Depression of T cell-mediated immunity reduces sulfadimethoxine-induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats

Abstract

We previously demonstrated that thyroid capsular inflammation induced by continuous treatment with the antithyroidal agent sulfadimethoxine is associated with development of invasive follicular cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive follicular cell carcinomas (2.8 +/- 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 +/- 1.0/rat, P < 0.01). Inducible nitric oxide synthase expression in the inflamed lesions was detected in three of 10 rnu/+rats but in none of the rnu/rnu animals. The results thus suggest that development of invasive carcinomas is enhanced by capsular inflammation mediated by T cells, and inducible nitric oxide synthase induction may play a role in tumor progression.

Figure 1

A carcinoma invading extrathyroidal tissue in a rnu/+ rat treated with sulfadimethoxine for 10 weeks after N‐bis(2‐hydroxypropyl)nitrosamine (DHPN)‐initiation. Hematoxylin and eosin (H&E); magnification, ×180.

Figure 2

Non‐neoplastic fibrous and inflammatory lesions in the thyroid capsular region. (a) Fibrous thickening of the thyroid capsule in a rnu/rnu rat treated with sulfadimethoxine for 10 weeks after N‐bis(2‐hydroxypropyl)nitrosamine (DHPN)‐initiation. Hematoxylin and eosin (H&E); magnification, ×180. (b–f) Capsular thickening with inflammation in a rnu/+ rat treated with sulfadimethoxine for 10 weeks after DHPN‐initiation. (b) H&E; magnification, ×180. (c) Some cells in the inner layer of the inflammation are positive for ED1, indicative of a macrophage nature. ED1 immunohistochemistry; magnification, ×360. (d) Some cells in the outer layer of the inflammation are positive for CD8a, indicative of a T‐cell nature. CD8a immunohistochemistry; magnification, ×360. (e) Some cells in the outer layer of the inflammation are positive for CD45R, indicative of a B‐cell nature. CD45R immunohistochemistry; magnification, ×360. (f) Some cells in the inner layer of the inflammation are regionally positive for inducible nitric oxide synthase (iNOS), indicative of macrophages or neighboring fibroblasts. iNOS immunohistochemistry; magnification, ×360.

Figure 3

Non‐neoplastic epithelial lesions in the thyroid capsular region. (a) Migration of follicular epithelial cells, isolated or forming microfollicles in a capsular lesion in a rnu/rnu rat. The inflammatory reaction is limited. Hematoxylin and eosin (H&E); magnification, ×360. (b) Disrupted structure of follicles along with an inflammatory reaction in the capsular region of a rnu/+ rat. H&E; magnification, ×360.