Administration route-dependent induction of antitumor immunity by interferon-alpha gene transfer.

Type I interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis, and immunomodulation. We have demonstrated that intratumoral injection of an IFN-α-expressing adenovirus effectively induces cell death of cancer cells and elicits a systemic tumor-specific immunity in several animal models. On the other hand, reports demonstrated that an elevation of IFN in the serum following an intramuscular delivery of a vector is able to activate antitumor immunity. In this study, we compared the intratumoral and systemic routes of IFN gene transfer with regard to the effect and safety of the treatment. Intratumoral injection of an IFN-α adenovirus effectively activated tumor-responsive lymphocytes and caused tumor suppression not only in the gene-transduced tumors but also in distant tumors, which was more effective than the intravenous administration of the same vector. The expression of co-stimulatory molecules on CD11c+ cells isolated from regional lymph nodes was enhanced by IFN gene transfer into the tumors. Systemic toxicity such as an elevation of hepatic enzymes was much lower in mice treated by intratumoral gene transfer than in those treated by systemic gene transfer. Our data suggest that the intratumoral route of the IFN vector is superior to intravenous administration, due to the effective induction of antitumor immunity and the lower toxicity. © 2010 Japanese Cancer Association

Research Activities in the Department of Medical Engineering

The Department of Medical Engineering is dedicated to the research and educational activities to fulfill its mission as educating medical professionals in medical engineering under the diploma policy and curriculum policy, that is, "research and education aiming for fostering professionals competent in comprehensive resolving capacity based upon a wide field of knowledge and vision in clinical engineering, which can be attained by wearing the basic knowledge of medical science and engineering." For this reason, the Faculty of the Department of Medical Engineering is composed of the two areas; PhDs in engineering-based clinical medicine, and mainly MDs in medical sciences and clinical medicine. To summarize the research activities at the Department of Medical Engineering, the authors will describe the overview of research activities being performed in the Department of Medical Engineering Fields, by dividing into 1) Research in Biomedical Engineering Fields, and 2) Research in Medical Science and Clinical Engineering Fields

NKG2A inhibits invariant NKT cell activation in hepatic injury

Activation of invariant NKT (iNKT) cells in the liver is generally regarded as the critical step for Con A-induced hepatitis, and the role of NK cell receptors for iNKT cell activation is still controversial. In this study we show that blockade of the NKG2A-mediated inhibitory signal with antagonistic anti-NKG2A/C/E mAb (20d5) aggravated Con A-induced hepatitis in wild-type, Fas ligand (FasL)-mutant gld, and IL-4-deficient mice even with NK cell and CD8 T cell depletion, but not in perforin-, IFN-γ-, or IFN-γ- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN-γlevels and perforin-dependent cytotoxicity of liver mononuclear cells following Con A injection, but not their FasL/Fas-dependent cytotoxicity. However, blockade of NKG2A-mediated signals during the cytotoxicity effector phase did not augment cytotoxic activity. Activated iNKT cells promptly disappeared after Con A injection, whereas NK1 iNKT cells, which preferentially expressed CD94/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1 iNKT cells. Moreover, Con A-induced and α-galactosylceramide-induced hepatic injury was very severe in CD94/NKG2A-deficient DBA/2J mice compared with CD94/NKG2A-intact DBA/2JJcl mice. Overall, these results indicated that a NKG2A-mediated signal negatively regulates iNKT cell activation and hepatic injury

IFN-γ-mediated negative feedback regulation of NKT-cell function by CD94/NKG2

Activation of invariant natural killer T (iNKT) cells with CD1d-restricted T-cell receptor (TCR) ligands is a powerful means to modulate various immune responses. However, the iNKT-cell response is of limited duration and iNKT cells appear refractory to secondary stimulation. Here we show that the CD94/NKG2A inhibitory receptor plays a critical role in down-regulating iNKT-cell responses. Both TCR and NK-cell receptors expressed by iNKT cells were rapidly down-modulated by priming with a-galactosylceramide (α-GalCer) or its analog OCH [(2S,3S,4R)-1-O-(α-D-galactopyranosyl)-N-tetracosanoyl-2-amino- 1,3,4-nonanetriol)]. TCR and CD28 were re-expressed more rapidly than the inhibitory NK-cell receptors CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyperreactive to ligand restimulation. Of interest, α-GalCer was inferior to OCH in priming iNKT cells for subsequent restimulation because α-GalCer-induced interferon γ (IFN-γ) up-regulated Qa-1 expression and Qa-1 in turn inhibited iNKT-cell activity via its interaction with the inhibitory CD94/ NKG2A receptor. Blockade of the CD94/ NKG2-Qa-1 interaction markedly augmented recall and primary responses of iNKT cells. This is the first report to show the critical role for NK-cell receptors in controlling iNKT-cell responses and provides a novel strategy to augment the therapeutic effect of iNKT cells by priming with OCH or blocking of the CD94/ NKG2A inhibitory pathway in clinical applications