title: Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice.
abstract: There is compelling evidence that autoreactive CD8(+)T cells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an islet-restricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8(+)T cells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes in Itgae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbs to ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE(+) cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE(+)CD8(+)T effectors initiate the disease process.
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Barrie
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Mels
authors.initials: M
authors.lastname: Lodder
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Buss
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Amer
authors.initials: A
authors.lastname: Rajab
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Adin
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.affiliation: The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA gregg.hadley@osumc.edu.
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Hadley
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D018450:Disease Progression; D005260:Female; D039001:Integrin alpha Chains / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D039001:Integrin alpha Chains; C091367:alpha E integrins
keywords: autoimmune; diabetes; immune system; mouse