ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms.
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.
Luo
Xunrong
X
Division of Nephrology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. xunrongluo@northwestern.edu
Pothoven
Kathryn L
KL
McCarthy
Derrick
D
DeGutes
Mathew
M
Martin
Aaron
A
Getts
Daniel R
DR
Xia
Guliang
G
He
Jie
J
Zhang
Xiaomin
X
Kaufman
Dixon B
DB
Miller
Stephen D
SD
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
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
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