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A Novel Mechanism of Action for Anti-Thymocyte Globulin: Induction of CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells

Transplantation Research Center, Brigham and Women's Hospital, and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Nader Najafian, Brigham & Women’s Hospital, Transplantation Research Center, EBRC, 221 Longwood Avenue, 3rd Floor, Boston, MA 02115. Phone: 617-732-5259; Fax: 617-732-5254; E-mail: nnajafian{at}rics.bwh.harvard.edu

Received for publication May 1, 2006. Accepted for publication June 19, 2006.

T cell–depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thymocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4⁺CD25⁺ T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4⁺CD25^– into CD4⁺CD25⁺ T cells and to a lesser degree to proliferation of natural CD4⁺CD25⁺ T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoimmunity and clinical transplantation.

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