Nanoparticles can be used to accomplish antigen-specific immune tolerance in allergic and autoimmune disease. The available options for custom-designing tolerogenic nanoparticles (NPs) include the use of nanocarriers that introduce antigens into natural tolerogenic environments, such as the liver, where antigen presentation promotes tolerance to self or foreign antigens. Here, we demonstrate the engineering of a biodegradable polymeric poly (lactic-co-glycolic acid) (PLGA) nanocarrier for the selective delivery of the murine allergen, ovalbumin (OVA), to the liver. This was accomplished by developing a series of NPs in the 200-300 nm size range as well as decorating particle surfaces with ligands that targets scavenger and mannose receptors on specialized tolerogenic liver sinusoidal endothelial cells (LSECs). LSECs represent a major antigen presenting cell (APC) type in the liver capable of generating regulatory T-cells (Tregs). In vitro exposure of LSECs to NP OVA induced abundant TGF-β, IL-4 and IL-10 production, which

NY-ESO-1 is a tumor-specific shared antigen with distinctive immunogenicity. Both CD8 ؉ T cells and class-switched Ab responses have been detected from patients with cancer. In this study, a CD4 ؉ T cell line was generated from peripheral blood mononuclear cells of a melanoma patient and was shown to recognize NY-ESO-1 peptides presented by HLA-DP4, a dominant MHC class II allele expressed in 43-70% of Caucasians. The ESO p157-170 peptide containing the core region of DP4-restricted T cell epitope was present in a number of tumor cell lines tested and found to be recognized by both CD4 ؉ T cells as well as HLA-A2-restricted CD8 ؉ T cells. Thus, the ESO p157-170 epitope represents a potential candidate for cancer vaccines aimed at generating both CD4 ؉ and CD8 ؉ T cell responses. More importantly, 16 of 17 melanoma patients who developed Ab against NY-ESO-1 were found to be HLA-DP4-positive. CD4 ؉ T cells specific for the NY-ESO-1 epitopes were generated from 5 of 6 melanoma patients with NY-ESO-1 Ab. In contrast, no specific DP4-restricted T cells were generated from two patients without detectable NY-ESO-1 Ab. These results suggested that NY-ESO-1-specific DP4-restricted CD4 ؉ T cells were closely associated with NY-ESO-1 Ab observed in melanoma patients and might play an important role in providing help for activating B cells for NY-ESO-1-specific Ab production.A number of studies suggest that tumor-reactive T cells play an important role in mediating tumor regression. The molecular basis of T cell-mediated antitumor immunity has been elucidated by the identification of a number of tumor antigens recognized by CD8 ϩ T cells (1, 2). These MHC class I-restricted tumor antigens can be divided into several categories. The tissue-specific differentiation antigens, which include MART-1 (3), TRP-1͞gp75 (4), TRP-2 (5), and gp100 (6) are expressed in melanoma as well as normal melanocytes. Tumor-specific shared antigens such as MAGE-1 (7) and NY-ESO-1 (8, 9) are expressed in a wide variety of tumors such as breast cancer and lung cancer. The expression of these products is limited in cancer cells with the exception of normal testis. Tumor-specific unique or mutated antigens such as ␤-catenin (10) also have been described. Among these antigens, NY-ESO-1 is of particular interest because both cytotoxic T lymphocyte and Ab responses have been shown to react with this antigen (9, 11). NY-ESO-1 encodes two gene products recognized by CD8 ϩ T cell clones (9). In addition, high titers of Ab were detected from about 50% of patients with NY-ESO-1-positive tumor (12). Because of its strict tumor-specific expression pattern (8), NY-ESO-1 is potentially an important immune target for the development of immunotherapy for a variety of cancer types.Increasing evidence from both human and animal studies has indicated that CD4 ϩ T cells play a central role in initiating and maintaining host immune responses against cancer (2, 13). The observation that high titers of NY-ESO-1 antibodies were present in a high proportion of patients sugg...

In previous studies, the shared cancer-testis Ag, NY-ESO-1, was demonstrated to be recognized by both Abs and CD8+ T cells. Gene expression of NY-ESO-1 was detected in many tumor types, including melanoma, breast, and lung cancers, but was not found in normal tissues, with the exception of testis. In this study, we describe the identification of MHC class II-restricted T cell epitopes from NY-ESO-1. Candidate CD4+ T cell peptides were first identified using HLA-DR4 transgenic mice immunized with the NY-ESO-1 protein. NY-ESO-1-specific CD4+ T cells were then generated from PBMC of a patient with melanoma stimulated with the candidate peptides in vitro. These CD4+ T cells recognized NY-ESO-1 peptides or protein pulsed on HLA-DR4+ EBV B cells, and also recognized tumor cells expressing HLA-DR4 and NY-ESO-1. A 10-mer peptide (VLLKEFTVSG) was recognized by CD4+ T cells. These studies provide new opportunities for developing more effective vaccine strategies by using tumor-specific CD4+ T cells. This approach may be applicable to the identification of CD4+ T cell epitopes from many known tumor Ags recognized by CD8+ T cells.