Table of Contents  

Ringdén: Graft-versus-host disease, a major complication after stem cell transplantation – home care for prevention and stromal cells for therapy


Allogeneic haematopoietic stem cell transplantation (HSCT) can cure a number of haematological malignancies such as leukaemias and lymphomas.1,2 The aim of using high-dose chemoradiotherapy is to kill as many malignant cells as possible and then rescue the patient using a haematopoietic stem cell graft. HSCT can also cure non-malignant disorders of the haematopoietic system, such as severe combined immunodeficiency and severe aplastic anaemia.35 HSCT may also be used as enzyme replacement to treat a variety of inborn errors of metabolism.611 Patients undergoing HSCT may have severe complications including toxicity of conditioning, infections by bacteria, fungi and viruses, and immunological complications such as graft failure and graft-versus-host disease (GVHD). Donor T-cells are responsible for triggering GVHD after activation by recipient antigens, which are expressed on host cells in the form of major histocompatibility complex, class I or class II antigens, viral antigens or minor antigenic peptides, including epithelial cell-associated antigens.1216 Antigen-presenting cells, dendritic cells or macrophages present the antigens to T-cells. Cytokines then stimulate T-helper cells, which release interleukin 2 (IL-2), activating cytotoxic T-cells. Natural killer (NK) cells and macrophages also participate in this process. The main target organs for acute GVHD in humans include the skin, gut and liver. Acute GVHD is graded on a scale from 0 to IV, where grade IV is life-threatening.17 Risk factors for acute GVHD include human leucocyte antigen (HLA) disparity between recipient and donor, female donor to male recipient, the host environment and seropositivity for several herpesviruses.12,18,19

As prophylaxis, cyclosporine and methotrexate were equally effective in preventing GVHD.20 However, the combination of cyclosporine and a short course of methotrexate was superior to monotherapy and has been the gold standard for prevention of GVHD.21,22 An effective way to prevent GVHD is T-cell depletion of the graft. However, this may increase the risk of graft failure and leukaemic relapse.23,24

In unrelated donor transplants, antithymocyte globulin (ATG) decreased the risk of acute GVHD and improved survival.2527 A dose-finding study of ATG given to patients receiving unrelated transplants showed that a low dose increased the risk of severe acute GVHD, while a high dose increased the risk of serious infectious complications.28 Intermediate doses of ATG were balanced to give an optimal outcome. First-line treatment of acute GVHD include high doses of steroids29 and it was seen that early treatment may decrease the risk of severe acute GVHD.30 Patients with severe acute GVHD who failed treatment of steroids have an extremely poor outcome.31 Other treatments that have been tried for severe acute GVHD include ATG, monoclonal antibodies against T-cells (for instance OKT-3), anti-IL-2 antibodies, anti-IL-2 receptor antibodies, psoralene and ultraviolet light, mycophenolate mofetil, pentostatin, sirolimus, thalidomide and almost all immunosuppressive treatments.32 Transplant-related mortality increases with increasing grade of acute GVHD.33

Chronic GVHD generally appears from 3 months and later after HSCT and resembles autoimmune disorders.34 Symptoms include generalized sicca syndrome, oral mucositis, oesophageal and vaginal strictures, malabsorption, wasting, liver disease, pulmonary insufficiency, bronchiolitis obliterans, myositis, neuropathy and immune deficiency.35 Chronic GVHD may be graded as limited or extensive, or mild, moderate or severe.36 Chronic GVHD may be treated by steroids, cyclosporine, tacrolimus, azathioprine, 1 Gy of total body irradiation, thalidomide, mycophenolate mofetil, sirolimus or anti-B-cell antibodies.12,37

The graft-versus-cancer effect

Weiden et al.38 reported that patients with GVHD, especially chronic GVHD, had an increased probability of being in remission. Twins who underwent HSCT and did not develop GVHD ran a higher risk of relapse than recipients of grafts from HLA-identical siblings.39,40 A European study showed that chronic GVHD had a stronger antileukaemic effect than acute GVHD in patients with acute leukaemia;41 the best leukaemia-free survival was seen in patients with mild acute and mild chronic GVHD.33,42 A graft-versus-leukaemia effect may also be seen in the absence of GVHD.43 This effect is not different using HLA-matched unrelated donors compared with HLA-identical sibling transplants.44 Bacigalupo et al.45 showed that in patients with acute myeloid leukaemia a high dose of cyclosporine was associated with an increased risk of leukaemic relapse, compared with a lower dose.45 We attempted to take advantage of the graft-versus-leukaemia effect by reducing the immunosuppressive therapy.46 By giving low doses of cyclosporine combined with methotrexate and discontinuing immunosuppression early, we were able to increase the risk of mild acute and chronic GVHD, and reduce the risk of leukaemic relapse. This strategy improved the long-term leukaemia-free survival.47 It is also possible to enhance the graft-versus-leukaemia effect by treatment with immunocompetent donor T-cells, known as donor lymphocyte infusion (DLI).48 Patients receiving DLI at an early stage, for example molecular or cytogenetic relapse, have a better response to this therapy than patients treated for more advanced haematological relapse.49 There also appears to be an antileukaemic cell-dose effect. Recipients of syngeneic grafts receiving a higher than median donor nucleated cell dose > 3 × 108/kg had a reduced risk of relapse compared with those receiving a lower cell dose.50 In another study, we found that recipients of peripheral blood stem cell transplants from HLA-identical sibling grafts receiving more than the median dose (≥ 6 × 106 CD34+ cells/kg) had a reduced risk of relapse and improved leukaemia-free survival compared with those receiving a lower stem cell dose < 6 × 106/kg.51

Haematopoietic stem cell transplantation has also been tried in patients with metastatic solid tumours and a poor prognosis. Childs et al.52 were the first to report an HSCT-associated antitumour effect in metastatic renal carcinoma. This group reported an overall response rate of 44% in 50 patients who underwent HSCT for metastatic renal carcinoma.53 Such an antitumour effect in renal carcinoma was confirmed by our group and in Europe.54,55 Survival was improved particularly in those treated with DLI and who developed chronic GVHD, being 70% at 3 years after HSCT.54

Other solid tumours in which HSCT has induced an antitumour response include metastatic colon carcinoma, ovarian carcinoma and pancreatic carcinoma.5659 We combined liver transplantation as debulking with HSCT in patients with advanced liver cancer.60,61 Most patients with various advanced solid tumours died of progressive disease.55 However, 7 years ago we performed Whipple’s surgery in two patients with pancreatic carcinoma, followed by HSCT. Both patients are alive and free of tumour at the time of publishing; in contrast, 16 control patients who did not have an HLA-identical sibling donor and only underwent radical Whipple’s surgery died from tumour progression within 1 year (Omazic B and Ringdén O, Karolinska Institutet, 2014, unpublished data).

Home care during the neutropenic phase after allogeneic haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation patients are, as a rule, treated in laminar airflow rooms or in isolation rooms in the hospital for protection against infectious complications.6265 For 15 years we challenged this routine by letting patients living within 1 or 2 hours’ driving distance from our hospital be treated at home after HSCT.66 The patients received conditioning and the graft at our unit, but after this they went home. An experienced nurse from our unit visited the patient once or twice daily until engraftment and an absolute neutrophil count of > 0.5 × 109/l was achieved. When 36 patients had been treated at home, we compared them with control patients treated in the hospital.67 The patients spent a median of 16 days at home (range 0–26 days), but if they had a fever or other problems they were admitted to the hospital for antibiotics and could then return home. Before discharge to the outpatient clinic after HSCT, the home-care patients spent a median of 4 days (range 0–39 days) in the hospital. Among the advantages, the home-care patients were discharged earlier [relative risk (RR) 0.33, P = 0.03], had fewer days on total parenteral nutrition (RR 0.24, P < 0.01), fewer acute GVHD grades II–IV (RR 0.25, P = 0.01), lower transplant-related mortality (TRM) (RR 0.22, P = 0.04), and lower costs (RR 0.37, P < 0.05) than the control patients treated in hospital. Survival at 2 years was 70% in the home-care group compared with 57% in the control group (P < 0.03). Thereafter, home care became routine.

An unexpected finding was that home-care patients were less likely to develop grade II–IV acute GVHD, 17% compared with 44% in the control patients (P < 0.01). There may be several reasons for this. First, patients at home had better nutrition; second, there was a trend for the prevalence of bacteraemia and infections, which can trigger GVHD, to be lower in home-care patients; and, third, the bacterial environment at home may be safer than in hospital, where many strange and resistant bacterial strains may exist. As an example, gnotobiotic mice have a lower risk of developing life-threatening GVHD.68,69 A study in patients undergoing HSCT for severe aplastic anaemia also found that those treated in laminar airflow rooms were less likely to develop acute GVHD than those treated in regular hospital rooms.70

It is also cheaper to be treated at home.66 Home-care patients can be discharged earlier to the outpatient clinic and required less total parenteral nutrition, antibiotics and, in addition, TRM is reduced and more patients survive.

We feared that the home-care patients might have an increased risk of relapse compared with patients treated in the hospital, as there is an association between GVHD and a reduced risk of leukaemic relapse, as discussed above. There is also a close correlation between acute and chronic GVHD.35,71 Therefore, we completed a long-term follow-up of outcome in the home-care patients with emphasis on chronic GVHD, relapse and survival.72 The cumulative incidence of chronic GVHD was 52% in the home-care group compared with 57% in the hospital controls. TRM was 13% and 44% respectively (P = 0.002). The probability of relapse was similar in the two groups, 39% in those treated at home and 29% in the hospital controls. Four-year survival was 63% in the home-care patients as opposed to 44% in the controls (P = 0.04). In multivariate analysis, the only factor significant for poor survival was acute GVHD grades II–IV (relative hazard 2.41, P = 0.005). If GVHD was excluded, home care was associated with better survival (relative hazard 0.23, P = 0.019).

In contrast to many other modalities decreasing GVHD, home care seems to be optimal because it reduced acute GVHD and TRM, but had no effect on chronic GVHD and relapse. Thereby, survival was improved.

A study at our centre found a correlation between the number of days with no oral intake, before the diagnosis of acute GVHD, and the incidence of grade III–IV acute GVHD. In multivariate analysis, no oral intake was associated with acute GVHD grades III–IV (odds ratio 7.66; P = 0.016).73 Therefore, we suspected that the lower incidence of acute GVHD among home-care patients may be due to better oral intake compared with patients isolated in hospital.67 We therefore carried out a new matched-pair analysis with 76 home-care patients matched with a similar number of hospital controls – matched for age, sex, diagnosis, disease status, type of donor, conditioning, ATG, stem cell source and GVHD prophylaxis. Multivariate analysis showed that improved oral nutrition was strongly correlated with a decreased risk of acute GVHD grades II–IV [hazard ratio (HR) 0.95, P = 0.014] compared with home care (HR 0.49, P = 0.06).74 The conclusion from this study was that oral nutrition is a strong factor that contributes to the reduced risk of acute GVHD in patients treated at home compared with those treated in the hospital, where total parenteral nutrition is more common.

As a result, we improved oral nutrition in the hospital by having a special nutritional team of nurses. This team had the task of encouraging the patients in the hospital to increase their oral intake, with the aim of decreasing the incidence of acute GVHD. This nutritional team was introduced at our centre on 1 September 2006. We completed a new matched-pair analysis of 146 home-care patients and 146 hospital control patients.75 In this study we compared four groups, original home-care patients and original control patients (before 1 September 2006), and new home-care patients and new control patients (after 1 September 2006 when the nutritional team was introduced). We found that oral nutrition was indeed significantly improved in the hospital. The median oral intake in the hospital control patients before 1 September 2006 was 18.5 kcal/kg/day, compared with 25.6 kcal/kg/day in the new control patients (P = 0.002). However, this did not decrease the risk of acute GVHD in the new control patients. Among the four groups, the prevalence of acute GVHD grades II–IV was 15% in the original home-care patients (n = 76). Among the other three groups, acute GVHD grades II–IV occurred in 32–44% of the patients, but TRM did not differ between the four groups. There was a correlation between oral nutrition and low incidence of acute GVHD (P = 0.02). However, there was a stronger correlation in univariate analysis between number of days at home and incidence of acute GVHD (P = 0.005). In multivariate analysis, home care versus hospital was associated with a lower incidence of acute GVHD (HR 0.41, P = 0.02), but number of days at home was even more significant (HR 0.92, P = 0.004). Oral nutrition was not associated with a decreased risk of acute GVHD (HR 0.98, P = 0.13). Probability of relapse was the same in the home-care patients, 30%, as the hospital control patients, among whom the rate of relapse was 28%. There was a trend for better survival in the home-care patients than in the hospital control patients (P = 0.07). The conclusion from 15 years’ experience of home care was that home care is safe and that many days spent at home is correlated with a low risk of acute GVHD. Subsequent to this, we now encourage home-care patients to stay at home as many days as possible and to be sent back home even after readmission to the hospital and treatment with antibiotics – home care is encouraged.75 This practice has now started in the USA and Germany.

Stromal cells for treatment of graft-versus-host disease and toxicity

Definition and properties of mesenchymal stem cells

Mesenchymal stem cells (MSCs) are isolated from bone, fat and fetal tissues, cord blood and the placenta.7678 Friedenstein et al.79 were the first researchers to describe MSCs.79 MSCs are rare and, in the bone marrow, they have been estimated to account for 1 out of 10 000 nucleated cells. MSCs may be useful in regenerative medicine because they can differentiate into several cells of mesenchymal cell lineage, such as bone, cartilage, tendon, cardiomyocytes, muscle or fat.80,81 MSCs may also be useful for haematopoietic support because they secrete several cytokines that influence the differentiation of haematopoietic stem cells82,83 and they stain positive for CD29, CD73, CD90, CD105 and CD166.81 However, there is no specific marker to identify MSCs as they are negative for haematopoietic markers such as CD34, CD45 and CD14. MSCs from bone marrow have the capacity to differentiate into bone, cartilage and fat after addition of exogenous factors.79,81,84 MSCs are not true stem cells because they cannot maintain a whole tissue compartment and cannot regenerate; however, they are multipotent in vivo and have the capacity to differentiate after in utero infusion in to newborn mice and chicken embryos.85,86

Immunogenicity and homing

Mesenchymal stem cells express HLA class I molecules on the cell surface, but not HLA class II84 – only after stimulation with interferon-γ can HLA class II be expressed on the cell surface. MSCs induce very low immunogenicity and low proliferation even after differentiation to bone, chondrocytes or adipocytes.87 MSCs are not lysed by cytotoxic T-cells to the same extent as target leucocytes from the same individual.88 NK cells capable of lysing K562 leukaemia target cells induced little lysis of MSCs. Fas-ligand and co-stimulatory molecules, such as B7-1, B7-2, CD40 and CD40L, are not expressed on MSCs.89 Human MSCs were rejected when they were injected into infarcted rat myocardium, demonstrating that xenografting rejection occurs.90 Even in the case of auto- or allo-transplantation, MSCs do not seem to be long-lived because they are extremely difficult to detect in vivo after infusion into humans.91 Infused MSCs first home to the lung and thereafter to the liver and spleen, and are subsequently detected in small numbers in almost all organs.92,93 We were able to demonstrate DNA from donor MSCs at autopsy in the gut, abdominal lymph node and urinary bladder, associated with GVHD of the gastrointestinal tract and haemorrhagic cystitis.94,95

Immune modulation

I became interested in MSCs because they have the ability to inhibit T-cell alloreactivity. Thus, the mixed lymphocyte culture (MLC) reaction was inhibited by MSCs.84,87,89,96,97 Lymphocyte response to phytohaemagglutinin was inhibited in enriched CD3+, CD4+ and CD8+ T-cells by MSCs.98 MSCs constantly inhibited MLC at high concentrations, but variably inhibited and stimulated MLC when used at low concentrations (1:1000).84 We also found that MSCs induce suppression in MLC after differentiation to osteocytes, chondrocytes and adipocytes.87 Interferon-γ stimulation of MSCs enhanced suppression in MLC using undifferentiated or differentiated MSCs. When MSCs were added to the MLC, specific cytotoxic T-cell lysis was inhibited.88 However, no inhibition was seen when MSCs were added in the cytotoxic phase of the 51Cr release assay. Inhibition by human alloreactivity in vitro in MLC was caused by soluble factors, because MSCs inhibited response in MLC even if they were separated by a transwell membrane.88 MSCs affect T-cells, B-cells, dendritic cells and NK cells, and almost the whole immune system.99 However, B-cells are stimulated to IgG secretion when co-cultured with MSCs.100 Regulatory T-cells and activated T-cells are increased after MSC stimulation.101 A variety of factors are used by MSCs to suppress immune responses. Some of these factors are constitutively produced by MSCs, such as HLA-G,102 prostaglandin E2103 and galectines.104,105 MSCs can also be activated by stimulation of their toll-like receptors.105 An important mediator of suppression by MSCs is the T-cell inhibitory enzyme indoleamine-2,3-deoxygenase (IDO).106 MSC-produced IDO is involved in the induction of regulatory T-cells and inhibition of Th17 differentiation.107,108 MSC-derived IDO also promotes differentiation of macrophages towards an M2 phenotype.109 Activated MSCs can modulate adaptive immune cells through contact-dependent mechanisms that include activation of the PD-1 passway,110 fas-mediated T-cell apoptosis,111 engagement of VCAM-1 and ICAM-1,112 or through up-regulation of CD39 and increase in adenosine production.113 Nitric oxide synthesis is a main mediator of MSC-induced suppression in mice.114

Mesenchymal stem cells and animal models of graft-versus-host disease

Several mouse studies found no effect on GVHD using MSCs at any dose.115,116 Some studies showed improved survival following infusion of MSCs at day +2 or day +20, but not at earlier or later infusion.117 In that study, interferon-γ-activated MSCs were used. Min et al.118 used IL-10-transduced MSCs and reported improved survival. CXCR4-transduced MSCs also improved survival and lowered histopathological damage in mice with GVHD.119 MSCs failed to prevent acute GVHD in the canine model;120 thus, the animal data have not shown any convincing evidence for MSCs or other stromal cells as a useful treatment for GVHD.

Clinical experience using stromal cells for treatment of acute and chronic graft-versus-host disease

It was safe to infuse MSCs, as demonstrated in pilot studies in which these cells were given to promote engraftment following autologous or allogeneic haematopoietic stem cell transplantation.91,121 Bartholomew et al.96 showed in a baboon model that MSCs prolonged skin allograft survival.96 At our unit, a 9-year-old boy with acute lymphoblastic leukaemia developed therapy-resistant grade IV acute GVHD with voluminous haemorrhagic diarrhoea and highly elevated bilirubin. GVHD was non-responsive to treatment with cyclosporine, high-dose prednisolone, repeated pulses with methylprednisolone, extracorporeal psoralen combined with ultraviolet A and several infusions of infliximab (Remicade®, Merck Sharp & Dohme Ltd, White House Station, NJ, USA) and daclizumab (Zenapax®, Hoffman-LaRoche, Basel, Switzerland). Based on our knowledge that MSCs inhibited alloreactivity in vitro despite HLA incompatibility between MSCs and stimulator and responder cells, I aspirated bone marrow from his HLA-haploidentical mother and 2 × 106  MSC/kg was infused with subsequent normalization of stool and bilirubin within a week of MSC infusion.98 Subsequently, he had minimal residual disease of acute lymphoblastic leukaemia and therefore I decided to discontinue treatment with cyclosporine. Following this, GVHD reappeared with haemorrhagic voluminous diarrhoea and bilirubin increased to 350 mmol/l. In response to this, we infused 1 × 106 MSC/kg from his mother, which had been stored frozen in liquid nitrogen. The patient responded again and was sent home.

In the initial compassionate-use study, seven more patients were included.94 Although some patients did not respond, and several died from infection, survival was significantly better than that of similar patients not treated with MSCs. Among those patients, resolution of GVHD was seen in the gastrointestinal tract, liver and skin. A patient with chronic GVHD had a partial response. This study prompted me to initiate a larger European phase II study in patients with therapy-resistant acute GVHD treated in five centres.122 This study included 55 patients treated with MSCs at a median dose of 1.4 × 106 MSCs/kg (range 0.4–9× 106 MSCs/kg). The patients received from one to five infusions of MSCs from HLA-identical siblings, HLA-haploidentical donors and a majority from unrelated HLA-mismatched third-party donors. Complete response to MSC infusion was seen in 30/55 patients (55%) and partial response was seen in nine patients. Children tended to respond better to the treatment, with 68% responding, compared with 43% of adults (P = 0.07). Among the complete responders, 2-year survival was 52%, which was significantly higher than the 2-year survival of 16% among those with partial or no response (P = 0.018). Our findings that MSCs could cure life-threatening acute GVHD opened up a new field of cell therapy in regenerative medicine. MSCs are now used for a variety of autoimmune disorders such as multiple sclerosis and Crohn’s disease, and have also been used to treat myocardial infarctions.

Subsequent to our promising results, there has been a number of reports using various types of MSCs to treat acute GVHD; Fang et al.123 treated six patients with adipose tissue-derived MSCs for steroid-refractory acute GVHD and von Bonin et al.124 used MSCs expanded in platelet lysate medium for GVHD. Overall, there are reports from several publications on 190 patients who have been treated with a cell dose ranging from 0.4 to 9.0 × 106/kg from 1 to 21 doses, with a complete response of 52%, a partial response of 23% and no response in 25% of the patients (studies summarised in Ringdén125). Osiris Therapeutics (MD, USA) used expanded MSCs for grade II–IV acute GVHD with an initial response of 94% and a complete response of 77%.126 Subsequently, Osiris Therapeutics carried out a prospective double-blind placebo-controlled phase III study in which patients with grade II–IV acute GVHD were randomised to either Prochymal® (Osiris Therapeutics, Columbia, MD, USA) or placebo in a ratio of 2:1.127 Overall complete response at 28 days was 45% in the Prochymal group and 46% in the placebo group. However, among 61 patients with acute GVHD of the liver, complete response was 76% in the Prochymal group and 47% in the placebo group (P = 0.026). In 71 patients with gastrointestinal acute GVHD, complete response was 88% in the Prochymal group compared with 64% in the placebo group (P = 0.018). In this study, there was also a trend for a better outcome in children than in adults, and so Prochymal is now registered in Canada and New Zealand for the treatment of severe acute GVHD in children. There are few long-term reports of the use of MSCs for the treatment of acute GVHD; at our centre, 31 patients treated with MSCs for acute GVHD or haemorrhagic cystitis were followed for more than 4 years.128 Survival was better for those patients who had received MSCs from passages 1–2, 75% at 1 year, as opposed to 21% among those receiving MSCs from passages 3–4 (P < 0.01).

Although bone marrow-derived MSCs are the most employed, adipose-, umbilical cord-, or placenta tissue-derived stromal cells have also been utilized for treatment of acute GVHD.123,129,130 In a mixed-lymphocyte reaction, we compared three different sources of stromal cells from the placenta, the fetal membrane, the umbilical cord and from placental villi.131 Decidual stromal cells from the fetal membrane were the most consistent in inhibiting mixed lymphocyte culture, and they were therefore selected for a clinical pilot study. Subsequently, we used decidual stromal cells for the treatment of severe steroid-refractory grade III–IV acute GVHD.130 The median age of the patients was 57 years and there was one child in the study. Two patients had a complete response, four had a partial response and three patients became long-term survivors. This study showed that decidual stromal cells could cure life-threatening acute GVHD.

Stromal cells for treatment of chronic GVHD

Chronic GVHD resembles autoimmune diseases and, since MSCs had an effect on experimental autoimmune diseases, chronic GVHD would be an ideal disease for treatment with stromal cells.132 In the first patient we treated, we saw a partial response by resolution of liver GVHD after MSC treatment.94 Several reports included 61 patients treated for chronic GVHD with a complete response rate of 26%, a partial response rate of 48% and no response in 26%.125 The MSC dose ranged from 0.2 to 20 × 106/kg and 1–11 doses were given. Weng et al.133 reported on 19 patients with refractory chronic GVHD and saw response in 74% of the patients.133

Stromal cells for tissue toxicity and haemorrhages

Mesenchymal stem cells seem to home to sites of injury.134 When treating patients with acute GVHD, we found that haemorrhages stopped when the patients were treated with MSCs.94 Therefore, we used MSCs for haemorrhagic cystitis.95 The first two patients had life-threatening haemorrhagic cystitis grade V, and both died from multi-organ failure, but transfusion requirements were dramatically decreased after MSC infusions. Among 10 patients treated at an earlier stage of haemorrhagic cystitis, eight had a complete response and two were non-responders. Gross haematuria disappeared after a median of 3 days (range 1–14 days). We also treated major gastrointestinal haemorrhages in a 68-year-old man who had multispecific anti-HLA antibodies and was refractory to platelet transfusions. Surgery was impossible, but this patient responded to MSC infusion after an infusion of 2 × 106 MSCs/kg pooled from two donors.135 After this, we studied the effect of MSCs on the coagulation system and found that there was a profound effect on coagulation.136,137 We also saw that MSCs could cure colon perforation and peritonitis twice in a patient with HSCT;95 this finding was confirmed in a Japanese patient.138


Graft-versus-host disease causes morbidity and mortality after HSCT and severe steroid-refractory acute GVHD is a life-threatening disease. GVHD may also induce an anticancer effect. Care at home instead of isolation in hospital may decrease the risk of acute GVHD without harnessing the graft-versus-leukaemia effect and thereby improve survival. Therefore, home care should be encouraged. Stromal cells from various sources have immunomodulatory properties and can heal damaged tissue. We found that they could reverse life-threatening acute GVHD in some, although not all, patients. Stromal cells have also been used successfully for treating chronic GVHD and tissue damage including haemorrhages. Although promising, more research is required to make stromal cell therapy an established treatment for GVHD.



Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49:511–33.


Appelbaum FR, Sullivan KM, Buckner CD, et al. Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation. J Clin Oncol 1987; 5:1340–7.


Storb R, Doney KC, Thomas ED, et al. Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients. Blood 1982; 59:236–46.


Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 1968; 2:1366–9.


Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with the Wiskott–Aldrich syndrome. Lancet 1968; 2:1364–6.


Hobbs JR. Bone marrow transplantation for inborn errors. Lancet 1981; 2:735–9.


Groth CG, Ringdén O. Transplantation in relation to the treatment of inherited disease. Transplantation 1984; 38:319–27.


Hoogerbrugge PM, Brouwer OF, Bordigoni P, et al. Allogeneic bone marrow transplantation for lysosomal storage diseases. The European Group for Bone Marrow Transplantation. Lancet 1995; 345:1398–402.


Ringdén O, Remberger M, Svahn BM, et al. Allogeneic hematopoietic stem cell transplantation for inherited disorders: experience in a single center. Transplantation 2006; 81:718–25.


Ringdén O, Ahstrom L, Lonnqvist B, Baryd I, Svedmyr E, Gahrton G. Allogeneic bone marrow transplantation in a patient with chemotherapy-resistant progressive histiocytosis X. N Engl J Med 1987; 316:733–5.


Ringdén O, Groth CG, Erikson A, Granqvist S, Mansson JE, Sparrelid E. Ten years’ experience of bone marrow transplantation for Gaucher disease. Transplantation 1995; 59:864–70.


Ringdén O, Deeg HJ. Clinical spectrum of graft-versus-host disease. In: Ferrara JLM, Deeg HJ, Burakoff S (eds.) Graft vs Host Disease, 2nd edn. New York: Marcel Dekker Inc.; 1996, pp. 525–59.


Storb R, Thomas ED. Graft-versus-host disease in dog and man: the Seattle experience. Immunol Rev 1985; 88:215–38.


van Bekkum DW. Graft-versus-Host Disease. New York: Marcel Dekker Inc.; 1985.


de Gast GC, Gratama JW, Ringdén O, Gluckman E. The multifactorial etiology of graft-versus-host disease. Immunol Today 1987; 8:209–12.


Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 1999; 5:347–56.


Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18:295–304.


Gale RP, Bortin MM, van Bekkum DW, et al. Risk factors for acute graft-versus-host disease. Br J Haematol 1987; 67:397–406.


Bostrom L, Ringdén O, Gratama JW, Jacobsen N, Zwaan F, Nilsson B. The impact of pretransplant herpesvirus serology on acute and chronic graft-versus-host disease. Leukaemia Working Party of the European Group for Bone Marrow Transplantation. Transplant Proc 1990; 22:206–7.


Ringdén O, Backman L, Lonnqvist B, et al. A randomized trial comparing use of cyclosporin and methotrexate for graft-versus-host disease prophylaxis in bone marrow transplant recipients with haematological malignancies. Bone Marrow Transplant 1986; 1:41–51.


Storb R, Deeg HJ, Pepe M, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 1989; 73:1729–34.


Ringdén O, Horowitz MM, Sondel P, et al. Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia? Blood 1993; 81:1094–101.


Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78:2120–30.


Ringdén O, Remberger M, Aschan J, Lungman P, Lonnqvist B, Markling L. Long-term follow-up of a randomized trial comparing T cell depletion with a combination of methotrexate and cyclosporine in adult leukemic marrow transplant recipients. Transplantation 1994; 58:887–91.


Ringdén O, Remberger M, Persson U, et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15:619–25.


Remberger M, Storer B, Ringdén O, Anasetti C. Association between pretransplant thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors. Bone Marrow Transplant 2002; 29:391–7.


Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001; 98:2942–7.


Remberger M, Svahn BM, Mattsson J, Ringdén O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation 2004; 78:122–7.


Groth CG, Gahrton G, Lundgren G, et al. Successful treatment with prednisone and graft-versus-host disease in an allogeneic bone-marrow transplant recipient. Scand J Haematol 1979; 22:333–8.


Ringdén O, Persson U, Johansson SG, et al. Early diagnosis and treatment of acute human graft-versus-host disease. Transplant Proc 1983; 15:1490–4.


Remberger M, Aschan J, Barkholt L, Tollemar J, Ringdén O. Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin. Clin Transplant 2001; 15:147–53.


Ringdén O. Management of graft-versus-host disease. Eur J Haematol 1993; 51:1–12.


Ringdén O, Hermans J, Labopin M, Apperley J, Gorin NC, Gratwohl A. The highest leukaemia-free survival after allogeneic bone marrow transplantation is seen in patients with grade I acute graft-versus-host disease. Acute and Chronic Leukaemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Leuk Lymphoma 1996; 24:71–9.


Sullivan KM, Shulman HM, Storb R, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57:267–76.


Ringdén O, Paulin T, Lonnqvist B, Nilsson B. An analysis of factors predisposing to chronic graft-versus-host disease. Exp Hematol 1985; 13:1062–7.


Carlens S, Ringdén O, Remberger M, et al. Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis. Bone Marrow Transplant 1998; 22:755–61.


Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood 2004; 104:2603–6.


Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304:1529–33.


Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75:555–62.


Ringdén O, Zwaan F, Hermans J, Gratwohl A. European experience of bone marrow transplantation for leukemia. Transplant Proc 1987; 19:2600–4.


Ringdén O, Labopin M, Gluckman E, et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 18:921–9.


Ringdén O, Horowitz MM. Graft-versus-leukemia reactions in humans. The Advisory Committee of the International Bone Marrow Transplant Registry. Transplant Proc 1989; 21:2989–92.


Ringdén O, Labopin M, Gorin NC, et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 2000; 111:1130–7.


Ringdén O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood 2009; 113:3110–18.


Bacigalupo A, Van Lint MT, Occhini D, et al. Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 1991; 77:1423–8.


Carlens S, Aschan J, Remberger M, Dilber M, Ringdén O. Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia. Bone Marrow Transplant 1999; 24:629–35.


Olsson R, Remberger M, Hassan Z, Omazic B, Mattsson J, Ringdén O. GVHD prophylaxis using low-dose cyclosporine improves survival in leukaemic recipients of HLA-identical sibling transplants. Eur J Haematol 2010; 84:323–31.


Kolb HJ, Mittermuller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76:2462–5.


Carlens S, Remberger M, Aschan J, Ringdén O. The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse. Biol Blood Marrow Transplant 2001; 7:31–8.


Barrett AJ, Ringdén O, Zhang MJ, et al. Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia. Blood 2000; 95:3323–7.


Ringdén O, Barrett AJ, Zhang MJ et al. Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 2003; 121:874–85.


Childs RW, Clave E, Tisdale J, Plante M, Hensel N, Barrett J. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect. J Clin Oncol 1999; 17:2044–9.


Childs RW, Srinivasan R. Allogeneic hematopoietic cell transplantation for solid tumors. In: Blume KG, Forman SJ, Appelbaum FR (eds.) Thomas’ Hematopoietic Cell Transplantation, 3rd edn. Oxford: Blackwell Publishing Ltd; 2004, pp. 1177–87.


Barkholt L, Bregni M, Remberger M, et al. Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe. Ann Oncol 2006; 17:1134–40.


Hentschke P, Barkholt L, Uzunel M, et al. Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma. Bone Marrow Transplant 2003; 31:253–61.


Bay JO, Fleury J, Choufi B, et al. Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma: results of five patients. Bone Marrow Transplant 2002; 30:95–102.


Omuro Y, Matsumoto G, Sasaki T, et al. Regression of an unresectable pancreatic tumor following nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. Bone Marrow Transplant 2003; 31:943–5.


Zetterquist H, Hentschke P, Thorne A, et al. A graft-versus-colonic cancer effect of allogeneic stem cell transplantation. Bone Marrow Transplant 2001; 28:1161–6.


Ueno NT, Cheng YC, Rondon G, et al. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood 2003; 102:3829–36.


Ringdén O, Soderdahl G, Mattsson J, et al. Transplantation of autologous and allogeneic bone marrow with liver from a cadaveric donor for primary liver cancer. Transplantation 2000; 69:2043–8.


Soderdahl G, Barkholt L, Hentschke P, et al. Liver transplantation followed by adjuvant nonmyeloablative hemopoietic stem cell transplantation for advanced primary liver cancer in humans. Transplantation 2003; 75:1061–6.


Buckner CD, Clift RA, Sanders JE, et al. Protective environment for marrow transplant recipients: a prospective study. Ann Intern Med 1978; 89:893–901.


Mahmoud HK, Schaefer UW, Schuning F, et al. Laminar air flow versus barrier nursing in marrow transplant recipients. Blut 1984; 49:375–81.


Passweg JR, Rowlings PA, Atkinson KA, et al. Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia. Bone Marrow Transplant 1998; 21:1231–8.


Skinhoj P, Jacobsen N, Hoiby N, Faber V. Strict protective isolation in allogenic bone marrow transplantation: effect on infectious complications, fever and graft versus host disease. Scand J Infect Dis 1987; 19:91–6.


Svahn BM, Bjurman B, Myrback KE, Aschan J, Ringdén O. Is it safe to treat allogeneic stem cell transplant recipients at home during the pancytopenic phase? A pilot trial. Bone Marrow Transplant 2000; 26:1057–60.


Svahn BM, Remberger M, Myrback KE, et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002; 100:4317–24.


van Bekkum DW, Knaan S. Role of bacterial microflora in development of intestinal lesions from graft-versus-host reaction. J Natl Cancer Inst 1977; 58:787–90.


Jones JM, Wilson R, Bealmear PM. Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras. Radiat Res 1971; 45:577–88.


Storb R, Prentice RL, Buckner CD, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med 1983; 308:302–7.


Storb R, Prentice RL, Sullivan KM, et al. Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med 1983; 98:461–6.


Svahn BM, Ringdén O, Remberger M. Long-term follow-up of patients treated at home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 2005; 36:511–16.


Mattsson J, Westin S, Edlund S, Remberger M. Poor oral nutrition after allogeneic stem cell transplantation correlates significantly with severe graft-versus-host disease. Bone Marrow Transplant 2006; 38:629–33.


Svahn BM, Remberger M, Heijbel M, et al. Case–control comparison of at-home and hospital care for allogeneic hematopoietic stem-cell transplantation: the role of oral nutrition. Transplantation 2008; 85:1000–7.


Ringdén O, Remberger M, Holmberg K, et al. Many days at home during neutropenia after allogeneic hematopoietic stem cell transplantation correlates with low incidence of acute graft-versus-host disease. Biol Blood Marrow Transplant 2013; 19:314–20.


Brooke G, Rossetti T, Pelekanos R, et al. Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials. Br J Haematol 2009; 144:571–9.


Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98:2396–402.


In‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004; 22:1338–45.


Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968; 6:230–47.


Haynesworth SE, Baber MA, Caplan AI. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone 1992; 13:69–80.


Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276:71–4.


Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996; 166:585–92.<585::AID-JCP13>3.0.CO;2-6


Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998; 176:57–66.<57::AID-JCP7>3.0.CO;2-7


Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57:11–20.


Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nature Med 2000; 6:1282–6.


Pochampally RR, Neville BT, Schwarz EJ, Li MM, Prockop DJ. Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick embryos without evidence of cell fusion. Proc Natl Acad Sci USA 2004; 101:9282–5.


Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31:890–6.


Rasmusson I, Ringdén O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76:1208–13.


Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75:389–97.


Grinnemo KH, Mansson A, Dellgren G, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 2004; 127:1293–300.


Koc ON, Gerson SL, Cooper BW, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18:307–16.


Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003; 101:2999–3001.


Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169:12–20.


Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81:1390–7.


Ringdén O, Uzunel M, Sundberg B, et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007; 21:2271–6.


Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30:42–8.


Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99:3838–43.


Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol 2004; 60:307–15.


Le Blanc K, Ringdén O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11:321–34.


Rasmusson I, Le Blanc K, Sundberg B, Ringdén O. Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol 2007; 65:336–43.


Maccario R, Podesta M, Moretta A, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90:516–25.


Selmani Z, Naji A, Gaiffe E, et al. HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells. Transplantation 2009; 87(Suppl. 9):S62–6.


Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815–22.


Gieseke F, Bohringer J, Bussolari R, Dominici M, Handgretinger R, Muller I. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 2010; 116:3770–9.


Sioud M, Mobergslien A, Boudabous A, Floisand Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol 2010; 71:267–74.


Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103:4619–21.


Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 2010; 90:1312–20.


Tatara R, Ozaki K, Kikuchi Y, et al. Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation. Cytotherapy 2011; 13:686–94.


Francois M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 2012; 20:187–95.


Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 2005; 35:1482–90.


Akiyama K, Chen C, Wang D, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012; 10:544–55.


Ren G, Zhao X, Zhang L, et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 2010; 184:2321–8.


Saldanha-Araujo F, Ferreira FI, Palma PV, et al. Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes. Stem Cell Res 2011; 7:66–74.


Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2:141–50.


Sudres M, Norol F, Trenado A, et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176:7761–7.


Badillo AT, Peranteau WH, Heaton TE, Quinn C, Flake AW. Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft-versus-host disease. Br J Haematol 2008; 141:224–34.


Polchert D, Sobinsky J, Douglas G, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 2008; 38:1745–55.


Min CK, Kim BG, Park G, Cho B, Oh IH. IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39:637–45.


Chen W, Li M, Li Z, et al. CXCR4-transduced mesenchymal stem cells protect mice against graft-versus-host disease. Immunol Lett 2012; 143:161–9.


Mielcarek M, Storb R, Georges GE, et al. Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2011; 17:214–25.


Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005; 11:389–98.


Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371:1579–86.


Fang B, Song Y, Liao L, Zhang Y, Zhao RC. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 2007; 39:3358–62.


von Bonin M, Stolzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant 2009; 43:245–51.


Ringdén O. Mesenchymal stem cells for treatment and prevention of graft-versus-host disease and graft failure after hematopoietic stem cell transplantation and future challenges. In: Chase LG, Vemuri MC (eds.) Mesenchymal Stem Cell Therapy. New York: Springer Verlag, Humana Press; 2013, pp. 173–206.


Kebriaei P, Isola L, Bahceci E, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 2009; 15:804–11.


Martin PJ, Uberti J, Soiffer R, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized placebo-controlled multicenter phase III trial in GVHD. Biol Blood Marrow Transplant 2010; 16(Suppl.):S169–70.


von Bahr L, Sundberg B, Lonnies L, et al. Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant 2012; 18:557–64.


Wu KH, Chan CK, Tsai C, et al. Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation 2011; 91:1412–16.


Ringdén O, Erkers T, Nava S, et al. Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells 2013; 31:592–601.


Karlsson H, Erkers T, Nava S, Ruhm S, Westgren M, Ringdén O. Stromal cells from term fetal membrane are highly suppressive in allogeneic settings in vitro. Clin Exp Immunol 2012; 167:543–55.


Ringdén O, Keating A. Mesenchymal stromal cells as treatment for chronic GVHD. Bone Marrow Transplant 2011; 46:163–4.


Weng JY, Du X, Geng SX, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 2010; 45:1732–40.


Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med 2003; 5:1028–38.


Ringdén O, Leblanc K. Pooled MSCs for treatment of severe hemorrhage. Bone Marrow Transplant 2011; 46:1158–60.


Moll G, Jitschin R, von Bahr L, et al. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PLOS One 2011; 6:e21703.


Moll G, Rasmusson-Duprez I, von Bahr L, et al. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells 2012; 30:1565–74.


Sato K, Ozaki K, Mori M, Muroi K, Ozawa K. Mesenchymal stromal cells for graft-versus-host disease: basic aspects and clinical outcomes. J Clin Exp Hematopathol 2010; 50:79–89.

Add comment 

Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA