PMID- 12352878 OWN - NLM STAT- MEDLINE DCOM- 20021023 LR - 20190713 IS - 0041-1337 (Print) IS - 0041-1337 (Linking) VI - 74 IP - 5 DP - 2002 Sep 15 TI - Rhesus monocyte-derived dendritic cells modified to over-express TGF-beta1 exhibit potent veto activity. PG - 629-37 AB - BACKGROUND: The tolerogenic activity of allogeneic bone marrow cells (BMCs) associates with functional inactivation of alloreactive T cells and has been attributed to a veto effect. Studies in mice and rhesus monkeys indicated that the CD8alpha molecule expressed on a subpopulation of allogeneic BMCs is necessary to induce signal transduction within the BMCs to increase veto effector molecules such as transforming growth factor (TGF)-beta1. In vitro activation of alloreactive cytotoxic T-lymphocyte precursor enhances their susceptibility to veto-mediated functional inactivation by specific alloantigen-bearing BMCs. Accordingly, we examined a hypothesis that mature rhesus monkey (Rh) monocyte-derived dendritic cells (MDDCs) modified by gene transfer to over-express active TGF-beta1 might mediate veto activity without the need to express CD8alpha. METHODS: Rh MDDCs were modified by recombinant adenovirus (Ad) transduction and characterized by phenotype and functional studies. RESULTS: Rh MDDC transduction with Ad vectors using conventional methods was remarkably inefficient. However, a single-chain anti-CD40/soluble Coxsackie and adenovirus receptor-fusion protein (G28/sCAR) permitted high-efficiency transduction of Rh MDDCs by retargeting Ad to Rh MDDC CD40. Mature Rh MDDCs that were transduced to overexpress active TGF-beta1 (AdTGF-beta1 Rh MDDC) significantly suppressed alloimmune responses in [ H]thymidine uptake mixed leukocyte reaction assays. We showed by the carboxyfluorescein succinimidyl ester dilution method that allogeneic mature AdTGF-beta1 Rh MDDCs inhibited proliferation of CD4 and CD8 responder T cells. Notably, AdTGF-beta1 Rh MDDC abrogated alloimmune responses induced by control AdGFP Rh MDDC in an antigen-specific manner. CONCLUSIONS: These results suggest that nonhuman primate mature MDDCs can be genetically engineered to function as alloantigen-specific cellular immunosuppressants, an approach that has potential to facilitate induction of allograft tolerance in vivo. FAU - Asiedu, Clement AU - Asiedu C AD - Department of Surgery, Division of Transplant Immunology, University of Alabama at Birmingham, 35294, USA. FAU - Dong, Sai S AU - Dong SS FAU - Pereboev, Alexander AU - Pereboev A FAU - Wang, Weila AU - Wang W FAU - Navarro, Jesus AU - Navarro J FAU - Curiel, David T AU - Curiel DT FAU - Thomas, Judith M AU - Thomas JM LA - eng GR - N01 CO-97110/CO/NCI NIH HHS/United States GR - R01 CA86881/CA/NCI NIH HHS/United States GR - R21 AI44322/AI/NIAID NIH HHS/United States GR - U19 DK57858/DK/NIDDK NIH HHS/United States GR - U19DK57958/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Transplantation JT - Transplantation JID - 0132144 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (B7-1 Antigen) RN - 0 (B7-2 Antigen) RN - 0 (CD40 Antigens) RN - 0 (HLA-DR Antigens) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (Luminescent Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (Transforming Growth Factor beta) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 3.2.1.23 (beta-Galactosidase) SB - IM MH - Adenoviridae MH - Animals MH - Antibodies, Monoclonal MH - Antigens, CD/immunology MH - B7-1 Antigen/immunology MH - B7-2 Antigen MH - CD40 Antigens/immunology MH - Dendritic Cells/*immunology MH - Flow Cytometry MH - Genes, Reporter MH - Green Fluorescent Proteins MH - HLA-DR Antigens/immunology MH - Lipopolysaccharide Receptors/immunology MH - Luminescent Proteins/genetics/metabolism MH - Lymphocyte Culture Test, Mixed MH - Macaca mulatta MH - Membrane Glycoproteins/immunology MH - Monocytes/*immunology MH - Transduction, Genetic MH - Transforming Growth Factor beta/*genetics MH - beta-Galactosidase/genetics/metabolism EDAT- 2002/09/28 04:00 MHDA- 2002/10/31 04:00 CRDT- 2002/09/28 04:00 PHST- 2002/09/28 04:00 [pubmed] PHST- 2002/10/31 04:00 [medline] PHST- 2002/09/28 04:00 [entrez] AID - 10.1097/00007890-200209150-00008 [doi] PST - ppublish SO - Transplantation. 2002 Sep 15;74(5):629-37. doi: 10.1097/00007890-200209150-00008.