Mannan decelerates the clearance of human red blood cells in SCID mouse

Abstract

Mannans and its related compounds decelerated human (Hu) red blood cell (RBC)-clearance in severe combined immunodeficiency (SCID) mice by inhibiting erythro-phagocytosis of macrophages. Chimeric SCID mice for Hu-RBC which are generated by repeated transfusions with mature Hu-RBCs are described recently as a model for Plasmodium falciparum infection, though the Hu-RBC clearance in the mice at present is very rapid and the parasitemia in the mice is only erratic. Here, we aimed to study the method to decelerate Hu-RBC clearance in SCID mice, to establish a suitable mouse model for malaria parasites. Yeast and Candida mannans as well as lactoferrin, a glycoprotein containing both oligomannoside- and N-acetyllactosamine-type glycans, decelerated Hu-RBC clearance, but instead other saccharides such as carboxymethyl chitin, N-acetylglucosamine, and d-glucose did not. Yeast mannan and lactoferrin interfered significantly with in vitro Hu-RBC-phagocytosis which was also inhibited by mannopentaose and mannotoriose. d-mannose exhibited a moderate inhibitory activity. N-acetyl-d-glucosamine, however, showed only a slight inhibitory activity, but d-glucose had no inhibitory activity on Hu-RBC phagocytosis. These results may postulate that Hu-RBC clearance in SCID mouse might be mediated by receptor–ligand binding by a macrophage lectin like receptor with mannose specificity.

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.