Mannan decelerates the clearance of human red blood cells in SCID mouse
Introduction
Severe combined immunodeficient (SCID) mice can be made chimeric for red blood cells (RBC) by repeated transfusions with mature xenogeneic RBCs. Thus it would appear that this chimera should be possible to support the growth of protozoan hemoparasites which are, by nature, not infectious to mice. Indeed, recently we have accomplished an almost complete substitution with bovine RBCs and found that this RBC-substituted SCID mice allowed a significant and a continuous growth of bovine Babesia and Theileria at over 40% by parasitemia levels (Tsuji et al., 1992, Tsuji et al., 1995a; Nakamura et al., 1995). Moreover, in the case of B. bovis infection the mice were found to develop a fatal cerebral babesiosis which was characterized by adherence of infected Bo-RBC to the endothelium of the cerebral mircovessels by conical projections of the membrane, which are similar to those of human cerebral malaria (Tsuji et al., 1996).
Chimeric mice for Hu-RBC were developed more recently by us and two other groups (Tsuji et al., 1995b; Badell et al., 1995; Moore et al., 1995), but the parasitemias by Plasmodium falciparum are only erratic, at levels of 0.1 to 2%. This inferior growth of malaria parasites in the chimeric mice might be attributable to the rapid Hu-RBC clearance, although the methods to decelerate Hu-RBC clearance in SCID mice, such as X-ray irradiation, dichloromethylene-biphosphate treatment or Hu-serum administration had been utilized in those experiments. The half-life of single Hu-RBC in the SCID mice, about 48 h or less, was significantly less than the 120 day life span in a human host (Rajian et al., 1996) and was only 1/25 of Bo-RBC life span in SCID mice (Ishihara et al., 1994a).
It has been described, in some reports, that membrane integrated C-type lectins on the macrophage can mediate erythro-phagocytosis by directly binding to sugar ligands on the surface of senescent or degenerated RBCs (Muller et al., 1983; Sheiban and Gershon, 1993). Thus, we examined here whether and what kind of sugar ligands is functioning on the Hu-RBC clearance in SCID mice, and demonstrated that some compounds with mannose specificity exhibited the direct inhibitory activity, possibly by interfering with the receptor–ligand binding of Hu-RBC by mouse macrophages.
Section snippets
Chemicals
Yeast mannan (mannan purified from Saccharomyces cerevisiae; Nacalai Tesque, Tokyo), α1→3,α1→6 mannotriose (Funakoshi, Tokyo), α1→3,α1→6 mannopentaose (Funakoshi), d-mannose (Wako Pure Chemical, Tokyo), N-acetyl-d-glucosamine (Seikagaku, Tokyo) and bovine lactoferrin (Wako Pure Chemical) were dissolved in phosphate buffered saline (PBS) before use. Candida mannan with 4500 MW, purified from the Candida albicans by the method as described previously (Bishop et al., 1960), was similar in
Mannan decelerates the clearance of transfused Hu-RBCs from the blood circulation of SCID mice
Fig. 1Fig. 2 depict the results of Hu-RBC clearance inhibition tests, showing that the Hu-RBC clearance in SCID mice was decelerated significantly by mannans from yeast and Candida as well as by bovine lactoferrin. There was no adverse effect in the yeast mannan- and lactoferrin-treated mice even at 1000 and 4000 μg/mouse, respectively. Whereas Candida mannan displayed some clinical symptoms including far hair, slow responsiveness, and occasional death at a dose of 1000 μg/mouse. However,
Discussion
In the present report we studied the method to prolong the Hu-RBC life span in SCID mice by interfering xenogeneic RBC clearance and demonstrated that yeast and Candida mannans and bovine lactoferrin, a glycoprotein of the transferrin family containing both oligomannose-type and N-acetyllactosamine-type glycans, inhibited significantly Hu-RBC clearance in SCID mice (Fig. 1). While CM-chitin, a partially carboxymethylated polysaccharide composed of N-acetyl-d-glucosamine showed no inhibitory
Acknowledgements
This work was supported in part by Grant-in-Aid from Science Research Promotion Fund from Japan Private School Promotion Foundation. The authors are grateful to Mr. Satoru Arai, Mr. Kim Sam-Ju, Mr. Naoya Uchiyama, and Miss Chiaki Daita for technical assistance, and Dr. Masaaki Miyazawa, School of Medicine, Kinki University for encouragement and critical discussions.
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