title: Transient B-cell depletion with anti-CD20 in combination with proinsulin DNA vaccine or oral insulin: immunologic effects and efficacy in NOD mice.
abstract: A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.
authors: La Jolla Institute for Allergy and Immunology, Diabetes Center, La Jolla, CA, USA.
authors: Ghanashyam
authors: G
authors: Sarikonda
authors: Sowbarnika
authors: S
authors: Sachithanantham
authors: Yulia
authors: Y
authors: Manenkova
authors: Tinalyn
authors: T
authors: Kupfer
authors: Amanda
authors: A
authors: Posgai
authors: Clive
authors: C
authors: Wasserfall
authors: Philip
authors: P
authors: Bernstein
authors: Laura
authors: L
authors: Straub
authors: Philippe P
authors: PP
authors: Pagni
authors: Darius
authors: D
authors: Schneider
authors: Teresa Rodriguez
authors: TR
authors: Calvo
authors: Marilyne
authors: M
authors: Coulombe
authors: Kevan
authors: K
authors: Herold
authors: Ronald G
authors: RG
authors: Gill
authors: Mark
authors: M
authors: Atkinson
authors: Gerald
authors: G
authors: Nepom
authors: Mario
authors: M
authors: Ehlers
authors: Teodora
authors: T
authors: Staeva
authors: Hideki
authors: H
authors: Garren
authors: Lawrence
authors: L
authors: Steinman
authors: Andrew C
authors: AC
authors: Chan
authors: Matthias
authors: M
authors: von Herrath
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy / Q000276:immunology; D007328:Insulin / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000276:immunology; D011384:Proinsulin / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007328:Insulin; D019444:Vaccines, DNA; D015847:Interleukin-4; D011384:Proinsulin
references: Eur J Immunol. 2002 Dec;32(12):3657-66
references: 12516557
references: J Clin Invest. 1999 Jul;104(2):189-94
references: 10411548
references: Pediatr Diabetes. 2004;5 Suppl 2:23-8
references: 15601371
references: J Immunol. 2008 Dec 15;181(12):8298-307
references: 19050246
references: Int Immunol. 2012 Apr;24(4):233-42
references: 22298883
references: J Immunol. 2008 Mar 1;180(5):2863-75
references: 18292508
references: J Immunol. 1998 Aug 1;161(3):1163-8
references: 9686575
references: J Immunol. 2007 Jul 15;179(2):1004-12
references: 17617592
references: N Engl J Med. 2002 May 30;346(22):1692-8
references: 12037148
references: J Clin Invest. 2006 May;116(5):1371-81
references: 16628253
references: J Immunol. 1999 Jul 15;163(2):743-50
references: 10395666
references: Trends Immunol. 2008 Jan;29(1):34-40
references: 18289504
references: Rev Diabet Stud. 2005 Fall;2(3):121-35
references: 17491687
references: Diabetes Care. 2005 May;28(5):1068-76
references: 15855569
references: J Clin Invest. 2003 May;111(9):1365-71
references: 12727928
references: J Clin Invest. 2007 Dec;117(12):3857-67
references: 18060033
references: J Exp Med. 2012 Jan 16;209(1):51-60
references: 22213807
references: Diabetes. 2011 Nov;60(11):2914-21
references: 21926271
references: J Clin Invest. 1996 Sep 15;98(6):1324-31
references: 8823297
references: Diabetes. 2011 Apr;60(4):1237-45
references: 21307076
references: Diabetes. 2005 Jun;54(6):1763-9
references: 15919798
references: Ann N Y Acad Sci. 2011 Dec;1243:119-34
references: 22211897
references: J Immunol. 1999 Aug 15;163(4):1833-8
references: 10438916
references: Nature. 2005 May 12;435(7039):220-3
references: 15889095
references: Diabetologia. 2010 Sep;53(9):1958-70
references: 20490452
references: J Autoimmun. 2010 Jun;34(4):408-15
references: 19931408
references: Clin Exp Immunol. 2010 May;160(2):176-84
references: 20629979
references: J Immunol. 2001 Nov 15;167(10):5535-8
references: 11698422
references: N Engl J Med. 2009 Nov 26;361(22):2143-52
references: 19940299
references: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4658-63
references: 20176942
references: Lancet. 2008 Nov 15;372(9651):1746-55
references: 18814906
references: Sci Transl Med. 2012 Jan 25;4(118):118ra12
references: 22277969
references: Diabetes. 2010 Sep;59(9):2087-93
references: 20805382
references: J Immunol. 2001 Sep 1;167(5):2950-5
references: 11509644
references: Clin Exp Immunol. 2009 Feb;155(2):156-65
references: 19040615
references: Lancet. 2011 Jul 30;378(9789):412-9
references: 21719096