Converting nonhuman primate dendritic cells into potent antigen-specific cellular immunosuppressants by genetic modification

Clement Asiedu, Alexander Pereboev, David T. Curiel, Sai Sai Dong, Anne Hutchings, Judith M. Thomas

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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-β1 (TGF-β1), 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-β1- 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-β1 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-β1 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.

Original languageEnglish
Pages (from-to)297-302
Number of pages6
JournalImmunologic Research
Volume26
Issue number1-3
DOIs
StatePublished - 2002

Keywords

  • Bone marrow cells
  • Dendritic cells
  • Gene transfer
  • Tolerance
  • Transformation growth factor-β1
  • Veto

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