Takayuki Yoshimoto

Interleukin-12-Dependent Mechanisms in the Clearance of Blood-Stage Murine Malaria Parasite Plasmodium berghei XAT, an Attenuated Variant of P. berghei NK65

The mechanism of development of host resistance to blood-stage malarial infection was studied by use of an irradiation-induced attenuated variant, Plasmodium berghei XAT, obtained from a lethal strain, P. berghei NK65. The infection enhanced mRNA expression of interleukin (IL)-12 p40 and also of interferon (IFN)-gamma, IL-4, IL-10, and cytokine-inducible nitric oxide synthase (iNOS) in spleen. Treatment of these mice with anti-IL-12 or anti-IFN-gamma led to the progression of parasitemia and fatal outcome. Anti-IL-12 treatment significantly reduced the secretion and mRNA expression of IFN-gamma and greatly diminished the augmentation of iNOS mRNA expression. In addition, recombinant IL-12 administration delayed the onset of parasitemia because of the enhanced IFN-gamma production. These results suggest that blood-stage P. berghei XAT infection induces IL-12 production, which is important for the development of host resistance via IFN-gamma production.

Biology of mouse mammary tumor virus (MMTV)

Mouse mammary tumor viruses (MMTV) replicate in the mammary gland, appear as infectious particles in mothers milk and invade the sucking pups from the intestinal tract. The immune system is essential for MMTV in the gut to reach the mammary gland. These properties make the life cycle of MMTV unique. We review the oncologically and immunologically intriguing events caused by MMTV in relation to the life cycle of the virus.

Antitumor activity exhibited by Fas ligand (CD95L) overexpressed on lymphoid cells against Fas+ tumor cells

Abstract Lymph node (LN) cells of Fas-mutant mice lpr/lpr (lpr) and lprcg/lprcg (lprcg) express an increased level of Fas ligand (FasL) (CD95L). We examined the antitumor potential of cell-bound FasL on these LN cells against Fas+ tumor cells. Fas+ F6b and Fas− N1d cells were produced from murine hepatoma MH134 (Fas−) by gene transfection. lpr and lprcg LN cells inhibited growth of F6b but not N1d cells in vitro. Neither gld/gld lpr/lpr (gld/lpr) LN cells, which lack both FasL and Fas, nor wild-type LN cells showed growth-inhibitory activities against F6b and N1d cells. The effector cells and molecule were CD4−CD8− T cells and FasL, respectively. The tumor neutralization test and adoptive transfer demonstrated that lpr and lprcg, but not gld/lpr, LN cells retarded the growth of F6b cells. Although anti-Fas antibody and FasL cause severe liver failure, wild-type mice injected with lpr LN cells appeared clinically normal. Adoptive transfer of lpr LN cells to F6b-bearing mice exerted the same antitumor activity in wild-type and gld/lpr recipient mice, indicating the applicability of cell-bound FasL for Fas-mediated target therapy of cancer. These results suggest that antitumor activity was dependent on the Fas-FasL system and that lymphoid cells overexpressing FasL can be powerful antitumor effector cells against Fas+ tumor cells.

NOVEL MUTANT MICE SECRETING SOLUBLE CD4 WITHOUT EXPRESSION OF MEMBRANE-BOUND CD4

Mutant mice derived from C57BR/cdJ mice were found to have a novel genetic defect in CD4 expression. Flow‐cytometric analysis demonstrated that there were no CD4+ cells in either the thymus or the peripheral lymphoid organs of the mutant mice. Thymocytes of the mutant mice expressed an amount of CD4 mRNA comparable to normal mouse thymocytes, but the mutant CD4 mRNA was slightly smaller in size than normal CD4 mRNA. The sequence analysis of the mutant CD4 cDNA obtained from thymic RNA revealed that the defect in the CD4 expression was attributable to the deletion of the entire exon VIII, encoding a transmembrane domain of the CD4 molecule. Moreover, soluble CD4 was detected both in the culture supernatant of thymocytes and sera from mutant mice. The analysis of the genomic DNA sequence elucidated that one thymine was substituted for 14 base pairs at the junction between exon VIII and intron VIII in the mutant mice, which could possibly account for the alternative splicing of CD4 mRNA. These mutant mice showed reduced delayed‐type hypersensitivity reactions against sheep red blood cells and antibody production against T‐dependent antigen but not against T‐independent antigen. Thus, these mutant mice have a novel defect in CD4 expression where CD4 mRNA is alternatively spliced to delete a transmembrane domain, giving rise to secretion of soluble CD4 instead of expression of membrane‐bound CD4.