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

Abstract

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(+)CD25(high)CD127(low/-) 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 chronic GvHD.

T cell Reconstitution in Allogeneic Haematopoietic Stem Cell Transplantation: Prognostic Significance of Plasma Interleukin‐7

“…Therefore, increased availability of IL-7 may enhance peripheral expansion in response to both high-affinity and low-affinity antigens [8] and may promote alloreactivity to low-affinity minor antigens and thereby progression to aGVHD. In addition, elevated IL-7 levels may cause a functional shift within the T cell compartment, as IL-7 has minimal impact on the homoeostatic proliferation of regulatory T cells (Tregs) [33,43] that are thought to inhibit the development of aGVHD and found at reduced levels in patients with aGVHD [44,45].…”

Mechanistic approaches for the prevention and treatment of chronic GVHD

“…56,62 Impaired Treg reconstitution appears predictive for subsequent chronic GVHD in some, but not all, studies. 57,[62][63][64][65] Analysis of Treg homeostasis after HSCT has shown that Treg deficiency after HSCT appears to result primarily from decreased thymic production of Tregs. Although there is a compensatory increased homeostatic proliferation of circulating memory Tregs, this is ultimately insufficient to prevent Treg deficiency, due in part to proliferation-induced telomere shortening, 66 enhanced death signaling, and apoptosis of rapidly dividing Treg.…”

Chemokine-mediated tissue recruitment of CXCR3+ CD4+ T cells plays a major role in the pathogenesis of chronic GVHD

“…8 However, literature regarding Tregs is still controversial, with a reduction in CD4 ϩ CD25 high CD127 low Tregs being associated with aGVHD but not cGVHD. 9 Clarke et al reported an increase of peripheral Tregs in patients with cGVHD. 10 More recently, Th17 ϩ T cells have also been implicated in the pathogenesis of the disease.…”