Defining the Ability of Cyclophosphamide Preconditioning to Enhance the Antigen-specific CD8+ T-cell Response to Peptide Vaccination: Creation of a Beneficial Host Microenvironment Involving Type I IFNs and Myeloid Cells

• DOI: 10.1097/01.cji.0000211311.28739.e3
• Publication Date: 2006-12-19T09:02:45Z
• Authors: Mohamed L. Salem; Andre N. Kadima; Sabry A. EL-Naggar; Mark P. Rubinstein; Yian Chen; William E. Gillan...; David J. Cole
• Keywords: Adoptive Cell Transfer

Although cyclophosphamide (CTX) has been clearly shown to enhance active specific and adoptive immunotherapies, the mechanism(s) underlying these beneficial effects have not defined. To define impact of CTX preconditioning on antigen-specific CD8 T-cell response peptide vaccination, we used an transfer model based OT-1 receptor transgenic mouse. dramatically enhanced vaccination. Specifically, significantly expansion function responding T cells as demonstrated by flow cytometry cytokine production. In parallel experiments, attempted therapy. therapy increased relative number activation status myeloid dendritic cells, was associated with induction significant levels inflammatory cytokines interferon-alpha, monocyte chemoattractant protein-1, IL-6. Adoptive experiments into type I IFNR-/- CR3-/- mice confirmed that were at least partially dependent interferons cells. up 150x10(6) naive spleen time did abrogate therapy, suggesting creation a niche in immune system may be required. decreased absolute, but CD4+CD25+ Treg consistent possibility regulatory targeted Of note, combination synthetic TLR3 agonist further CD8+ response. Taken together, our data suggest modulates components innate resulting host microenvironment. Specific targeting effectiveness for immunotherapy.