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

Abstract

An increasing number of studies indicate that a subset of CD4+ T cells with regulatory capacity (regulatory T cells; Tregs) can function to control organ-specific autoimmune disease. To determine whether abnormalities of thymic-derived Tregs play a role in systemic lupus erythematosus, we evaluated Treg prevalence and function in (New Zealand Black × New Zealand White)F1 (B/W) lupus-prone mice. To explore the potential of Tregs to suppress disease, we evaluated the effect of adoptive transfer of purified, ex vivo expanded thymic-derived Tregs 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+CD62Lhigh B/W Tregs 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 Tregs 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.

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…In a recent study by Scalapino and colleagues, it was demonstrated that the peripheral Treg frequency in the NZB/W F1 lupus strain of mice was reduced at a young age (8-10 wk). In contrast, in the aged diseased mice (48-52 wk), Treg frequency was found to be significantly increased in the renal draining lymph nodes while it was decreased in the spleen as compared to normal BALB/c mice [45]. The disparity in findings from the present study may reflect differences in the kinetics of disease progression, in relation to the age-dependent Treg changes, between the MRL/lpr and NZB/W strains.…”

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

“…We have previously reported that older B6.NZBc13 mice exhibit almost half the proportion of Tregs than age-matched B6 mice [5]. As exogenous transfer of Tregs has been shown to delay disease progression and autoantibody production in lupus prone NZB/W F1 mice, Tregs derived from B6 BM cells may be responsible for the regulation of T-cell tolerance and antibody production seen in B6.NZBc13 MC mice [33,34]. Alternatively, the identification of an apoptotic debris clearance defect on NZB c13 suggests that the failure to effectively clear apoptotic debris contributes to the breach of tolerance in these mice.…”

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

“…Interestingly, in a similar study, it was demonstrated that peripheral Treg frequency in the NZB/W F1 strain of mice, another spontaneous lupus mouse model, was rather reduced at young age. In contrast, in the aged and diseased mice, a higher Treg frequency was detected in the renal draining lymph nodes, though also decreased in the spleen, as compared to normal BALB/c mice [50]. This may again reflect the differences in severity and kinetics of disease progression, in relation to the age-dependent Treg cell changes, between the MRL/lpr and NZB/W F1 strains.…”

“…Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90]. Again, alternative findings demonstrating lupus Treg being functionally normal [49,50,62,67,85], or at least normal in majority of patients tested [48,64], or even enhanced in some way [68,80,87] added further confusion as well as interest to the matter. Upon a closer examination, these seemingly discrepant findings can in fact be logically explained.…”