Absence of Lymph Nodes in NOD Mice Treated With Lymphotoxin-β Receptor Immunoglobulin Protects From Diabetes

Absence of Lymph Nodes in NOD Mice Treated With Lymphotoxin-β Receptor Immunoglobulin Protects From Diabetes Matteo G. Levisetti 1 2 , Anish Suri 2 , Katherine Frederick 2 and Emil R. Unanue 2 1 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri Address correspondencereprint requests to Emil R. Unanue, MD, Campus Box 8118, 660 S. Euclid Av., St. Louis, MO 63110. E-mail: unanue{at}pathology.wustl.edu Abstract Pregnant nonobese diabetic (NOD) mice were treated with lymphotoxin-β receptor immunoglobulin fusion protein (LTβR-Ig) or control human immunoglobulin on days embryonic day 11 (E11) and E14, and offspring were followed for the development of anti–β-cell antibodies, islet pathology, and hyperglycemia. The development of anti–β-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 lymphoid structures in the control animals; however, mice treated with LTβR-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 LTβR-Ig–treated mice were devoid of any insulitis. None of the LTβR-Ig–treated mice ( n = 22) developed diabetes; in contrast, 80% of the control mice ( n = 46) developed diabetes at 1 year of age. The LTβR-Ig–treated mice did not contain diabetogenic T-cells. 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–β-cell autoimmunity. Footnotes LTβR-Ig, lymphotoxin-β receptor immunoglobulin fusion protein. Accepted September 1, 2004. Received March 29, 2004. DIABETES