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Suppression of Disease in New Zealand Black/New Zealand White Lupus-Prone Mice by Adoptive Transfer of Ex Vivo Expanded Regulatory T Cells¹

Kenneth J. Scalapino^*, Qizhi Tang, Jeffrey A. Bluestone, Mark L. Bonyhadi and David I. Daikh^2,*

^* Department of Medicine, Division of Rheumatology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121; Department of Medicine, University of California San Francisco Diabetes Center, University of California San Francisco, San Francisco, CA 94121; and Xcyte, Seattle, WA 98104

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_regs play a role in systemic lupus erythematosus, we evaluated T_reg prevalence and function in (New Zealand Black x New Zealand White)F₁ (B/W) lupus-prone mice. To explore the potential of T_regs 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 T_regs 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.

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