Mesenchymal Stem Cells Derived from Different Donors as Salvage Therapy for Resistant Severe Acute Graft-Versus-Host Disease

Severe Acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT), especially severe intestinal aGVHD, is associated with a high morbidity and mortality rate and is a major threat to a successful outcome. Currently, corticosteroids are still the first-line treatment for established aGVHD with a response rate of 30–50%; however, patients who fail on standard therapy have poor outcome, and therapeutic options avail able for them are limited. Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into different tissues and also have immunomodulatory effects, inhibit T-cell proliferation in mixed lymphocyte cultures, prolong skin allograft survival. Recently, Le Blanc and Fan B et al. respec tively reported their experience of using vitro expanded MSCs to treat severe, resistant aGVHD of the gut and liver, and the results showed rapid improvement after infusion of MSC. Thus, MSC may be used for the treatment of severe acute GVHD. The purpose of our study was to evaluate further the efficacy of ex vivo expanded MSC as the salvage therapy for severe refractory acute GVHD. Between February, 2006, and July, 2007, four patients with gastrointestinal grade III to IV acute GVHD after sibling HLA-identical hematopoietic stem cell transplantation, who didn’t respond to steroid therapy (≥2mg per kg per day) for more than seven days, or with progression at least within 72 hours were treated with MSC. The study was approved by the Ethics Committee at Guangdong Provincial People’s Hospital. All patients and the MSC donors gave them written informed consent. Eleven infusions of MSCs were given Fone patient had one infusion, others had two or more infusions. All of them, the first-infusion MSCs were derived from their HLA-identical sibling donors, and the second or more MSCs were derived from different HLA-mismatched unrelated donors. The median dose given to patients was 0.5×10⁶ cells per kg(range: 0.3 to 0.8×10⁶ cells per kg). Median time from tansplantation of haemopoietic stem cells to infusion of MSCs was 58 days (range 28–63days). No patients had acute side-effects either during or after infusion. Total response rate was 100%. Two patients achieved complete response and the others achieved partial response. Four patients with gut aGVHD, two of them achieved complete response after the first dose infusion, and the other two achieved partial response and good partial response after the second and the third infusion, respectively. Otherwise, two of four patients with liver aGVHD, achieved partial response and complete response after the second and the third infusion. The median time from first infusion of MSCs to primary response time and fully response time was 3 days and 23 days(range: 2 to 5 days; 10 to 72 days) after MSC transfusion, respectively. Two patients had died of multiple cerebral infarction and the other one died of multiorgan failure. Just case 2 was alive and developed gut chronic GVHD. At last follow-up (July 31, 2008), the patient was in stable state and his immunosuppressive therapy is being tapped. In conclusion, our preliminary results support the hypothesis that MSC derived from either bone marrow or umbilical cord blood, HLA-identical or HLA-mismatched, single donor’s or multiple donors’ MSCs can be used safely and has encouraging efficacy in the treatment of patients with severe acute GVHD who was refractory to conventional immunosuppressive threapy, although our result may have been influenced by the small number of patients studies and the short observation period, however, in view of the dismal outcome in patients with grades III–IV acute GVHD, MSC seems promising.