http://www.medpagetoday.com/tbprint.cfm?tbid=21437

Allogeneic mesenchymal stem cell transplantation resulted in improvements in disease activity, serologic markers, and renal function in patients with refractory systemic lupus erythematosus (SLE), a pilot study conducted in China found.

Twelve months after stem cell transplantation, scores on the SLE disease activity index among 12 patients fell to 3.2 from a baseline score of 12.1 (P<0.05), according to Jun Liang, MD, of Nanjing University, and colleagues. Four of those patients showed "remarkable improvement" at one year, with scores of zero, the researchers reported online in the Annals of the Rheumatic Diseases. Some patients with refractory SLE remain symptomatic and at risk for progressive organ damage, including lupus nephritis, even with highly potent immunosuppressive regimens.

Hematopoietic stem cell transplantation has been tried in a few cases and led to some improvement, but was associated with mucositis, infections, and pulmonary injury. Mesenchymal stem cells are less immunogenic then hematopoietic stem cells, because they lack the expression of costimulatory molecules and can escape alloantigen recognition. Recent studies have suggested that mesenchymal stem cells from patients with SLE are defective in several ways, including their cytokine secretion, phenotype, growth, and immunomodulatory activities. Liang and colleagues therefore hypothesized that SLE is a mesenchymal stem cell-mediated disease, and suggested that allogenic, rather than autologous, bone marrow mesenchymal stem cell transplantation might be an effective treatment. So between March 2007 and November 2008 they enrolled 15 patients (14 women) with refractory disease along with healthy family member donors. The patients' average age was 28.3 years, and average disease duration was 91.1 months.

Maintenance treatment one month after the transplantation included prednisone, 5 to 10 mg/day, and cyclophosphamide, 0.4 to 0.6 g every two to three months. No other immunosuppressive medications were permitted unless a patient relapsed. Mean follow-up was 17.2 months, and 13 of the patients had been followed for at least one year. All patients experienced a reduction in 24-hour proteinuria, which decreased significantly by one week from 2,538 mg to 1,430 mg (P<0.01). Among 11 patients who had longstanding fatigue, weight loss, or low-grade fever, eight no longer had these symptoms three months after transplantation. Additionally, in eight patients who had cutaneous manifestations, severe lesions healed completely in four and at least partially in the other four. Arthritis improved in four of six patients who had musculoskeletal involvement, serositis resolved in two, neurologic manifestations cleared in one, and refractory hypertension became controllable in five. Antibody levels also fell, with serum titers of anti-double stranded DNA antibodies reaching a statistically significant difference from baseline at one and three months (P<0.05). Two patients relapsed, one at six months and the other at 24 months. No serious adverse events were seen during follow-up.

Possible mechanisms by which allogeneic mesenchymal stem cell transplantation might improve lupus include altering the cytokine profile toward a Th1 phenotype and expansion of regulatory T cells, which suppress the activity of autoreactive T cells, according to the researchers. In this study, the effect of transplantation on regulatory T cells was assessed by flow cytometric analysis of the Foxp3+ CD4 T-cell subset, determining that the percentage of these cells increased to 4.58 from 2.56 (P<0.05) at baseline.

Another possible mechanism involves the ability of mesenchymal stem cells to differentiate into endothelial cells. Patients with lupus exhibit excessive endothelial cell apoptosis by serum IgG, and alterations in endothelial cells are thought to contribute to nephron damage.

"We hypothesize that, to some extent, differentiation of [mesenchymal stem cells] to endothelial cells reconstructs the structure of the nephron and improves renal function," Liang and colleagues wrote.

However, they added, there are as yet no data to confirm or refute this hypothesis.

They noted that their follow-up was short, and that randomized trials will be needed to test this approach against more conventional therapies and to clarify clinical response criteria, post-transplant immunotherapy, and treatment of relapses.

July 29, 2010 (MedPage Today)