Biomedical subjects

Nobusuke Nishi

Publications and source records attributed to Nobusuke Nishi.

3 recordsLinked to original sources

PubMed2003

Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells.

CD1d-restricted natural killer T (NKT) cells play important regulatory roles in various immune responses. NKT cell-derived T helper (Th) 1 cytokines are important in the induction of antitumor immune responses in mice. Because the CD1d-restricted Valpha24(+) Vbeta11(+) NKT cell population in cancer patients is decreased both in size and in its capacity to secrete IFN-gamma, therapeutic strategies based on reconstitution of type 1 polarized Valpha24(+) Vbeta11(+) NKT cells merit additional investigation. Here, we report the simultaneous strong expansion and type 1 polarization of human invariant Valpha24(+) Vbeta11(+) NKT cells using alpha-galactosylceramide-loaded type 1 dendritic cells and interleukin 15. Type 1 polarized Valpha24(+) Vbeta11(+) NKT cells produced high levels of IFN-gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, and induced strong cytotoxicity in Jurkat cells in an alpha-galactosylceramide-dependent manner. Importantly, the cytokine profile of Valpha24(+) Vbeta11(+) NKT cells that were initially expanded under Th2 polarizing conditions could be reversed to a Th1 cytokine profile, indicating the plasticity of the cytokine profile of the human adult Valpha24(+) Vbeta11(+) NKT cell population.

Adult↗

PubMed2002

Selective decrease in circulating V alpha 24+V beta 11+ NKT cells during HIV type 1 infection.

CD1d-restricted NKT cells express an invariant TCR and have been demonstrated to play an important regulatory role in a variety of immune responses. Invariant NKT cells down-regulate autoimmune responses by production of type 2 cytokines and can initiate antitumor and antimicrobial immune responses by production of type 1 cytokines. Although defects in the (invariant) Valpha24+Vbeta11+ NKT cell population have been observed in patients with cancer and autoimmune diseases, little is known regarding the protective role of Valpha24+Vbeta11+ NKT cells in human infectious disease. In a cross-sectional study in HIV-1-infected individuals, we found circulating numbers of Valpha24+Vbeta11+ NKT cells to be reduced, independent of CD4+ T cell counts, CD4:CD8 ratios, and viral load. Because a small minority of Valpha24+Vbeta11+ NKT cells of healthy donors expressed HIV-1 (co)receptors and the vast majority of Valpha24+Vbeta11+ NKT cells in HIV-1-infected individuals expressed the Fas receptor, the depletion was more likely due to Fas-mediated apoptosis than to preferential infection of Valpha24+Vbeta11+ NKT cells by HIV-1. A longitudinal cohort study, in which patients were analyzed before seroconversion and 1 and 5 years after seroconversion, demonstrated that a large proportion of the depletion occurred within the first year postseroconversion. In this longitudinal study no evidence was found to support an important role of Valpha24+Vbeta11+ NKT cells in determining the rate of progression during HIV-1 infection.

Adult↗

PubMed2002

A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors.

PURPOSE: alpha-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients. EXPERIMENTAL DESIGN: Patients with solid tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients. RESULTS: Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days. CONCLUSION: i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.

Adult↗