Frequency of CD4+CD25hiFOXP3+ Regulatory T Cells Has Diagnostic and Prognostic Value as a Biomarker for Acute Graft-versus-Host-Disease

Abstract

The relationship between regulatory T cells (Tregs) and acute graft-versus-host disease (GVHD) in clinical allogeneic bone marrow transplantation (BMT) recipients is not well established. We conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4+CD25hiFOXP3+ lymphocytes in 215 BMT patients. Autologous BMT patients (N=90) and allogeneic BMT patients without GVHD (N=65) had similar Treg frequencies, whereas allogeneic patients with GVHD (N=60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset and correlated with eventual maximum grade of GVHD (p<0.001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (p=0.003). Patients with Treg frequencies less than the median had higher non-relapse mortality than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at two years (38% vs. 63%, p=0.03). Treg frequency may therefore have important prognostic value as a biomarker of acute GVHD.

Stem cell source-dependent reconstitution of FOXP3+ T cells after pediatric SCT and the association with allo-reactive disease

“…In line with several previous studies in adult patients 19,20 and with one other pediatric study, 22 we found in our pediatric patient group a strong inverse correlation between FOXP3 þ T-cell frequencies early after HSCT and the development of alloreactive disease. This correlation also held true for the number of FOXP3 þ T cells within the grafts and alloreactivity.…”

“…As has previously been shown in adult patients, 20 pediatric patients who developed allo-reactive disease showed lower proportions of FOXP3 þ T cells before the development of alloreactive disease than patients who did not develop allo-reactive disease (P ¼ 0.01, Figure 1b). Owing to the low number of patients per subgroup, analysis according to stem cell source was not possible.…”

“…FOXP3 þ T-cell frequencies early after pediatric HSCT showed a strong inverse correlation with the development of early allo-reactive disease, this is similar to what has been shown in adult patients. 17,19,20,29 In the first weeks following HSCT, the T-cell compartment repopulates rapidly through lymphopenia-induced expansion of mature T cells contained within the stem cell allograft. At this early stage, the thymus has a minor role in T-cell reconstitution also in children.…”

“…Clinical studies in adult patients have shown increased FOXP3 þ Treg proportions in the donor graft or FOXP3 þ Treg proportions early after HSCT to be negatively correlated with aGvHD. 5,[17][18][19][20][21] In pediatric patients, data on such a correlation are very few. 22 The aim of this single-center study is to obtain a clearer insight into the reconstitution pattern of FOXP3 þ T cells in pediatric MSD, MUD and UCB HSCT recipients, and the possible relationship to the development of early allo-reactive disease.…”

Reconstitution of regulatory T-cell subsets after allogeneic hematopoietic SCT

“…2,3 Several studies correlating Treg reconstitution and GVHD suggest that an imbalance between effector T cells and Tregs within the GVHD process may be more important than the absolute numbers of circulating Tregs. [4][5][6][7] However, Tregs are a heterogeneous population. Indeed, just as for conventional T cells, naive (nTreg) and memory Treg (mTreg) subsets have already been described.…”