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Dendritic cells engineered to express the Flt3 ligand stimulate type I immune response, and induce enhanced cytoxic T and natural killer cell cytotoxicities and antitumor immunity.

AbstractBACKGROUND:
Tumor antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of antitumor immune responses. Fms-like tyrosine kinase 3 ligand (Flt3L) is a regulator of hematopoietic cell development.
METHODS:
To investigate the potential effect of Flt3L transgene expression on DC-based cancer vaccines, we constructed a recombinant adenovirus AdVFlt3L expressing Flt3L, transfected DCs with AdVFlt3L, and investigated the efficacy of antitumor immunity by vaccination of DC(Flt3L) engineered to express Flt3L transgene.
RESULTS:
Our data demonstrated that AdVFlt3L transfection up-regulated the expression of cytokine IL-1beta and chemokines MIP-1alpha, MIP-1beta, IP-10, MCP-1 and MIP-2, and stimulated DC(Flt3L) cell proliferation in vitro and migration toward regional lymph nodes in vivo. Our data also demonstrated that vaccination of Mut1-pulsed DC(Flt3L) cells was able to stimulate (i). a type 1 immune response comprising CD4(+) Th1 and CD8(+) Tc1 activation and (ii). around 2- and 3-fold enhanced tumor-specific cytotoxic T lymphocyte (CTL) and non-specific NK responses (p < 0.05) than vaccination with similarly pulsed control virus-transfected and untransfected DCs, respectively. More importantly, vaccination of Mut1-pulsed DC(Flt3L) cells induced enhanced antitumor immunity in vivo, even against poorly immunogenic 3LL tumor cells. Vaccinations of Mut1-pulsed DCs, DC(pLpA) and DC(Flt3L) all protected mice from challenge of low dose (0.5 x 10(5)) tumor cells. However, only vaccination of the last one was able to protect 63% (6/8) mice from challenge of high dose (3 x 10(5)) 3LL tumor cells (p < 0.01).
CONCLUSIONS:
DCs engineered to secrete Flt3L may offer a new strategy in DC-based cancer vaccines.
AuthorsYongqing Liu, Hui Huang, Zhuang Chen, Li Zong, Jim Xiang
JournalThe journal of gene medicine (J Gene Med) Vol. 5 Issue 8 Pg. 668-80 (Aug 2003) ISSN: 1099-498X [Print] England
PMID12898636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2003 John Wiley & Sons, Ltd.
Chemical References
  • Adjuvants, Immunologic
  • Cancer Vaccines
  • Chemokines
  • Cytokines
  • Membrane Proteins
  • flt3 ligand protein
Topics
  • Adenoviridae (genetics, metabolism)
  • Adjuvants, Immunologic (metabolism)
  • Animals
  • Cancer Vaccines
  • Cell Line, Tumor
  • Cell Movement (physiology)
  • Chemokines (metabolism)
  • Cytokines (metabolism)
  • Dendritic Cells (immunology, physiology)
  • Female
  • Humans
  • Immune System (physiology)
  • Killer Cells, Natural (immunology, metabolism)
  • Membrane Proteins (genetics, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms (immunology, metabolism)
  • Survival Rate
  • T-Lymphocytes (cytology, metabolism)
  • T-Lymphocytes, Cytotoxic (immunology, metabolism)
  • Transgenes

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