Induction of anti-whole GAD65 reactivity in vivo results in disease suppression in type 1 diabetes.
Most type 1 diabetes mellitus is caused by autoimmune pancreatic beta-cell destruction. Several antigens such as insulin, glutamic acid decarboxylase (GAD) and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) are considered to take part in the autoimmune destructive process. Because the role of GAD in the disease process of type 1 diabetes is still controversial, we investigated the disease phenotype upon in vivo induction of whole GAD65 reactivity using a GAD65 homo knockout NOD splenocytes to NOD-scid transfer system. Splenocytes from 8 to 10-week-old female GAD65 homo knockout (=KOT splenocytes) or age-matched wild type (=WTT splenocytes) NOD mice were transferred into female NOD-scid recipients. As compared to recipients of WTT splenocytes, the onset of diabetes in recipients of KOT splenocytes was significantly delayed (p<0.001). Moreover, TGF-beta expression was enhanced in the pancreas from recipients of KOT splenocytes. Splenocytes from recipients of KOT splenocytes produced IL-10 (/IFN-gamma) upon GAD65 stimulation, whereas those from recipients of WTT splenocytes did not. Based upon these results, we propose that anti-whole GAD65-reactive T cells have the ability to regulate the development of type 1 diabetes.
Kanazawa
Yasuhiko
Y
Department of Internal Medicine, Keio University School of Medicine, Shimanomachi Shinjuku-ku, Tokyo, Japan.
Shimada
Akira
A
Oikawa
Yoichi
Y
Okubo
Yoshiaki
Y
Tada
Ai
A
Imai
Takatoshi
T
Miyazaki
Junichi
J
Itoh
Hiroshi
H
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005968:Glutamate Decarboxylase / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology; D013154:Spleen / Q000201:enzymology / Q000276:immunology
D000906:Antibodies; D016207:Cytokines; D005968:Glutamate Decarboxylase