Pregnant nonobese diabetic (NOD) mice were treated with lymphotoxin-␤ receptor immunoglobulin fusion protein (LT␤R-Ig) or control human immunoglobulin on days embryonic day 11 (E11) and E14, and offspring were followed for the development of anti-␤-cell antibodies, islet pathology, and hyperglycemia. The development of anti-␤-cell surface antibodies was abrogated in treated mice compared with controls. Autopsy examination of the mice at 30 weeks of age revealed normal development of secondary

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... mphoid structures in the control animals; however, mice treated with LT␤R-Ig had no axillary, inguinal, popliteal, or peripancreatic lymph nodes. Histological examination of the pancreata of the control mice revealed a severe and destructive mononuclear cellular infiltrate in the islets, whereas the islets of the LT␤R-Ig-treated mice were devoid of any insulitis. None of the LT␤R-Ig-treated mice (n ‫؍‬ 22) developed diabetes; in contrast, 80% of the control mice (n ‫؍‬ 46) developed diabetes at 1 year of age. The LT␤R-Ig-treated mice did not contain diabetogenic Tcells. However, the treated mice developed diabetes upon inoculation with diabetogenic T-cells. In this model of spontaneous autoimmune diabetes, secondary lymphoid structures, most likely the peripancreatic lymph nodes, were essential for the development of pathologic anti-␤-cell autoimmunity.