COMPROMISED ALLOGRAFT-REJECTION RESPONSE IN TRANSGENIC MICE EXPRESSING ANTISENSE SEQUENCES TO RETINOIC ACID RECEPTOR BETA(2)

Transgenic mice expressing antisense sequences to retinoic acid recept or beta(2) (AS-RAR beta(2) mice) were generated. The transgene was exp ressed in T cells, macrophages, and non-T spleen cells. These AS-RAR b eta(2) mice had four- to sevenfold higher endogenous RAR beta(2) messa ges in their macrophages, comparing with their nontransgenic littermat es, but the RAR beta protein level was significantly lower in these ce lls. This suggests that the antisense message interferes with RAR beta (2) translation, and there is a feedback control of the RAR beta(2) mR NA level in the macrophages. The endogenous RAR beta(2) message was no t detectable in T and B cells of either the transgenic or nontransgeni c mice. These mice appeared to be healthy upon visual inspection. When transplanted with allogenic cardiac grafts heterotopically, the mice showed significantly compromised rejection response. These mice had a decrease of the macrophage population in spleen, using the nontransgen ic littermates as references. The generation of alloantigen-specific T cell cytotoxicity was decreased in these AS-RAR beta(2) mice. These r esults suggest that macrophage development and T cell function ave aff ected by antisense expression of RAR beta(2), and that anomaly in thes e cells might be contributing factors to the compromised immune respon se observed in the AS-RAR beta(2) mice.