Figure 4: Evaluation of pneumonitis and sialadenitis in Treg cell- and CCR2-Treg cell-transferred MRL/lpr mice. The degrees of pneumonitis and sialadenitis of control and treated 17-week-old MRL/lpr mice were scored as described in Materials and methods. Values are presented as the mean and standard deviation (n = 5 to 7 mice per group). Similar results were observed in two independent experiments. *P < 0.01 versus control by Student's t test. CCR2-Treg cell, CD4+CD25+Foxp3+ CCR2-transfected T cell; MRL/lpr, MRL/MpJ-lpr/lpr; Treg cell, CD4+CD25+Foxp3+ T cell.

Mentions: Cultured Treg cells and CCR2-Treg cells were transferred via retro-orbital injection into 12-week-old MRL/lpr mice (at the early stage of pneumonitis and sialadenitis). Either 1 × 105 or 5 × 105 cells were injected into the mice twice every 2 weeks, and then the mice were sacrificed 3 weeks after the last injection to evaluate the pathological changes. As shown in Figures 3 and 4, MRL/lpr mice that had undergone transfer of either 1 × 105 or 5 × 105 CCR2-Treg cells demonstrated significantly reduced (P < 0.01) infiltration of mononuclear cells into the perivascular and peribronchiolar lesions and alveolar areas in comparison with Treg cell-transferred MRL/lpr mice (lesion index: perivascular 1.06 ± 0.14 versus 1.52 ± 0.22 and 0.70 ± 0.19 versus 1.41 ± 0.05, peribronchiolar 1.14 ± 0.10 versus 1.52 ± 0.19 and 0.65 ± 0.13 versus 1.54 ± 0.22, and alveolar 1.02 ± 0.13 versus 1.41 ± 0.20 and 0.71 ± 0.13 versus 1.37 ± 0.11, respectively). On the other hand, there was no significant difference of mononuclear cell infiltration in these areas among control MRL/lpr mice and mice that had undergone transfer of 1 × 105 or 5 × 105 Treg cells.

Hasegawa H, Inoue A, Muraoka M, Yamanouchi J, Miyazaki T, Yasukawa M - Arthritis Res. Ther. (2007)

Bottom Line: MRL/lpr mice to which CCR2-Treg cells had been transferred showed significantly reduced progression of pneumonitis and sialadenitis in comparison with MRL/lpr mice that had received Treg cells.This was due to more pronounced migration of CCR2-Treg cells and their localization for a longer time in MCP-1-expressing lung and submandibular gland, resulting in stronger suppressive activity.This method may provide a new therapeutic approach for organ-specific autoimmune diseases in which the target antigens remain undefined.

Affiliation: First Department of Internal Medicine, Division of Pathogenomics, Ehime University School of Medicine, Shitsukawa 454, Toon City, Ehime 791-0295, Japan. hitoshih@m.ehime-u.ac.jp

Abstract: Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in animal models of autoimmune diseases. Chemokines play an important role in the development of autoimmune diseases in animal models and humans. The present study was performed to investigate whether the progression of organ-specific autoimmune diseases could be reduced more markedly by accumulating chemokine receptor-expressing CD4+CD25+ regulatory T cells efficiently in target organs in MRL/MpJ-lpr/lpr (MRL/lpr) mice. CD4+CD25+Foxp3+ T cells (Treg cells) and CD4+CD25+Foxp3+ CCR2-transfected T cells (CCR2-Treg cells) were transferred via retro-orbital injection into 12-week-old MRL/lpr mice at the early stage of pneumonitis and sialadenitis, and the pathological changes were evaluated. Expression of monocyte chemoattractant protein-1 (MCP-1)/CCL2 was observed in the lung and submandibular gland of the mice and increased age-dependently. The level of CCR2 expression and MCP-1 chemotactic activity of CCR2-Treg cells were much higher than those of Treg cells. MRL/lpr mice to which CCR2-Treg cells had been transferred showed significantly reduced progression of pneumonitis and sialadenitis in comparison with MRL/lpr mice that had received Treg cells. This was due to more pronounced migration of CCR2-Treg cells and their localization for a longer time in MCP-1-expressing lung and submandibular gland, resulting in stronger suppressive activity. We prepared chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression by accumulating in target organs. This method may provide a new therapeutic approach for organ-specific autoimmune diseases in which the target antigens remain undefined.