Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4+CD25highCD127low/− regulatory T cells

Defects in central and peripheral tolerance are thought to contribute to life-threatening graft-versus-host disease (GvHD), a severe complication following allogeneic stem cell transplantation (SCT). Recent investigations have demonstrated regulatory T cells (Tregs) to suppress allogeneic immune reactions. Therefore, SCT patients with no or critically low numbers of Tregs may have an increased risk of GvHD. To address this hypothesis, we analyzed the recovery of CD4+CD25highCD127low/− Tregs in the peripheral blood of patients who have never developed GvHD (n= 6), patients who developed acute/chronic GvHD (n=18), and patients who developed chronic GvHD without an earlier acute manifestation (n=5) every 30 days for the first 6 months after peripheral blood SCT (PBSCT). The number of Tregs continuously improved in acute/chronic GvHD patients, but always remained lower than Tregs quantified in patients who never developed a GvHD. In contrast, chronic GvHD patients who did not develop acute GvHD earlier displayed significantly increased Treg cell numbers at the timepoint of chronic inflammation. These results indicate that numerically deficient Tregs following PBSCT are associated with the development of acute but not chronicAllogeneic stem cell transplantation (SCT) is an effective strategy for treating hematological malignancies. However, graft-versus-host disease (GvHD) following SCT occurs in about one third of HLA-matched related donor transplantations and in about two thirds of patients who are transplanted from an HLA-mismatched and/or -matched unrelated donor [1] with a mortality rate up to 50–60% [2]. T cell depletion from the graft represents an effective approach but favors graft-rejection and aborts the graftversus- leukemia effect. Evidence demonstrating the pivotal role that regulatory T cells (Tregs) play in GvHD development include the observation that adoptive transfer of Tregs in rodent models ameliorates this allogeneic immune response and depletion of Tregs from the stem cell graft accelerates GvHD [3–6]. Initial promising results from a clinical study investigating the adoptive transfer of donor Tregs in an HLA haploidentical setting suggest that human Tregs provide beneficial effects against the development of GvHD [7]. Human studies investigating the impact of Tregs on GvHD following allogeneic SCT are conflicting, possibly due to the heterogeneity of study populations. In acute GvHD, reduced frequencies of Tregs have been shown independently of the stem cell source [8]. A study in chronic GvHD has observed increased CD4+CD25high Treg cell numbers including a high number of peripheral blood stem cell transplantations (PBSCT) [9]. In contrast, others identified decreased frequencies of circulating Tregs in chronic GvHD patients [10, 11]. However, these studies included a higher number of bone marrow (BMT) and cord blood transplantations. Here, we present the kinetic reconstitution of CD4+CD25high CD127low/− Tregs during the first 6 months following