Acute Graft-versus-host disease (aGvHD) classically develops within 100 days after allogeneic stem cell transplantation. The condition is characterized by sequential pathophysiologic events leading to tissue damage. Target organs are skin, liver, gut, but also hematopoiesis and the lung. The incidence of aGvHD is approx. 20-80% and graded according to organ involvement and clinical symptoms. Grade III-IV is significantly associated with mortality and morbidity caused by organ failure and a high rate of infections [1, 2].

The first-line treatment of aGvHD is primarily through steroids in combination with established immunosuppressive drugs like methotrexat, sirolimus, and mycophenolate [3, 4]. Steroid-refractory (SR) is representing more than 50% of aGvHD III-IV and is associated with poor outcome [5]. There are no guidelines for second-line treatment options for steroid-refractory aGvHD and best available treatment is associated with significant side-effects (prolonged immune-suppression). Therapeutic options for SR-aGvHD are highly needed and will significantly improve the outcome of allo-HSCT.

MSCs show significant and encouraging results in the treatment of aGvHD with response rates of approximately 50% [6-8]. First clinical studies showed promising results for Alpha-1-Antitrypsin in steroid resistant GvHD [9]. The commercially available substance isolated from human derived plasma is considered as safe (MA for AAT-deficiency)[10]. MSC-expressed AAT will be safe, since the maximal clinical dose (200x106 MSC/ infusion) generate approximately 1,3 mg AAT in 48 h. The total amount of AAT in human serum for a 70 kg patient is 6800 mg. The added AAT corresponds therefore only to 0.03% of the total amount.

From the scientific point of view, the combination of MSC and locally active AAT will add synergistic activity. MSc-AAT showed positive effects in murine in vivo models for aGvHD with improved efficacy compared to native MSC or plasma-derived AAT, respectively. Therefore, we hypothesize that MSc-AAT act synergistically in patients and may improve the rate of complete response significantly in aGvHD without the risk of prolonged immunosuppression.

Approximately 22,000 bone marrow transplants are performed annually in the United States. Up to 30% of the recipients of stem cells or bone marrow transplantation from HLA-identical related donors and up to 80% of those who receive cells from other sources will develop at least Grade 2 aGvHD despite immunosuppressive prophylaxis. The initial management of acute GvHD consists of high dose steroids. But only approximately 50% of patients improve with either a complete response (CR) or partial response (PR) following treatment with steroids. Even patients that respond to steroid therapy have a reduced long term survival (36% for responders versus 17% for non-responders at 2 years). A plethora of commercially available products and experimental therapies are being tested in steroid resistent aGvHD in clinical trials.

In preclinical models we could demonstrate a superior effect for MSC-AAT. MSC-AAT were at least 100 fold more effective than native MSC´s in a xenogenic GvHD model.