It is hypothesized that the local delivery of anti-inflammatory proteins by adoptive cellular gene therapy using retrovirally transduced type two collagen (CII)-specific T-cell hybridomas or autologous dendritic cells (DCs) in a murine model of rheumatoid arthritis (RA), collagen induced arthritis (CIA), will provide therapeutic effects. In addition, through the use of microarray technology, it will be possible to study changes in gene expression following successful therapy, leading to insights into the mechanisms of action of successful therapeutic regimens in this animal model and possible identification of new targets for immune intervention with potential use in human disease. This hypothesis will be explored through three specific aims:
SpecificAim #1 : To study the effects of combining IL-12p40 or IL-4 with anti-TNF or Gal-1 using local delivery of these molecules by adoptive cellular gene therapy using retrovirally transduced CII-specific T-cell hybridomas in CIA;
Specific Aim #2 : To use the retroviral vectors developed previously in our lab to transduce autologous DCs for adoptive cellular gene therapy and trafficking studies in vivo;
and Specific Aim #3 : To use cDNA microarray technology to assess gene expression patterns in treated versus untreated joints in an attempt to assess mechanism(s) of therapy in mice with CIA that were successfully treated by adoptivecellular gene therapy and to identify additional potential targets of therapy (molecules or pathways) through gene identification and characterization. It is hoped that these studies will allow transfer of the technology by adaptation of adoptive cellular gene therapy to human RA.
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