Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo, expanded regulatory T cells

An increasing number of studies indicate that a subset of CD4(+) T cells with regulatory capacity (regulatory T cells; T-regs) can function to control organ-specific autoimmune disease. To determine whether abnormalities of thymic-derived T,,g, play a role in systemic lupus erythematosus, we evaluated T-reg prevalence and function in (New Zealand Black X New Zealand White)F-1 (B/W) lupus-prone mice. To explore the potential of T-g to suppress disease, we evaluated the effect of adoptive transfer of purified, ex vivo expanded thymic-derived T-regs on the progression of renal disease. We found that although the prevalence of Tregs is reduced in regional lymph nodes and spleen of prediseased B/W mice compared with age-matched non-autoimmune mice, these cells increase in number in older diseased mice. In addition, the ability of these cells to proliferate in vitro was comparable to those purified from non-autoimmune control animals. Purified CD4(+)CD25(+)CD62L(high) B/W T-regs were expanded ex vivo 80-fold, resulting in cells with a stable suppressor phenotype. Adoptive transfer of these exogenously expanded cells reduced the rate at which mice developed renal disease; a second transfer after treated animals had developed proteinuria further slowed the progression of renal disease and significantly improved survival. These studies indicate that thymic-derived T-regs may have a significant role in the control of autoimmunity in lupus-prone B/W mice, and augmentation of these cells may constitute a novel therapeutic approach for systemic lupus erythematosus.