title: A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice.
abstract: OBJECTIVE
  To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal.
  
  
  METHODS
  Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig.
  
  
  RESULTS
  BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice).
  
  
  CONCLUSIONS
  The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.
authors.affiliation: Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. paolo.fiorina@childrens.harvard.edu
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.forename: Mollie
authors.initials: M
authors.lastname: Jurewicz
authors.forename: Alessandra
authors.initials: A
authors.lastname: Petrelli
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Liu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Law
authors.forename: Christian
authors.initials: C
authors.lastname: Schuetz
authors.forename: Michele
authors.initials: M
authors.lastname: Carvello
authors.forename: Elena
authors.initials: E
authors.lastname: Orsenigo
authors.forename: Shaoping
authors.initials: S
authors.lastname: Deng
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Javeed M
authors.initials: JM
authors.lastname: Ansari
authors.forename: Carlo
authors.initials: C
authors.lastname: Staudacher
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: James
authors.initials: J
authors.lastname: Markmann
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000961:Antilymphocyte Serum; D015551:Autoimmunity / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000601:surgery; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010047:Ovalbumin / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D010047:Ovalbumin; C512542:thymoglobulin
references.citation: Transplant Proc. 1973 Mar;5(1):733-5
references.pmid: 4572133
references.citation: N Engl J Med. 2005 Aug 25;353(8):770-81
references.pmid: 16120857
references.citation: Diabetes. 2009 Oct;58(10):2277-84
references.pmid: 19628781
references.citation: Diabetes. 2003 Apr;52(4):957-64
references.pmid: 12663467
references.citation: J Am Soc Nephrol. 2006 Oct;17(10):2844-53
references.pmid: 16914538
references.citation: Diabetes. 2009 Oct;58(10):2267-76
references.pmid: 19602536
references.citation: J Immunol. 1995 Jun 1;154(11):5757-68
references.pmid: 7751626
references.citation: J Immunol. 2004 Dec 1;173(11):6727-34
references.pmid: 15557165
references.citation: J Immunol. 2007 Jul 1;179(1):120-5
references.pmid: 17579029
references.citation: Lancet. 2008 Aug 2;372(9636):383-91
references.pmid: 18632147
references.citation: J Immunol. 2001 Feb 1;166(3):1572-82
references.pmid: 11160198
references.citation: Am J Transplant. 2008 Oct;8(10):1990-7
references.pmid: 18828765
references.citation: Clin Immunol. 2008 Feb;126(2):140-7
references.pmid: 17889619
references.citation: N Engl J Med. 2006 Nov 9;355(19):1967-77
references.pmid: 17093248
references.citation: J Immunol. 2003 Oct 1;171(7):3348-52
references.pmid: 14500627
references.citation: Diabetes. 2008 Nov;57(11):3013-24
references.pmid: 18689692
references.citation: J Immunol. 2008 Jul 15;181(2):1025-33
references.pmid: 18606654
references.citation: Diabetes Care. 2008 Mar;31(3):436-8
references.pmid: 18071001
references.citation: Nat Rev Immunol. 2004 Apr;4(4):259-68
references.pmid: 15057784
references.citation: J Immunol. 1997 Mar 15;158(6):2947-54
references.pmid: 9058834
references.citation: Nat Med. 2004 Jan;10(1):87-92
references.pmid: 14647496
references.citation: Immunity. 2005 Aug;23(2):115-26
references.pmid: 16111631
references.citation: Diabetes. 2002 Nov;51(11):3202-10
references.pmid: 12401711
references.citation: Diabetes. 2008 Feb;57(2):405-14
references.pmid: 18039815
references.citation: J Rheumatol. 2006 Nov;33(11):2162-6
references.pmid: 17014006
references.citation: N Engl J Med. 2006 Sep 28;355(13):1318-30
references.pmid: 17005949
references.citation: N Engl J Med. 2005 Sep 15;353(11):1114-23
references.pmid: 16162882
references.citation: N Engl J Med. 2002 May 30;346(22):1692-8
references.pmid: 12037148
references.citation: JAMA. 2005 Feb 16;293(7):830-5
references.pmid: 15713772
references.citation: J Immunol. 2009 Apr 15;182(8):4608-15
references.pmid: 19342635
references.citation: J Exp Med. 1996 Jun 1;183(6):2541-50
references.pmid: 8676075
references.citation: Diabetes. 2007 Apr;56(4):912-20
references.pmid: 17287465
references.citation: Annu Rev Immunol. 2001;19:225-52
references.pmid: 11244036
references.citation: J Immunol. 2004 Jan 1;172(1):15-9
references.pmid: 14688303
references.citation: J Clin Invest. 2008 May;118(5):1806-14
references.pmid: 18431516
references.citation: Am J Transplant. 2008 Nov;8(11):2463-70
references.pmid: 18808408