Humans  ↑Donor engraftment↓Clinical score↓Leukemia relapse  ↑CD3+CD8+ T cell reconstitution↑CD3−CD(16+56)+ T cells reconstitution↑CD3+CD(16+56)+ T cells reconstitution
(44)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  None
(45)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  ↓CD3+/CD4+ T cells ratio
(46)  GVHD  Umbilical cord blood  None  Humans  ↑Donor engraftment↓Clinical score  None
(47)  GVHD  Bone marrow  None  Humans  ↑Pneumonia-related death  None
(49)  GVHD  Bone marrow  MSCs at first or second passage  Humans  ↑Survival rates↑Infection-related death Effectiveness MSCs at first or second passage > effectiveness MSCs at third or fourth passage  ↓IL-2 receptor in the serum
MSCs at third or fourth passage
(50)  GVHD  Bone marrow  None  Humans  ↓ccK18↓K18  ↑IL-2↑IL-6↓IFN-γ/IL-4 ratio↑CD4+/CD8+ ratio↓HLA-DR+CD4+ T-cells↓HLA-DR+CD8+ T-cells↑CD4+CD25med−hi CD127loFOXP3+ Treg-cells↓Th17 cells↑Treg/Th17 ratio↓CD56bright NK-cells
(51)  GVHD  Bone marrow  None  Humans  ↑Acute GVHD disease prophylaxis↑Survival rates  ↑FGF receptor gene↓PPAR-γ gene↓IGF-1 gene
(52)  GVHD  Bone marrow  None  Humans  ↓Clinical score  None
(53)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Chronic GVHD incidence  ↑CD4+/CD8+ ratio↑CD4+CD25+Foxp3+ Tregs cells↑T cell reconstitution (↑sjTRECs)
(54)  GVHD  Bone marrow  None  Humans  ↓Acute GVHD incidence↓Clinical score  None
(55)  GVHD  Bone marrow  None  Humans  ↓Nephrotic syndrome symptoms  ↓IFN-γ↓TNF-α↓CD19+ B cell↑Bregs cells↑Tregs cells
(56)  GVHD  Bone marrow  None  Humans  ↓Clinical score↑Survival rates↓Gut, skin and liver pathology  None
(57)  GVHD  Bone marrow  None  Humans  ↓Clinical score↑Survival rates  None
(58)  GVHD  Bone marrow  None  Humans  ↑Survival rates  ↑IL-2 receptor lymphocyte gene expression↑IFN- γ lymphocyte gene expression↑FoxP3 lymphocyte gene expression↑CTLA-4 lymphocyte gene expression↑IL-10 lymphocyte gene expression↑Foxp3+ Tregs cells
(60)  GVHD  Bone marrow  None  Humans  ↑Survival rates  ↑Anti-fetal calf serum antibodies↓Alloantibodies
(62)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  None
(63)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Bilirubin concentration  None
(64)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Skin and mucosal pathology  ↓IL-1β↓IFN-γ↓TNF-α
(65)  GVHD  Umbilical cord stroma  None  Humans  ↓Chronic GVHD incidence↓Lung pathology↑Survival rates  ↑Th1/Th2 cells ratio↑Treg cells↑CD27+ memory B lymphocytes↓NK cells
(66)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Gastrointestinal acute GVHD symptoms↓Gastrointestinal pathology↓CK18↓sCK18F↓sCK18F/CK18 ratio  ↓TNF-α receptor↓IL-2 receptor
(67)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score↓Gut, skin and liver pathology  None
(68)  GVHD  Bone marrow  MSCs from single donorsMSCs from pooled bone marrow mononuclear cells of eight “3rd-party” donors (MSCs end-products)  Humans  ↑Survival rates↓Clinical score Effectiveness MSCs end-products > effectiveness MSCs from single donors  None
(69)  GVHD  Bone marrow  None  Humans  ↑Donor engraftment  ↓Donor T-cell proliferation
(70)  GVHD  Bone marrow  None  Humans  ↓Survival rates  ↓T cell reconstitution (↓TRECs)↓B cell reconstitution (↓IgM)↓IgG
(71)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score↓CK18  ↓TNF-α receptor↓Elafin↓IL-2 receptor↓Reg3α↓HGF↓IL-8↓CCL2↓CD40L↓CXCL9↓CXCL10↑NGF↑IL-10↑IL-12↑IFN-γ↑IL-15↑CCL7↑bFGF↑GM-CSF↑TNF-α↑IL-23↑Granzyme B
(52)  Hemophagocytic syndrome  Bone marrow  None  Humans  ↓Clinical score  Not assessed
(73)  Hemophagocytic syndrome  Bone marrow  None  Humans  ↓Disease severity↓Serum ferritin↓Serum triglycerides↓Serum lactate dehydrogenase  ↑IL-10↓IL-8↓IL-6↓IL-15↓IL-17↓TNF-α
Both the methodology employed and the results obtained by each article are represented in this table. HGF, hepatocyte growth factor; IGF-1, insulin like growth factor 1; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; PGE2, prostaglandin E2; TNF-α, tumor necrosis factoralpha; IL-2, interleukin-2; IL-4, interleukin-4; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-12, interleukin-12; IL-15, interleukin-15; IL-23, interleukin-23; IDO, indoleamine-pyrrole 2,3-dioxygenase; TGF-β, transforming growth factor beta; NGF, nerve growth factor; NK cells, natural killer cells; Th1 cells, type 1 T helper cells; Th2 cells, type 2 T helper cells; Th17 cells, type 17 T helper cells; Treg cells, regulatory T cells; Bregs cells, regulatory B cells; ccK18, caspase-cleaved cytokeratin 18; K18, keratin 18; CK18, cytoskeletal keratin 18; sCK18F, soluble cytokeratin 18 fragments; PPAR-γ, peroxisome proliferator-activated receptor; sjTRECs, signal joint T-cell receptor excision circles; TRECs, T-cell receptor excision circles; CCL2, C-C motif chemokine ligand 2; CCL7, C-C motif chemokine ligand 7; CXCR4, C-X-C chemokine receptor type 4; CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgM, immunoglobulin M; IgG, immunoglobulin G; Reg3α, regenerating islet derived protein 3 alpha; GM-CSF, granulocyte-macrophage colony-stimulating factor; PDL-1, programmed death-ligand 1; Cox-2, cyclooxygenase-2; NRP-1, neuropilin-1.