title: ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms.
abstract: A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing beta cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptor-programmed death ligand 1 signaling pathway and CD4(+)CD25(+)Foxp3(+) regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.
authors.affiliation: Division of Nephrology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. xunrongluo@northwestern.edu
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Pothoven
authors.forename: Derrick
authors.initials: D
authors.lastname: McCarthy
authors.forename: Mathew
authors.initials: M
authors.lastname: DeGutes
authors.forename: Aaron
authors.initials: A
authors.lastname: Martin
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Guliang
authors.initials: G
authors.lastname: Xia
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Dixon B
authors.initials: DB
authors.lastname: Kaufman
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005022:Ethyldimethylaminopropyl Carbodiimide / Q000494:pharmacology*; D005404:Fixatives / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000601:surgery; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D005404:Fixatives; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; D005022:Ethyldimethylaminopropyl Carbodiimide
references.citation: Toxicol In Vitro. 2005 Jun;19(4):541-6
references.pmid: 15826812
references.citation: J Immunol. 2002 Nov 1;169(9):4712-6
references.pmid: 12391178
references.citation: Transplantation. 1986 Aug;42(2):191-6
references.pmid: 2943063
references.citation: J Immunol. 1988 May 15;140(10):3324-30
references.pmid: 2834436
references.citation: J Clin Invest. 2007 Sep;117(9):2553-61
references.pmid: 17786244
references.citation: Diabetes. 2005 Jul;54(7):2060-9
references.pmid: 15983207
references.citation: Transplantation. 2006 Jul 27;82(2):180-7
references.pmid: 16858280
references.citation: N Engl J Med. 2005 Dec 1;353(22):2342-51
references.pmid: 16319383
references.citation: Nat Med. 2008 Jan;14(1):88-92
references.pmid: 18066074
references.citation: J Immunol. 2008 Mar 1;180(5):3103-12
references.pmid: 18292533
references.citation: Nat Rev Immunol. 2007 Sep;7(9):665-77
references.pmid: 17690713
references.citation: Nat Rev Immunol. 2005 Apr;5(4):343-9
references.pmid: 15775994
references.citation: J Immunol. 2000 Jan 15;164(2):670-8
references.pmid: 10623809
references.citation: Nat Immunol. 2006 Jun;7(6):652-62
references.pmid: 16633346
references.citation: J Immunol. 1990 Feb 1;144(3):909-15
references.pmid: 1688591
references.citation: J Immunol. 2007 Feb 15;178(4):2212-20
references.pmid: 17277126
references.citation: J Immunol. 1992 May 1;148(9):2748-55
references.pmid: 1374098
references.citation: Transplantation. 1994 Oct 27;58(8):966-8
references.pmid: 7940748
references.citation: Am J Transplant. 2007 Oct;7(10):2311-7
references.pmid: 17845564
references.citation: Clin Immunol. 2003 Sep;108(3):190-8
references.pmid: 14499242
references.citation: N Engl J Med. 2008 Jan 24;358(4):362-8
references.pmid: 18216356
references.citation: N Engl J Med. 2006 Sep 28;355(13):1318-30
references.pmid: 17005949
references.citation: Hum Immunol. 2006 Sep;67(9):665-75
references.pmid: 17002896
references.citation: J Immunol. 2005 Apr 15;174(8):4525-34
references.pmid: 15814673
references.citation: Annu Rev Immunol. 2005;23:515-48
references.pmid: 15771580
references.citation: Nature. 2005 May 12;435(7039):220-3
references.pmid: 15889095
references.citation: Nat Med. 2008 May;14(5):528-35
references.pmid: 18438416
references.citation: Transplant Proc. 2005 Oct;37(8):3438-40
references.pmid: 16298621
references.citation: Front Biosci. 2007 May 01;12:4042-9
references.pmid: 17485357
references.citation: Eur J Immunol. 1995 Sep;25(9):2643-9
references.pmid: 7589139
references.citation: J Exp Med. 1979 Mar 1;149(3):758-73
references.pmid: 85683
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2821-6
references.pmid: 17307871
references.citation: Nat Med. 2005 Jun;11(6):605-13
references.pmid: 15937473
references.citation: J Exp Med. 2006 Nov 27;203(12):2737-47
references.pmid: 17116737
references.citation: N Engl J Med. 2008 Jan 24;358(4):353-61
references.pmid: 18216355
references.citation: Am J Transplant. 2008 Feb;8(2):298-306
references.pmid: 18190656