UV-inactivated, replication-defective Sendai virus particles [hemagglutinating virus of Japan envelope (HVJ-E)] injected into murine colon carcinoma (CT26) tumors growing in syngeneic BALB/c mice eradicated 60% to 80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive antitumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient mice. Murine and human dendritic cells underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by dendritic cells after HVJ-E stimulation showed that the amount of interleukin-6 (IL-6) released was comparable to that elicited by live HVJ. + regulatory T cell (Treg)-mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, antitumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. This is the first report to show that HVJ-E alone can eradicate tumors and the mechanism through which it induces antitumor immune responses. Because it can enhance antitumor immunity and simultaneously remove Treg-mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.

No abstract

We have already demonstrated that inactivated, replication-defective Sendai virus particles (HVJ-E) have a powerful antitumor effect by both the generation of tumor-specific cytotoxic T cells and inhibition of regulatory T cell activity. Here, we report that HVJ-E also has an antitumor effect through non-T cell immunity. Microarray analysis revealed that direct injection of HVJ-E induced the expression of CXCL10 in established Renca tumors. CXCL10 was secreted by dendritic cells in the tumors after HVJ-E injection. Quantitative real-time RT-PCR and immunohistochemistry revealed that CXCR3+ cells (predominantly NK cells) infiltrated the HVJ-E-injected tumors. Moreover, HVJ-E injection caused systemic activation of NK cells and enhanced their cytotoxity against tumor cells. In an in vivo experiment, approximately 50% of tumors were eradicated by HVJ-E injection, and this activity of HVJ-E against Renca tumors was largely abolished by NK cell depletion using anti-asialo GM1 antibody. Since HVJ-E injection induced systemic antitumor immunity by enhancing or correcting the chemokine-chemokine receptor axis, it might be a potential new therapy for cancer.

Anadsorption isotherm for a heterogeneous surface is described on the basis of a multi-site occupancy model followed by a group-contribution assumption. Equations of single-and multi-component adsorptions are derived for systems of molecules consisting of several functional groups and a surface composed of active sites of different energies interacting with the groups independently. The isotherm equation reduces to the expression derived by Sparnaayin the special case wherea moleculeoccupies one site of the surface. The theory is applied to adsorption equilibria for systems of oxygen, nitrogen, and carbon monoxideon Molecular Sieves 5Aand 10X. Correlations of single-component isotherms are excellent for nitrogen and oxygen and fairly good for carbon monoxide; predictions of adsorption isotherms of binary gas mixtures are made satisfactorily by means of parameters determined from the best fit to each single-component isotherm. Intr oductionIt is known that the influence of surface heterogeneity on a single-component adsorption isotherm is the decrease of the slope of adsorption against pressure. Sparnaay7) suggested many types of isotherms having a low slope of adsorption by assuming different kinds of active sites; however, the fundamental equation is based on the Langmuir model, characterized as a localized monolayer in which a molecule occupies one active site.2'3)In a previous paper concerning a multi-site occupancy model,5) the authors pointed out that the slope of an adsorption isotherm decreases with increasing number of sites occupied by a molecule even when a homogeneoussurface is assumed. An extension to a heterogeneous surface of the multi-site occupancy model is given here, which may be characterized as a method of group contributions. Numerical examples and an application to adsorpReceived January 24, 1983. Correspondence concerning this article should be addressed to T. Katayama. M. Kuro-oka is now with Sanyo Electric Co., Ltd., Osaka 573. VOL. 17NO. 1 1984 tions on Molecular Sieves are included. The total number of active sites Mis the sum of all Ma's (a=a,b,à"à"à"m). A molecule consists of k groups; the numbers of sites occupied by each group are nun2, à"-nk. Let -8a£ be the adsorption energy per site when a group i of a molecule is attached on an active site a. The adsorption energies are assumed to be independent of either neighboring groups or neighboring sites.WhenN molecules are adsorbed on a heterogeneous surface, the partition function of the system Q(N, M9 T) may be written as Q=h" I^(iV,M,{Nai})expwhere Nai is the number of adsorption-pairs of sites a and a group /; {Nai} is a distribution of adsorption pairs (Na0,Nal, ---Nmk) where the subscript aO stands for the site a to be empty; g(N,M, {Nai)} is a combinatorial factor, which is the number of distinguishable ways of distributing the TV molecules on the Msites under the condition of a specified distribution {N^}; js is the internal and vibrational partition function of a molecule, which is assumed to be independent of the frequency of ...

Fas ligand (CD95L) is synthesized both on the cell surface membrane and in a soluble form. Although CD95L contributes to immune privilege in the cornea and testis, the functions of these alternatively processed proteins are not well understood. Some reports suggest that the cytotoxicity of soluble CD95L is insignificant, whereas others show potent responses in vivo, including hepatocyte apoptosis that causes liver failure. We show here that extracellular matrix proteins interact with soluble CD95L and potentiate its pro-apoptotic activity. The cytotoxicity of supernatants from CD95L-expressing cells was increased by incubation on tissue culture plates coated with these matrix proteins; this effect was mediated by trimeric soluble CD95L. With the use of immunoprecipitation, it was found that CD95L binds directly to fibronectin. In addition, immunohistochemical analysis of the cornea revealed that soluble CD95L binds primarily to extracellular matrix. The retention of soluble CD95L on extracellular matrices is likely to play an important role in the development of peripheral tolerance in immune-privileged sites.