The activity of immunoregulatory T cells mediating active tolerance is potentiated in nonobese diabetic mice by an IL-4-based retroviral gene therapy.
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.
Yamamoto
A M
AM
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.
Chernajovsky
Y
Y
Lepault
F
F
Podhajcer
O
O
Feldmann
M
M
Bach
J F
JF
Chatenoud
L
L
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics*; D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007110:Immunity, Active / Q000235:genetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D007515:Islets of Langerhans / Q000473:pathology; D019041:L-Selectin / Q000096:biosynthesis; D017710:Lymphocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D019076:Transgenes / Q000276:immunology; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019041:L-Selectin; D015847:Interleukin-4; D001616:beta-Galactosidase