Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

Profile of maternal CD4 T-cell effector function during normal pregnancy and in women with a history of recurrent miscarriage.

The traditional paradigm suggests that during normal pregnancy maternal immunological tolerance of the allogenic fetus is association with a maternal T-lymphocyte shift from a Th1 to a Th2 phenotype, with the opposite effect reported in patients with recurrent miscarriage. However, studies on maternal peripheral blood are conflicting. In the present study, we characterized the maternal CD4 T-cell effector subsets, including the recently described Th17 subset, during normal pregnancy (cross-sectional cohort, n=71; longitudinal cohort, n=17) and contrasted this with women with recurrent miscarriage (n=24). Longitudinal analysis of peripheral blood from normal pregnancy demonstrated a fall in the percentage of Th17 cells between the first and second trimester (P≤0.05), but no significant changes were observed across gestation or the post-natal period in Th1 or Th2 subsets. In contrast, in women with a history of recurrent miscarriage, an elevated proportion of Th17 (0.314% compared with 0.097%; P=0.0009) and Th1 (12.4% compared with 5.3%; P=0.0002) cells was detected. The suggestion that Th17 cells may have a role in the normal events of implantation and early pregnancy requires further evaluation and mechanistic studies. The results of the present study, by conducting a careful longitudinal analysis, demonstrate that a peripheral Th1/Th2 shift is not a requirement for normal pregnancy. By contrast, the profound increase in Th1 and Th17 cells in women with recurrent miscarriage indicates that peripheral immunological dysfunction may be important in this group specifically, and these assays may be important in guiding therapeutic interventions in this group and warrant further investigation to determine whether they are predictive of outcome or responses to immunomodulatory therapy.