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*
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;
St. Bartholomew’s and Royal London School of Medicine and Dentistry, Bone and Joint Research Unit, London, United Kingdom;
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Fundacion Campomar, Buenos Aires, Argentina; and
¶ Kennedy Institute of Rheumatology, London, United Kingdom
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 
-galactosidase-transduced cells.
Protected mice showed a majority of islets (60%) presenting with
noninvasive peri-insulitis at variance with -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 -galactosidase-transduced cells, 
60% of
TCR
+ islet-infiltrating cells expressed
-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.
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