Absence of lymph nodes in NOD mice treated with lymphotoxin-beta receptor immunoglobulin protects from diabetes.
Pregnant nonobese diabetic (NOD) mice were treated with lymphotoxin-beta receptor immunoglobulin fusion protein (LTbetaR-Ig) or control human immunoglobulin on days embryonic day 11 (E11) and E14, and offspring were followed for the development of anti-beta-cell antibodies, islet pathology, and hyperglycemia. The development of anti-beta-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 LTbetaR-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 LTbetaR-Ig-treated mice were devoid of any insulitis. None of the LTbetaR-Ig-treated mice (n = 22) developed diabetes; in contrast, 80% of the control mice (n = 46) developed diabetes at 1 year of age. The LTbetaR-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-beta-cell autoimmunity.
Levisetti
Matteo G
MG
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Suri
Anish
A
Frederick
Katherine
K
Unanue
Emil R
ER
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007136:Immunoglobulins / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000276:immunology*; D053259:Lymphotoxin beta Receptor; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use
D007074:Immunoglobulin G; D007136:Immunoglobulins; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins