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Red blood cell alloimmunization is a major complication of transfusion therapy. Host immune markers that can predict antibody responders remain poorly described. As regulatory T cells (Tregs) play a role in alloimmunization in mouse models, we analyzed the Treg compartment of a cohort of chronically transfused patients with sickle cell disease (SCD, n = 22) and β-thalassemia major (n = 8) with and without alloantibodies. We found reduced Treg activity in alloantibody responders compared with nonresponders as seen in mice. Higher circulating anti-inflammatory IL-10 levels and lower IFN-γ levels were detected in non-alloimmunized SCD patients. Stimulated sorted CD4+ cells from half of the alloimmunized patients had increased frequency of IL-4 expression compared with nonresponders, indicating a skewed T helper (Th) 2 humoral immune response in a subgroup of antibody responders. All patients had increased Th17 responses, suggesting an underlying inflammatory state. Although small, our study indicates an altered immunoregulatory state in alloantibody responders which may help future identification of potential molecular risk factors for alloimmunization. Am. J. Hematol. 2011. © 2011 Wiley-Liss, Inc.

Transfusion therapy is a life-sustaining treatment for patients with sickle cell disease (SCD), but can cause serious complications including alloimmunization. We previously reported diminished regulatory T cells (Tregs) and skewed Th2 responses in alloimmunized SCD patients. We hypothesized that the B cell regulatory (Breg) compartment, which controls Treg and Th differentiation, may also be compromised in allosensitized SCD patients. Phenotypically, we did not find differences in the frequency or numbers of CD24hiCD38hi and CD24hiCD27+ B cell subsets, both previously identified as human Bregs, between alloimmunized and non-alloimmunized SCD patients on regular transfusions. However, at the functional level, CD19+ B cells from alloimmunized SCD patients expressed lower levels of IL-10 following stimulation as compared with non-alloimmunized patients (P < 0.05), and had reduced ability in inhibiting autologous CD14+ monocyte TNF-α expression (P < 0.05). These findings suggest that Bregs from alloimmunized and non-alloimmunized SCD patients differ in their ability to produce IL-10 and dampen monocyte activation, all consistent with an altered immunoregulatory state in alloimmunized SCD patients. Am. J. Hematol. 88:736–740, 2013. © 2013 Wiley Periodicals, Inc.