TGF-β₁ gene modified immature dendritic cells exhibit enhanced tolerogenicity but induce allograft fibrosis in vivo

Abstract

Administration of donor-derived immature dendritic cells (DC) can prolong the survival of MHC-mismatched cardiac allografts. Genetic modification of DC by immunosuppressive molecules can enhance their potential tolerogenicity. In this study bone marrow derived immature DC were genetically modified by transforming growth factor (TGF) β1 by recombinant Ad. TGF-β₁ gene modified immature DC (TGF-β-DC) displayed a characteristic phenotype of immature DC, decreased ability to secrete interleukin 12, and reduced allostimulatory ability. TGF-β-DC induced alloantigen-specific T cell hyporesponsiveness in vitro and in vivo, and Th2 cytokine polarization. mRNA expression of donor MHC class II (Ia^b) and human TGF-β₁ was detected in spleen and lymph nodes of the allogeneic recipients for 3 weeks after TGF-β-DC infusion, indicating that microchimerism of TGF-β-DC is exhibited in allogeneic recipients. In this murine cervical heterotopic heart transplantation model, the survival of the allograft in recipients intravenously infused with TGF-β-DC 7 days before transplantation was greatly prolonged, and about 67% of cardiac grafts survived more than 40 days. Histological analysis of the allografts showed that the normal myocardial architecture was well preserved, accompanied by very little necrotic cells, but interstitial fibrosis replaced myocytes, and moderate collagen suffused the whole cardiac allograft in the recipients infused with TGF-β-DC. mRNA expression of type III procollagen was markedly increased in the allografts of the recipients infused with TGF-β-DC. Our results suggest that infusion of TGF-β₁ gene modified immature DC prolongs the survival of the allograft through the effective induction of donor-specific T cell hyporesponsiveness. However, TGF-β₁ expressed by gene modified immature DC can cause the fibrosis of the allografts, which may limit the application of this approach in the allograft transplantation.