The effects of neonatal thymectomy on insulitis in non-obese diabetes (NOD) mice, which suffer from destruction of B cells in the pancreas, were studied histopathologically. Complete neonatal thymectomy reduced the incidence of insulitis in NOD mice, from 100% to 53% in males and from 100% to 69% in females at day 60; and from 100% to 44% in males and from 100% to 54% in females at day 100. The results suggest that the pathogenesis of insulitis in NOD mice may depend on an autoimmune mechanism related to the thymus, through which destruction of B cells in the pancreatic islets is mediated. NOD mice can therefore be useful as an animal model for studying the autoimmune etiology of type I diabetes in humans.

SUMMARY : Cynomolgus monkeys were fed with a virulent strain of type 1 poliovirus (Mahoney), and the site of initial multiplication of the virus in the alimentary tract was investigated immunofluorescently.The virus antigen appeared as short as 24 hr after the feeding in both the squamous epithelial cells of the oropharynx and the macrophages of lymphatic structure of the tonsils. The virus antigen was also detectable at the early stage of infection in the reticulo-endothelial cells of the lamina propria of the intestines.Multiplication of poliovirus in the endothelial cells was substantiated by electron-microscopic demonstration of a characteristic crystalline inclusion consisting of poliovirus-like particles in the cytoplasm of the cells. No convincing evidence supporting multiplication of the virus in the mucosal epithelium of the intestines was obtained.Macrophages with intracytoplasmic fluorescence appeared abundantly after the onset of viremia in the lymph nodes, the spleen and the liver. Poliovirus antigen appeared after the onset of paralysis in the central nervous system, particularly in high concentrations in the motor nerve cells of the spinal cord. Poliovirus antigen was also detectable in inflammatory cells, principally the neutrophilic leucocytes, of various tissues at the late stage of infection.

Varying doses of FK506, and a cell-depleting anti-CD4 monoclonal antibody, GK1.5, were tested as either monotherapy or in combination for their effect on the survival of renal subcapsular xenografts of organ-cultured fetal pig pancreas in three strains of mice. Subcutaneous injections of FK506 at 4.0 mg/kg/day for 28 d prevented graft rejection to day 35 posttransplantation (i.e., 7 days after cessation of treatment in NOD/Lt, and CBA mice) while BALB/c mice had intact grafts at 28 days. Lower doses were less effective and immunosuppression was less effective in NOD mice than in the other strains. Even 2.0 mg/kg/day of FK506 prevented rejection in CBA mice until day 35, but not in NOD/Lt mice. GK1.5 alone did not prevent rejection in NOD/Lt mice but when a low dose of FK506 (2.0 mg/day) was added, the grafts were present, essentially intact, at 35 days. There were no obvious toxic effects of FK506 in NOD/Lt and CBA mice. With FK506 treatment there was no significant difference in absolute numbers of total leucocytes or lymphocytes in peripheral blood and spleen, but there was a decrease in thymus cellularity. Flow cytometric analysis of lymphocyte subsets in blood and spleen also showed no significant differences, but in the thymus the percentage of immature CD4/CD8 "double positive" cells increased while the more mature CD3"high", and CD4 or CD8 "single-positive" cells decreased. Thus, prolonged discordant xenograft survival in mice is possible and the use of two agents that act on different parts of the immune system allows a reduction in the dose of FK506 to safe levels.

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