Converting nonhuman primate dendritic cells into potent antigen-specific cellular immunosuppressants by genetic modification.
T cell depletion plus donor bone marrow cell (BMC) infusion induces long-term kidney allograft survival in a limited number of rhesus macaque recipients. Therefore, there is a need to enhance the tolerogenic activity of donor BMCs. The tolerogenic effect of donor BMCs is ascribed to a veto activity, mediated by a CD8+ subset that upregulates immunoregulatory effector molecules, transforming growth factor-beta1 (TGF-beta), and FasL, after interaction with donor-reactive cytotoxic T lymphocyte precursors (CTLp), leading to clonal inactivation/deletion of donor-reactive CTLp. Of note, the receptors for TGF-beta1- and FasL-induced signal transduction are upregulated in activated T cells. Since mature dendritic cells (DCs) are exceptionally efficient activators of T cells, we postulated that mature DCs modified to overexpress TGF-beta1 and FasL might exert potent veto (i.e., inactivating/deleting) activity independent of CD8 expression. A fusion protein comprising antihuman CD40 single-chain antibody and soluble coxsackie-adenovirus receptor enabled high-efficiency transduction of rhesus monocyte-derived DCs (Rh MDDCs) by recombinant adenovirus (Ad). Mature Rh MDDCs transduced with Ad encoding active TGF-beta1 retained a mature phenotype yet exhibited potent alloantigen-specific cellular immunosuppression. Such modified MDDCs have the potential to promote tolerance induction to allografts in vivo.
Clement
Asiedu
A
Department of Surgery, University of Alabama at Birmingham, 35294, USA. JThomas@uab.edu
Pereboev
Alexander
A
Curiel
David T
DT
Dong
Sai Sai
SS
Hutchings
Anne
A
Thomas
Judith M
JM
D000818:Animals; D000941:Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D053222:Fas Ligand Protein; D005818:Genetic Engineering; D007108:Immune Tolerance / Q000235:genetics*; D007111:Immunity, Cellular; D016030:Kidney Transplantation / Q000276:immunology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous
D000941:Antigens; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1