Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis
Yoshitaka Morita, … , Kevin T. McDonagh, David A. Fox
Yoshitaka Morita, … , Kevin T. McDonagh, David A. Fox
Published May 15, 2001
Citation Information: J Clin Invest. 2001;107(10):1275-1284. https://doi.org/10.1172/JCI11490.
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Article

Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis

Abstract

Dendritic cells (DCs) are specialized antigen-presenting cells that migrate from the periphery to lymphoid tissues, where they activate and regulate T cells. Genetic modification of DCs to express immunoregulatory molecules would provide a new immunotherapeutic strategy for autoimmune and other diseases. We have engineered bone marrow–derived DCs that express IL-4 and tested the ability of these cells to control murine collagen-induced arthritis (CIA), a model for rheumatoid arthritis in which Th1 cells play a critical role. IL-4–transduced DCs inhibited Th1 responses to collagen type II in vitro. A single injection of IL-4–transduced DCs reduced the incidence and severity of CIA and suppressed established Th1 responses and associated humoral responses, despite only transient persistence of injected DCs in the spleen. In contrast, control DCs and IL-4–transduced T cells or fibroblastic cells failed to alter the course of the disease. The functional effects correlated well with the differential efficiency of DC migration from various sites of injection to lymphoid organs, especially the spleen. The ability of splenic T cells to produce IL-4 in response to anti-CD3 was enhanced after the administration of IL-4–transduced DCs. These results support the feasibility of using genetically modified DCs for the treatment of autoimmune disease.

Authors

Yoshitaka Morita, Jianmin Yang, Raj Gupta, Koichi Shimizu, Eric A. Shelden, Judith Endres, James J. Mulé, Kevin T. McDonagh, David A. Fox

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Efficiency of migration of DCs injected subcutaneously, intravenously, o...
Efficiency of migration of DCs injected subcutaneously, intravenously, or intraperitoneally to spleen and lymph nodes. (a) Functional migration assay. A total of 3 × 105 IL-4–transduced DCs pulsed with KLH were injected subcutaneously (s.c.), intravenously (i.v.), or intraperitoneally (i.p.). Spleen and inguinal lymph nodes were harvested 5 days after DC injection, and the isolated cells were cultured with (filled bars) or without (open bars) KLH (50 μg/ml). Cells from mice with no treatments were used as a control. Proliferation was measured as [3H]thymidine incorporation during the last 16 hours of the 72-hour culture. The results are expressed as mean cpm ± SEM from triplicate cultures. (b and c) Migration to spleen of EGFP-transduced DCs injected. A total of 3 × 106 EGFP-transduced DCs were injected subcutaneously, intravenously, or intraperitoneally into mice. Twenty-four hours later, spleens were removed, and the single-cell suspensions were analyzed by flow cytometry. At least 2 × 106 living cells were analyzed. Spleen cells from mice with no treatment were used as a negative control. Representative data are shown in b. (c) Mean percentage ± SEM of EGFP+ cells in spleen from two individual mice per group from which the control background is subtracted.