Background Information

In 1969, Nishizuka and Sakakura noted that chemical carcinogens failed to induce mammary carcinoma in day-3 thymectomized mice (Nishizuka and Sakakura, 1969). It turned out that day-3 thymectomy led to ovarian autoimmune disease and ovarian failure; with reduction in ovarian hormones, the mammary epithelium failed to develop. Later, Penhale reported autoimmune thyroiditis in thymectomized and irradiated rats (Penhale et al., 1973). Kojima and Prehn (1981) documented mouse strain variations in target-organ involvement following day-3 thymectomy; the variation was unrelated to the MHC haplotype. Recently, Teuscher and colleagues mapped two genetic loci in chromosomes 3 and 16 with linkage to ovarian atrophy and autoimmune oophoritis, respectively, in day-3 thymectomized mice (Teuscher et al., 1996). Additional approaches to induce the autoimmune diseases were also developed. Taguchi et al. (1986) induced a very broad spectrum of autoimmune diseases in athymic nu/nu mice engrafted with fetal rat thymus. Sakaguchi et al. (1985) reported the transfer of autoimmune disease to athymic nu/nu mice by normal T cells expressing low levels of CD5. More recently, such transfer was demonstrated using normal CD25- T cells (Sakaguchi et al., 1995; Suri-Payer et al., 1996).

These authors also described similar autoimmune diseases in mice expressing a Va transgene (Sakaguchi et al., 1994). Smith et al. (1991) described autoimmune oophoritis and gastritis in athymic nu/nu recipients of neonatal T cells and CD4+CD8- thymocytes from euthymic donors. In all cases, autoimmune diseases occur in mouse strains not prone to spontaneous autoimmunity. Target autoantigens, when known, approximate those of the corresponding human autoimmune diseases, such as H+K+ ATPase as the target antigen in human and murine autoimmune gastritis (Jones et al., 1991; Suri-Payer et al., 1996). Inasmuch as severe autoimmune disease occurs in multiple organs without deliberate immunization, adjuvant injection, or perturbation of target organ, findings based on these interesting autoimmune models are likely relevant to physiological tolerance and the pathogenesis of human autoimmune diseases. Most importantly, there is the common theme that all of the autoimmune diseases described in Table 15.16.1 are inhibited when the manipulated mice are reconstituted, in early life, with CD4+ (CD5high or CD25+) T cells from normal syngeneic adults (Sakaguchi et al., 1985, 1994, 1995; Taguchi et al., 1986; Sakaguchi and Sakaguchi, 1989; Smith et al., 1992; Suri-Payer et al., 1996). The models therefore provide excellent opportunity

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