Doi:10.1016/s0140-6736(08)60690-x

Articles
Mesenchymal stem cells for treatment of steroid-resistant,
severe, acute graft-versus-host disease: a phase II study
Katarina Le Blanc, Francesco Frassoni*, Lynne Ball*, Franco Locatelli, Helene Roelofs, Ian Lewis, Edoardo Lanino, Berit Sundberg, Maria Ester Bernardo, Mats Remberger, Giorgio Dini, R Maarten Egeler, Andrea Bacigalupo, Willem Fibbe, Olle Ringdén, on behalf of the Developmental Committee of the European Group for Blood and Marrow Transplantation Summary
Background Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation Lancet 2008; 371: 1579-86
with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed See Comment page 1553
to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation.
Methods Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with Haematology Centre and
the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II Centre of Allogeneic Stem Cell
experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to Transplantation, Division of
Clinical Immunology,
60 months' follow-up from infusion of the cells.
Karolinska University Hospital,
Huddinge, Stockholm, Sweden
Findings Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow (Prof K Le Blanc MD,
derived mesenchymal stem cells was 1.4×10⁶ (min-max range 0.4-9×10⁶) cells per kg bodyweight. 27 patients B Sundberg BSc,
received one dose, 22 received two doses, and six three to fi ve doses of cells obtained from HLA-identical sibling Prof O Ringdén MD); Centro
donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a Cellule Staminali e Terapia
complete response and nine showed improvement. No patients had side-eff ects during or immediately after infusions Cellulare e Divisione
Ematologia, Ospedale
of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent San Martino, Genova, Italy
malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had (F Frassoni MD,
lower transplantation-related mortality 1 year after infusion than did patients with partial or no response A Bacigalupo MD);
(11 [37%] of 30 vs 18 [72%] of 25; p=0.002) and higher overall survival 2 years after haemopoietic-stem-cell Dipartimento di Ematologia e
Oncologia, IRCCS G Gaslini,
transplantation (16 [53%] of 30 vs four [16%] of 25; p=0.018).
Genova, Italy (G Dini MD,
E Lanino MD); Department of
Interpretation Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an eff ective Paediatrics (L Ball MD,
therapy for patients with steroid-resistant, acute GVHD.
Prof R M Egeler MD) and
Department of
Immunohematology and
Funding Swedish Cancer Society, Children's Cancer Foundation, Swedish Research Council, Cancer Society in Blood Transfusion
Stockholm, Cancer and Allergy Foundation, Karolinska Institutet, Istituto Superiore di Sanità, European Union, (H Roelofs PhD,
Regione Lombardia, Fondazione CARIPLO, Associazione Italiana Ricerca contro il Cancro, Compagnia di San Paolo Prof W Fibbe MD), Leiden
University Medical Centre,
Torino, Progetto CARIGE Cellule Staminali, European Commission, Ministero dell'Università e della Ricerca Leiden, Netherlands;
Scientifi ca e Tecnologica, Ricerca Finalizzata Regione Liguria 2005 Assistenza Domiciliare, Dutch Programme for Onco-Ematologia Pediatrica,
Tissue Engineering.
Fondazione IRCCS Policlinico
San Matteo, Università di
Pavia, Italy (Prof F Locatelli MD,
Introduction
ments with allogeneic lymphocytes, mesenchymal stem M E Bernardo MD); and Division
Allogeneic haemopoietic-stem-cell transplantation is cells do not induce lymphocyte proliferation, interferon-γ of Haematology, Institute of
the treatment of choice for many malignant and production, or upregulation of activation markers.9,10
Medical and Veterinary Science,
non-malignant disorders.1,2 Severe graft-versus-host Mesenchymal stem cells suppress proliferation of Adelaide, Australia (I Lewis MD)
disease (GVHD) is a life-threatening complication after activated lymphocytes in vitro in a dose-dependent, Correspondence to: this treatment and donor lymphocyte infusion is used for non-HLA-restricted, manner.9-11 In a baboon skin-graft Institutet, Division of Clinical treatment or prevention of relapse of leukaemia.3,4 model, Bartholomew and co-workers11 showed that Immunology and Transfusion Steroids are still the fi rst-line treatment for established infusion of ex-vivo expanded donor-derived or third-party Medicine, SE-141 86 Stockholm, GVHD with a response rate of 30-50%; however, the cells prolonged the time to rejection of histoincompatible Sweden katarina.leblanc@ki.se
outcome for patients with severe, steroid-resistant, acute skin grafts. Furthermore, infused cells improve the GVHD is poor, and overall survival is low.1,3-5 outcome of acute renal, neural, and lung injury, possibly Mesenchymal stem cells are multipotent bone-marrow by promoting a shift from production of proinfl ammatory cells able to diff erentiate in vitro and in vivo into tissues cytokines to anti-infl ammatory cytokines at the site of of mesenchymal origin.6,7 Moreover, these cells provide injury.12-14support for the growth and diff erentiation of In phase I and II trials, HLA-identical mesenchymal haemopoietic progenitor cells in bone-marrow micro- stem cells expanded ex vivo have been infused to promote environments and, in animal models, promote haemopoietic recovery after autologous and allogeneic engraftment of haemopoietic cells.8 In co-culture experi- haemopoietic-stem-cell transplantation and to treat www.thelancet.com Vol 371 May 10, 2008
Articles
To facilitate large-scale, multicentre trials, the European Group for Blood and Marrow Transplantation Recipients
Developmental Committee has adopted a common protocol for expansion of mesenchymal stem cells. We report the results of a multicentre, phase II study of the use of these cells in 55 patients with severe and Diagnosis
Patients
Between October, 2001, and January, 2007, patients of all ages with grade 2-4 GVHD after haemopoietic-stem-cell transplantation, who did not respond to steroid treatment (≥2 mg per kg per day) for at least 7 days, or with progression of at least one grade within 72 h were eligible for the study. 55 patients were treated (table 1); 48 had developed GVHD after transplantation of haemopoietic stem cells and seven after donor lymphocyte infusion. Most patients had grade 3 or 4 GVHD involving two or three organs, confi rmed by biopsy in 36 patients Donors and cells
23 patients were treated at Karolinska University Hospital, Huddinge, Sweden (of whom, eight were previously reported21,22), 14 at Leiden University Medical Center, Leiden, the Netherlands, eight at Ospedale San Martino or Gaslini Institute, Genova, Italy, seven at IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy, and three patients were from Royal Adelaide GVHD prophylaxis
This phase II study was a prospective registration study to include all patients consecutively treated with mesenchymal stem cells in the participating centres of the European Group for Blood and Bone Marrow Transplantation mesenchymal stem cell consortium: the study was approved by the local ethics committees or institutional review boards of the participating institutions. Donors and patients, or their legal guardians, Cytomegalovirus serology
Procedures and defi nitions
Before treatment with haemopoietic stem cells, patients received either myeloablative or reduced-intensity conditioning (fi gure 1). Conditioning was myeloablative Data are numbers unless otherwise indicated. ALG=antilymphocyte globulin. ALL=acute lymphoblastic leukaemia. AML=acute myeloid leukaemia. in 37 patients, who were given cyclophosphamide (120 mg ATG=antithymocyte globulin. BM=bone marrow. CB=cord blood. CLL=chronic per kg) combined mainly with busulfan (16 mg per kg), lymphocytic leukaemia. CML=chronic myeloid leukaemia. JMML=juvenile melphalan, or fractionated whole-body irradiation myelomonocytic leukaemia. MMF=mycophenolate mofetil. PBSC=peripheral-blood stem cell. *Median (min-max range). (≥12 Gy). 18 patients had low-intensity conditioning †Early=non-malignant disease, fi rst complete remission, fi rst chronic phase; regimens with fl udarabine phosphate combined with late=beyond these stages at time of transplant.
various cytotoxic drugs or 2 Gy whole-body irradiation.
Table 1: Characteristics of patients and treatment
As GVHD prophylaxis, most patients received ciclosporin combined with either four doses of intravenous methotrexate or mycophenolate mofetil. In patients with osteogenesis imperfecta.15-20 So far, neither patients receiving cord-blood transplantation, ciclosporin acute nor long-term adverse events have been reported was combined with prednisolone. Recipients of after infusion of mesenchymal stem cells. Two reports haemopoietic stem cells from unrelated donors were on the use of in-vitro expanded cells for the treatment of treated with antithymocyte globulin, antilymphocyte severe, acute GVHD have recently been published.21,22 www.thelancet.com Vol 371 May 10, 2008
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All patients had been treated with prednisolone Number of patients
2 mg/kg per day or more as fi rst-line immunosuppressive GVHD therapy and were resistant to this treatment. GVHD severity
33 patients (60%) had failed two or more lines of immunosuppressive therapy before receiving Organ involvement
mesenchymal stem cells (table 2). All patients continued
treatment with steroids and a calcineurin inhibitor (n=53) or mycophenolate mofetil (n=2) at the time of infusion. 20 patients also continued additional treatments while GVHD confi rmed on biopsy
We defi ned resistance to treatment as no improvement GVHD treatment before MSC infusion
in overall grade of GVHD or progression. Acute GVHD was graded according to internationally accepted criteria by physicians at individual centres.23 When possible, we confi rmed diagnosis with biopsy of the involved We used best response to defi ne the response to treatment: complete response was loss of all symptoms of acute GVHD; partial response was improvement of at least one grade; stable disease was no change in GVHD grade; and progressive disease was worsening of GVHD. Patients were judged to have responded if they had either Previous failed therapy
complete or partial response. Transplantation-related mortality included all deaths associated with trans- plantation of haemopoietic stem cells except those related to recurrence of underlying disease.
Laboratory methods
Table 3 shows the characteristics of the donors and
ATG=antithymocyte globulin. MMF=mycophenolate mofetil. MSC=mesenchymal grafts. Mesenchymal stem cells were derived from stem cell. PUVA=psoralen and ultraviolet-A irradiation. *Numbers in brackets had
immunosuppressive therapy at time of MSC infusion. †One Thymoglobulin,
either HLA-identical stem-cell donors, haploidentical Genzyme, USA; one ATGAM, Upjohn, USA.
family donors, or unrelated HLA-mismatched donors. Clinical-grade mesenchymal stem cells were gener- Table 2: GVHD grade and organ involvement
ated under good manufacturing practice conditions according to a common protocol devised by the City, UT, USA, or Leiden University Medical Centre European Group for Blood and Bone Marrow Pharmacy, Netherlands) or washed repeatedly and Transplantation devel opmental committee and resuspended to a fi nal concentration of 2×10⁶ cells per mL approved by the medicinal-product agencies in the in saline solution according to local guidelines.
respective countries. Bone-marrow mononuclear cells Criteria for release of mesenchymal stem cells for were separated by density gradient centrifugation as clinical use included absence of visible clumps, previously described.7,8,10 spindle-shape morphology, absence of contamination by Washed cells were resuspended in Dulbecco's modifi ed pathogens (as documented by aerobic and anaerobic Eagle's medium-low glucose (Life Technologies, cultures before release), viability greater than 95%, and Gaithersburg, MD, USA, or Paisley, UK) supplemented immune phenotyping proving expression of CD73, with 10% fetal bovine serum (National Veterinary Institute, Uppsala, Sweden, or HyClone, Logan, UT, USA) and plated at a density of 160 000 cells per cm². Cultures were maintained at 37ºC in a humidifi ed atmosphere containing 5% CO₂ in 175 cm² fl asks (Falcon, Franklin Lakes, New Jersey, USA, or Greiner Bio-One, Frickenhausen, Germany). When the cultures were near confl uence (>80%), the cells were detached by treatment with trypsin and EDTA (Invitrogen, Grand Island, NY, USA, or Lonza Verviers, Verviers, Belgium) and replated at a density of 4000 cells per cm². When 2×10⁶ cells or more were obtained, they were harvested and either cryopreserved in Figure 1: Scheme of mesenchymal stem-cell therapy
10% dimethyl sulphoxide (Research Industries, Salt Lake MSC=mesenchymal stem cells.
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Children
All patients
Number of infusions by donor type
*At last data collection, March, 2007.
Culture passage at MSC harvest
Table 4: GVHD response and outcome
92 infusions of mesenchymal stem cells were given; Number of MSC infusions
27 patients had one infusion, while 28 had two or more (fi gure 1, table 3). Of the 28 patients treated with multiple infusions, 15 received cells derived from two or more donors. No patients had acute side-eff ects either during or after infusion; and none have had late side-eff ects so far. Median time from transplantation of haemopoietic stem cells to infusion of mesenchymal stem cells was Data are number or median (min-max range). MSC=mesenchymal stem cell.
103 days (min-max range 27-533).
Just over half the patients had a complete response, Table 3: Mesenchymal-stem-cell donor and graft characteristics
and about a fi fth had a partial response; most of the CD90, and CD105 surface molecules (>90%) and absence remainder had worsening disease (table 4). A greater proportion of children responded than did adults Cells were given as intravenous infusions. Cells for (p=0.07). Median time from fi rst infusion of mesenchymal 11 infusions were harvested fresh from culture and given stem cells to complete response was 18 days (min-max to the patients. In all other cases, frozen cells were thawed range 3-63). 30 patients achieving complete response were available for assessment at 6 weeks after infusion. Of these, four had died, 19 still had complete response, Statistical analysis
one had grade 1 and six had grade 2 acute GVHD.
Data were analysed as of last data collection in March, 2007. After one dose, 27 patients had complete response, two We estimated the probability of survival with the had partial response, and 26 did not respond. Of patients Kaplan-Meier method and signifi cance of diff erences with who responded to one dose, two were treated with the log-rank test (Mantel-Cox). Transplantation-related HLA-identical mesenchymal stem cells, three with mortality was estimated non-parametrically. Patients were haploidentical cells, and 24 with third-party cells. The censored at the time of death or last follow-up. Because median dose given to patients who responded to the fi rst relapse and non-relapse mortality are competing events, dose was 1.4×10⁶ cells per kg (min-max range 0.8×10⁶ to we estimated their incidence with a non-parametric 9×10⁶ cells per kg), which was similar to that given to estimator of cumulative incidence curves.25,26 All results non-responding patients (1.4×10⁶ cells per kg; 0.6×10⁶ to were expressed as 2-year probability of survival or 1-year 1.9×10⁶ cells per kg). Six children and one adult who cumulative incidence (%) of transplantation-related responded to the fi rst infusion were given a second mortality and 95% CI. We used Fisher's exact test to infusion to prevent GVHD recurrence when immuno-compare distribution of categorical variables. Analyses suppressive drug treatment was reduced.
were done with the cmprsk package (developed by Gray, 17 of the patients who did not have sustained complete June, 2001), Splus 6.2 software, and Statistica software.
response after the fi rst dose were treated with subsequent doses. Five patients had complete response but received Role of the funding source
several doses of mesenchymal stem cells because of The sponsors of this study had no role in study design, GVHD recurrence. Five patients had partial responses data collection, data analysis, data interpretation, or and were given multiple doses. One patient did not writing of the report. The corresponding author had full respond to 0.6×10⁶ cells per kg but responded to a second access to all the data and had fi nal responsibility for the dose of 2×10⁶ cells per kg. 12 patients did not respond decision to submit for publication.
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Complete respondersPartial responders and non-responders Number at risk
Figure 2: Survival from time of haemopoietic-stem-cell transplantation in patients given mesenchymal stem cells
Survival at the end of follow-up was 52% (95% CI 34-70%) for the 30 complete responders and 16% (0-32%) for the 25 partial responders or non-responders.
22 of 30 patients with grade 2 or 3 acute GVHD 34-70%) was signifi cantly better than that in the patients responded, compared with 17 of 25 with grade 4 disease with partial or no response (16%, 0-32%, p=0.018; (p=0.77). 28 (78%) of 36 patients with involvement of fi gure 2). The 100-day transplantation-related mortality one or two organs had a response compared with 11 (58%) from time of infusion of mesenchymal stem cells of 19 patients with involvement of three organs (p=0.21). was 13% (0-26%) for patients with complete response The age or HLA-match of the mesenchymal-stem-cell compared with 60% (41-79%) in other patients donor had no eff ect on response rate after infusion (data (p=0.002). Transplantation-related mortality 1 year after not shown). In patients receiving HLA-identical cells, infusion was 37% (19-55%) in complete responders two of fi ve responded to fi rst dose, compared with nine and 72% (55-89%) in patients with partial or no of 13 patients given haploidentical cells and 27 of response (p=0.002; fi gure 3). Of the survivors, six with 37 receiving unrelated cells. Median time from acute complete response developed chronic GVHD, which GVHD onset to treatment with mesenchymal stem cells was limited (mild) in four and extensive (severe or was 25 days (min-max range 3-114) in complete involving several organs) in two patients. Two patients responders, compared with 29 (3-116) days among all with partial or no response also developed extensive other patients (p=0.48). We noted variable responses GVHD. At last follow-up (March 1, 2007), eight with when cells expanded from one donor were given to complete response had discontinued all immuno-several recipients. There was no relation between the suppressive drugs.
treatment given before infusion of mesenchymal stem Three patients had recurrence of the original disease, one with multiple myeloma, one with acute lymphoblastic 21 patients were alive at the time of analysis (March, leukaemia, and one with acute myeloid leukaemia. One 2007) with a median follow-up of 16 months (min-max patient with Pearson's disease developed acute myeloid range 1.5-64 months) after infusion of mesenchymal leukaemia de novo originating in endogenous stem cells (table 4). The estimated probability of survival haemopoietic cells. All these patients died. Acute GVHD 2 years after haemo poietic-stem-cell transplantation for was the most common cause of death (18 patients), with the entire cohort of patients was 35% (95% CI 22-38%); or without concomitant infection. One patient died from in adults, 2-year survival was 26% (10-42%) compared chronic GVHD with obstructive bronchiolitis, and one with 45% (23-67%) in children (p=0.06). The 2-year patient died from multiorgan failure after severe probability of survival in complete responders (52%, haemorrhagic cystitis. Infections in patients who died www.thelancet.com Vol 371 May 10, 2008
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Complete respondersPartial responders and non-responders Number at risk
Figure 3: 1-year cumulative incidence of transplantation related mortality from time of infusion of mesenchymal stem cells
Transplantation related mortality was 37% (95% CI 19-55%) among the complete responders and 72% (55-89%) among the partial responders or non-responders.
due to acute GVHD included aspergillosis (fi ve), previously described for patients with a similar grade of cytomegalovirus (four), and septi enterococci (four), Klebsiella sp (one), Escherichia coli The response in patients with grade 2 and 3 acute (one), and an unidentifi ed pathogen (one). Three patients GVHD was similar to that in patients with grade 4. More had infection with Epstein-Barr virus, one of whom patients are needed to investigate responses to the developed post-transplantation lymphoproliferative dis- treatment in various subgroups. For example, the ease related to the virus. Of the patients who responded diff erence in response rate between children and adults to mesenchymal stem cells, nine died from infections. with acute GVHD of comparable severity was not Pathogens included Klebsiella sp, E coli, Pseudomonas, signifi cant. Because of the low number of patients, the adenovirus, and varicella zoster virus infection.
for diff erences the size of that between response rates in Discussion
adults and in children (estimated power 0.58). At least 39 of 55 patients with steroid-resistant, severe, acute 80 patients would be needed to detect such a diff erence GVHD responded to treatment with mesenchymal stem cells. Survival in those with complete response was At present, little is known about mechanisms of signifi cantly higher and transplantation-related mortality suppression of GVHD by mesenchymal stem cells. In after infusion was signifi cantly lower than in people with vitro, these cells have various eff ects on immune cells, partial or no response. The clinical course of the including T cells, antigen-presenting cells, natural-killer 13 patients with progressive disease despite treatment cells, and B cells.28-30 The biological relevance of these may represent the natural progression of severe GVHD in-vitro fi ndings is unknown. These cells might suppress resulting in death in most patients. No major toxicities donor-T-cell responses to recipient alloantigen. This were observed, and treatment with mesenchymal stem suppression is probably induced by several mechanisms, cells seemed to be safe.
including release of soluble factors, induction of Although various immunosuppressive treatments have regulatory T cells, and repair of damaged target organs.28-30 been used, there is no established therapy for Immunological studies specifi cally addressing this issue steroid-resistant, severe, acute GVHD.1,3-5 The outcome are needed to improve our understanding the treatment for patients who do not respond to corticosteroids is of acute GVHD.
therefore poor, and survival at 2 years is about 10%.4,5,27 In Our study was designed to assess safety and effi this study, survival in people who responded to mesenchymal stem cells for refractory acute GVHD. It mesenchymal stem cells was higher (52%) than was not designed to identify the best dose of mesenchymal www.thelancet.com Vol 371 May 10, 2008
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stem cells. At present we can note only that, on the one the best dose of cells in each infusion, and the possible hand, clinically meaningful responses were obtained interactions of cells with other drugs for acute GVHD after infusing a dose as low as 0.8×10⁶ cells per kg, require further investigation. Although the grim outlook whereas on the other, doses as high as 1.9×10⁶ cells per kg for patients who do not respond to treatment suggests were not successful in all cases. Thus any conclusion as that improved survival rate is probably related to infusions to relevant dose is premature.
of mesenchymal stem cells, randomised clinical studies In more than half of patients, a single dose produced a are needed to compare this treatment with more response, whereas in a few patients with partial response or with recurrence of GVHD, several doses were needed In summary, this study shows that more than half of to induce a lasting response. The response was not the patients with steroid-refractory acute GVHD restricted to single organs: skin, gastrointestinal tract, responded to treatment with mesenchymal stem cells. and liver GVHD showed similar responses. How long Whether the cell donor was HLA matched or unmatched mesenchymal stem cells survive after injection and to did not aff ect the success of treatment. Just over half of what extent they are able to target tissues are unknown.22 patients with a complete response were alive at 2 years.
Thus, whether GVHD multiorgan response to infusion Contributors
occurs because the cells reach the lymph nodes and KLB collected and summarised the data, wrote the article, and leads the
inhibit the immunological response that gives rise to European Group for Blood and Marrow Transplantation clinical
GVHD is unclear; they might alternatively or additionally
mesenchymal stem cell expansion consortium together with FF, FL, and WF. LB, IL, EL, MEB, GD, RME, and AB contributed patients. HR, BS, target various organs associated with a tissue-healing and MEB developed the laboratory culture. HR generated the production eff ect. Further tracking studies with labelled cells are documentation for the expansion consortium. MR did all statistical needed to address these issues.
analyses. OR initiated the use of mesenchymal stem cells for GVHD therapy and this study, contributed patients, and wrote the second half of Third-party mesenchymal stem cells were as eff ective the Article. All authors contributed data and participated in their as HLA-identical or haploidentical cells. This fi nding has interpretation and in fi nal writing of the Article.
practical implications and suggests that third-party cells Confl ict of interest statement
can be prepared and stored frozen to be used for GVHD We declare that we have no confl ict of interest.
therapy. Little is known about whether HLA disparity Acknowledgments
determines the response to treatment and survival of We thank Marina Podesta for excellent cell cultures, the staff at cells after systemic administration. Most data derived participating institutions for compassionate and competent care of from animals indicate short survival of mesenchymal patients, and colleagues from Utrecht, London, and Amsterdam for referring patients for treatment. This work was supported by the stem cells after injection in vivo. Clinical benefi t might Swedish Cancer Society, the Children's Cancer Foundation, the not require sustained engraftment of many cells but Swedish Research Council, the Cancer Society in Stockholm, the could possibly result from production of growth factors Cancer and Allergy Foundation, the Karolinska Institutet, the Tobias or temporary immunosuppression.
Foundation, Istituto Superiore di Sanità (National Programme on Stem Cells), the European Union (Framework Programme 6-AlloStem), With the poor health of patients receiving mesenchymal Regione Lombardia, Fondazione CARIPLO, Associazione Italiana stem cells, some deaths were expected, despite control of Ricerca contro il Cancro (AIRC), Compagnia di San Paolo Torino, GVHD. Infections are common in severe GVHD because Progetto CARIGE Cellule Staminali, the European Commission (grant of the state of immunodefi ciency that characterises these QLK3-CT-1999-00380), Ministero dell'Università e della Ricerca Scientifi ca e Tecnologica (grant MIUR-PRIN 2005, project patients. Whether treatment can further aggravate 2005063024_004), Ricerca Finalizzata Regione Liguria 2005 Assistenza
immune incompetence or not is unclear. To properly Domiciliare and the Dutch Program for Tissue Engineering.
answer the question of whether treatment increases the References
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