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Splenocytes from nonobese diabetic mice overexpressing murine IL (mIL)-4 upon recombinant retrovirus infection lose their capacity to transfer diabetes to nonobese diabetic-scid recipients. Diabetes appeared in 0-20% of mice injected with mIL-4-transduced cells vs 80-100% of controls injected with beta-galactosidase-transduced cells. Protected mice showed a majority of islets (60%) presenting with noninvasive peri-insulitis at variance with beta-galactosidase controls that exhibited invasive/destructive insulitis. Importantly, in all recipients, the transduced proteins were detected within islet infiltrates. Infiltrating lymphocytes from recipients of mIL-4-transduced cells produced high levels of mIL-4, as assessed by ELISA. In recipients of beta-galactosidase-transduced cells, approximately 60% of TCRalphabeta(+) islet-infiltrating cells expressed beta-galactosidase, as assessed by flow cytometry. The protection from disease transfer is due to a direct effect of mIL-4 gene therapy on immunoregulatory T cells rather than on diabetogenic cells. mIL-4-transduced purified CD62L(-) effector cells or transgenic BDC2.5 diabetogenic T cells still transferred disease efficiently. Conversely, mIL-4 transduction up-regulated the capacity of purified immunoregulatory CD62L(+) cells to inhibit disease transfer. These data open new perspectives for gene therapy in insulin-dependent diabetes using T cells devoid of any intrinsic diabetogenic potential.

Original publication

DOI

10.4049/jimmunol.166.8.4973

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

04/2001

Volume

166

Pages

4973 - 4980

Addresses

Institut National de la Santé et de la Recherche Médicale Unité 25, and Centre National de la Recherche Scientifique Unité MR8603, Hôpital Necker, Paris, France.

Keywords

Islets of Langerhans, Spleen, T-Lymphocyte Subsets, Cells, Cultured, Clone Cells, Animals, Mice, Inbred NOD, Mice, Transgenic, Mice, Mice, SCID, Retroviridae, Diabetes Mellitus, Type 1, beta-Galactosidase, L-Selectin, Receptors, Antigen, T-Cell, alpha-beta, Interleukin-4, Adjuvants, Immunologic, Lymphocyte Transfusion, Gene Therapy, Adoptive Transfer, Cell Movement, Immune Tolerance, Immunity, Active, Transgenes, Genetic Vectors, Female