Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse.
BACKGROUND
Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that induces insulin autoantibodies and prevents diabetes in the NOD. However, immunization with peptide without adjuvant may be insufficient to reverse disease or induce long-term tolerance. Furthermore, recent experience has demonstrated the potential dangers of disease exacerbation or anaphylaxis with peptide immunotherapy.


METHODS
Combination therapy of B:9-23 with a nondepleting anti-CD4 monoclonal antibody (YTS 177.9) was studied in female NOD mice from 4 through 6 weeks of age. Injections of either B:9-23 in saline, YTS 177.9 antibody, or both peptide and antibody were given to mice.


RESULTS
By 52 weeks follow-up, 40% of B:9-23-treated, 100% of YTS177.9-treated, and 70% of B:9-23 and YTS177.9 combination-treated mice remained diabetes-free. IAA, both spontaneous and induced by B:9-23, was almost completely suppressed in mice receiving YTS 177.9. In addition to suppression of IAA expression, anti-B:9-23 peptide antibodies are also suppressed in mice receiving B:9-23 with YTS 177.9, compared to B:9-23 alone.


CONCLUSIONS
A brief course of the nondepleting anti-CD4 monoclonal antibody (YTS 177.9) in NOD mice confers long-term protection from diabetes and insulitis and profoundly blocks spontaneous and B:9-23 peptide-induced insulin autoantibodies.
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B140, Denver, CO 80262, USA.
Edwin
E
Liu
Hiroaki
H
Moriyama
Johanna
J
Paronen
Norio
N
Abiru
Dongmei
D
Miao
Liping
L
Yu
Robert M
RM
Taylor
George S
GS
Eisenbarth
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007328:Insulin / Q000276:immunology* / Q000494:pharmacology; D007330:Insulin Antibodies / Q000097:blood / Q000378:metabolism*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D016019:Survival Analysis; D014611:Vaccination
D000906:Antibodies; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001786:Blood Glucose; D015704:CD4 Antigens; D007328:Insulin; D007330:Insulin Antibodies; D010446:Peptide Fragments; C097877:insulin B (9-23); D003520:Cyclophosphamide