Immunoregulation in human bone marrow transplantation?

Comment on Miura et al, page 2187

Quantification of Foxp3 messenger RNA was used to evaluate the reconstitution of the regulatory T-cell compartment after bone marrow transplantation.

CD4⁺ T cells that constitutively express the alpha chain of the interleukin 2 (IL-2) receptor (CD25) are enriched in thymus-derived suppressor cells that preferentially express Foxp3, a forkhead/winged-helix transcriptional regulator.¹  In the study presented by Miura and colleagues, Foxp3 mRNA was quantified in mononuclear cells (MNCs) to monitor regulatory T-cell reconstitution after autologous or allogeneic bone marrow transplantation (BMT). The authors detected lower Foxp3 expression levels in patients with graft-versus-host disease (GVHD) compared with patients without GVHD after allogeneic BMT as well as in breast cancer patients developing an autoimmune syndrome (autologous GVHD) that was purposely induced by the administration of cyclosporine A after highdose chemotherapy. Diminished Foxp3 expression correlated with a low number of T-cell receptor excision circles (TRECs) in MNCs from GVHD patients, suggesting that regulatory T cells regenerate from thymic precursors and that thymic dysfunction in autologous and allogeneic GVHD results in an impaired output of suppressor T cells, thereby perpetuating disease. Interestingly, response to GVHD therapy was accompanied by a recovery of the Foxp3⁺ T-cell pool in a limited number of serially examined patients.

This is the first report suggesting that suppressor cell–mediated regulation may play an important role in human GVHD pathophysiology. Although the results should be interpreted with caution, since a mere positive or negative correlation does not prove (or disprove) the biologic relevance of an observed phenomenon, they are well supported by several animal studies demonstrating a central role for regulatory T cells in the development and maintenance of peripheral tolerance to self-antigens and alloantigens.²  Sakaguchi and colleagues³  initially revealed the significance of CD4⁺CD25⁺ regulatory T cells for the protection from autoimmune diseases in mice that underwent thymectomy early in life. Similarly, adoptively transferred rat CD25⁺ regulatory T cells protect from autologous GVHD caused by cyclosporine treatment of syngeneic BM recipients.⁴  In murine models of allogeneic BMT, Johnson et al⁵  demonstrated that CD4⁺CD25⁺ regulatory T cells develop from bone marrow–derived T-cell precursors and depend on thymic maturation. Once generated, they modulate GVHD induced by the delayed infusion of donor lymphocytes.⁶  Furthermore, several groups reported that the cotransplantation of large numbers of donortype CD4⁺CD25⁺ regulatory T cells at the time of BMT protects recipients from lethal GVHD induced by nonregulatory T cells.⁶  Thus, there is increasing evidence for T-cell–mediated immunoregulation after allogeneic BMT, and the findings of Miura et al should encourage clinicians to further explore those mechanisms for the development of improved hematopoietic stem cell transplantation strategies. ▪