Maturation of dendritic cell precursors into IL12-producing DCs by J-LEAPS immunogens

Abstract

LEAPS (ligand epitope antigen presentation system) vaccines consist of a peptide containing a major histocompatibility antigen binding peptide conjugated to an immune cell binding ligand (ICBL) such as the 'J' peptide from beta-2-microglobulin. Treatment of monocytes, monocytes plus GMCSF, or monocytes plus GMCSF and IL4 with JgD (containing a peptide from gD of herpes simplex virus type 1) or JH (with a peptide from HIV p17 gag protein) was sufficient to promote their maturation into Interleukin 12 producing dendritic cells. JgD dendritic cells supported allotypic activation of T cells to produce Th1 related cytokines.

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“…J–LEAPS conjugates have previously been determined to enhance or focus on Th1 responses, enhance or stimulate IL-12p70 production [86,113,114], target CD8 + T cells [86], and result in an increased IFN-γ response in mice with reduced production of TNF-α [86,106,113,114], IL-1, IL-4 and IL-6 [86]. …”

“…The antigen-specific nature of LEAPS conjugates has been demonstrated by reduced morbidity and mortality as well as by induction of favorable immune responses to disease-related peptides (but not to unrelated peptides) upon challenge of LEAPS conjugate-treated mice with HSV [113] or influenza A [85] and in the CIA model [105]. Antigen specificity was also demonstrated in immunogenicity studies for LEAPS conjugates containing HIV or tuberculosis epitopes [97,98,115].…”

“…Treatment of human monocytes or mouse bone marrow DC precursors with J–LEAPS vaccines promotes their development into DCs, as indicated by increased surface expression of CD80, CD86, CD11c and MHC class II molecules [86,113]. These cells are activated, release IL-12 and promote the development of Th1 immune responses ex vivo .…”

“…These cells are activated, release IL-12 and promote the development of Th1 immune responses ex vivo . As for the peptide vaccines, the adoptive transfer of DCs activated by J–LEAPS vaccines for HSV or influenza enhanced or stimulated the production of IL-12p70 [86,113,114] and activated Th1 responses, but unlike in other approaches using TLR agonists, no TNF-α was generated [97,98]. …”

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“…Studies utilizing the J peptide from β2-microglobulin linked with a herpes simplex viral epitope demonstrated the induction of DC1s that secreted high amounts of IL-12 and induced an IFN-γ-secreting Th1 phenotype in both mouse and human DCs. These DCs treated with J-linked peptides did not require further treatment with TLR agonists and demonstrated antigen-specific T-cell responses [229,230]. Furthermore, adoptive transfers of DCs treated with J peptide linked to herpes simplex viral antigen in mice conferred therapeutic protection against subsequent infectious challenge [231].…”