Targeting CD22 reprograms B-cells and reverses autoimmune diabetes.
OBJECTIVE
To investigate a B-cell-depleting strategy to reverse diabetes in naïve NOD mice.


METHODS
We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes.


RESULTS
Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-cell-depleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4(+) T-cells into NOD.SCID hosts.


CONCLUSIONS
Targeting CD22 depletes and reprograms B-cells and reverses autoimmune diabetes, thereby providing a blueprint for development of novel therapies to cure autoimmune diabetes.
Fiorina
Paolo
P
Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Vergani
Andrea
A
Dada
Shirine
S
Jurewicz
Mollie
M
Wong
Masie
M
Law
Kenneth
K
Wu
Erxi
E
Tian
Ze
Z
Abdi
Reza
R
Guleria
Indira
I
Rodig
Scott
S
Dunussi-Joannopoulos
Kyri
K
Bluestone
Jeffrey
J
Sayegh
Mohamed H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000276:immunology; D011236:Prediabetic State / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D051918:Sialic Acid Binding Ig-like Lectin 2