In vivo BLyS/BAFF neutralization ameliorates islet-directed autoimmunity in nonobese diabetic mice.
B lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B cell compartment reduces the competitive constraint on the entry of newly emerging TR B cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. In this study we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TR-->FO selection by increasing TR B cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone B lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TR-->FO checkpoint, 2) abrogated serum insulin autoantibodies, 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction, and 6) disrupted CD4 T cell activation in NOD mice. Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.
Zekavat
Ghazal
G
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Rostami
Susan Y
SY
Badkerhanian
Armen
A
Parsons
Ronald F
RF
Koeberlein
Brigitte
B
Yu
Ming
M
Ward
Christopher D
CD
Migone
Thi-Sau
TS
Yu
Liping
L
Eisenbarth
George S
GS
Cancro
Michael P
MP
Naji
Ali
A
Noorchashm
Hooman
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects*; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007167:Immunotherapy; D007328:Insulin / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007328:Insulin; C505720:Tnfsf13b protein, mouse