BACKGROUND: Alloimmunization after exposure to donor red cell (RBC) antigens remains a major clinical problem in transfusion medicine, particularly for patients in need of chronic transfusions. The identification of T regulatory cells (Tregs) among the CD4+CD25+ T cell subset as key regulators of peripheral tolerance in mice as well as humans has opened an exciting era in the prevention and treatment of autoimmune disease and for improving organ transplantation. However, their potential in inducing transfusion tolerance so as to prevent or blunt the alloimmune response to allogeneic red cells has not been explored.

METHODS AND RESULTS: To determine a role for Tregs in control of alloimmune responses, we have manipulated Treg numbers by either depletion of CD25-expressing cells or transfer of purified CD4+CD25+ Treg cells in two different mouse models of RBC immunization. Using a mouse model of RBC immunization in which weekly injection of rat RBCs results in the development of antibodies to rat red cells, we previously showed that depletion with anti-CD25 increased the antibody response to rat RBCs (

Mqadmi et al., 2005, Blood, 105, 3746
). We now found that adoptive transfer of purified populations of CD4+CD25+ cells from non-primed C57/Bl6 mice into naïve syngeneic recipients (n=9) completely inhibited the anti-Ig response to rat RBCs in 8 out of 9 mice even up to 5 weeks post-immunization but transfer of control CD4+CD25- cells did not (p=0.029). As an experimental system to study regulation of antibody production following allogeneic RBC transfusion, we used red cells (equivalent to either 1 or 2 packed red cell units) from mice transgenic for human glycophorin A (GPA) blood group antigen as donor cells and transfused wild type C57/Bl6 mice to induce alloantibodies. We found that depletion with anti-CD25 enhanced the alloantibody (IgG and IgM) production (p=0.042), indicating that CD25 Tregs play an important role in regulation of alloantibody responses. More importantly, adoptive transfer of purified splenic population of CD4+CD25+ from naïve mice prevented the induction of IgG and IgM alloantibody production in transfusion recipients (n=8).

CONCLUSIONS: Altogether, our results demonstrate that Tregs control transfusion-associated alloantibody responses. Our data indicate that Treg immunotherapy by enhancement of Treg function may be exploited for future therapeutic approaches for suppressing transfusion immunization events.

Topics:
alloimmunization, antigens, cd25, erythrocytes, regulatory t-lymphocytes, isoantibodies, transfusion, immunoglobulin g, immunoglobulin m, transfer technique, antibodies

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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