Apoptosis as a target for gene therapy in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and infiltration of lymphocytes, macrophages and plasma cells, all of which manifest signs of activation. All these cells proliferate abnormally, invade bone and cartilage, produce an elevated amount of pro-inflammatory cytokines, metalloproteinases and trigger osteoclast formation and activation. Some of the pathophysiological consequences of the disease may be explained by the inadequate apoptosis, which may promote the survival of autoreactive T cells, macrophages or synovial fibroblasts. Although RA does not result from single genetic mutations, elucidation of the molecular mechanisms implicated in joint destruction has revealed novel targets for gene therapy. Gene transfer strategies include inhibition of pro-inflammatory cytokines, blockade of cartilage-degrading metalloproteinases, inhibition of synovial cell activation 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 and chronic inflammation. Particularly, we will high-light the importance of programmed cell death as a novel target for gene therapy using endogenous biological mediators, such as galectin-1, a beta-galactoside-binding protein that induces apoptosis of activated T cells and immature thymocytes.
Rabinovich
G A
GA
Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires, Córdoba 2351, 3er Piso, 1120 Buenos Aires, Argentina. gabyrabi@ciudad.com.ar
D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D015415:Biomarkers; D016207:Cytokines / Q000276:immunology*; D037161:Galectins; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006388:Hemagglutinins / Q000502:physiology; D006801:Humans
D015415:Biomarkers; D016207:Cytokines; D037161:Galectins; D006388:Hemagglutinins