Rheumatoid arthritis (RA) is characterized by chronic inflammation of the s
ynovial joints resulting from hyperplasia of synovial fibroblasts and infil
tration of lymphocytes, macrophages and plasma cells, all of which manifest
signs of activation. All these cells proliferate abnormally, invade bone a
nd cartilage, produce an elevated amount of pro-inflammatory cytokines, met
alloproteinases and trigger osteoclast formation and activation. Some of th
e pathophysiological consequences of the disease may be explained by the in
adequate apoptosis, which may promote the survival of autoreactive T cells,
macrophages or synovial fibroblasts Although RA does not result from singl
e genetic mutations, elucidation of the molecular mechanisms implicated in
joint destruction has revealed novel targets for gene therapy. Gene transfe
r strategies include inhibition of pro-inflammatory cytokines, blockade of
cartilage-degrading metalloproteinases, inhibition of synovial cell activat
ion and manipulation of the Th1-Th2 cytokine balance. Recent findings have
iluminated the idea that induction of apoptosis in the rheumatoid joint can
be also used to gain therapeutic advantage in the disease. In the present
review we will discuss different strategies used for gene transfer in RA an
d chronic inflammation. Particularly, we will highlight the importance of p
rogrammed cell death as a novel target for gene therapy using endogenous bi
ological mediators, such as galectin-1, a beta -galactoside-binding protein
that induces apoptosis of activated T cells and immature thymocytes.