Prevention of early loss of transplanted islets in the liver of mice by adenosine.
BACKGROUND
The low efficiency of islet transplantation necessitating sequential transplantations with the use of 2 to 3 donors for a recipient has been a major obstacle facing clinical islet transplantation. We determined whether adenosine has any beneficial effects on preventing early loss of transplanted islets in the liver, thereby facilitating successful islet transplantation from one donor to one recipient in mice.


METHODS
Two hundred islets, the number of islets from a single mouse pancreas, were grafted into the liver of streptozotocin-induced diabetic C57BL/6 mice. Adenosine was administered once at the time of islet transplantation. Mononuclear cells in the liver of mice receiving islets were isolated and examined by flow cytometry.


RESULTS
A single injection of adenosine at the time of transplantation ameliorated hyperglycemia of diabetic mice receiving 200 syngenic islets with suppression of interferon (IFN)-gamma production of hepatic NKT cells and neutrophils, while that of control did not. The IFN-gamma production of NKT cells and neutrophils in the liver of mice treated with alpha-galactosylceramide, a synthetic ligand of NKT cells was suppressed by adenosine. The beneficial effect of adenosine was also observed for BALB/c islet allografts when alloimmune rejection was prevented by anti-CD4 antibody.


CONCLUSIONS
Adenosine suppresses the NKT cell-mediated IFN-gamma production of neutrophils in the liver of mice receiving islets, thus leading to prevention of early loss of transplanted syngenic and allogenic islets. The findings indicate that adenosine may improve efficiency of clinical islet transplantation.
Nitta
Tomoyuki
T
Department of Regenerative Medicine and Transplantation, Faculty of Medicine Fukuoka University, Fukuoka, Japan.
Itoh
Takeshi
T
Matsuoka
Nobuhide
N
Mera
Toshiyuki
T
Kojima
Daibo
D
Nakano
Masahiko
M
Yamashita
Yuichi
Y
Yasunami
Yohichi
Y
D000241:Adenosine / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001786:Blood Glucose / Q000187:drug effects; D039481:CD11b Antigen / Q000032:analysis; D015704:CD4 Antigens / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D004176:Dipyridamole / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005699:Galactosylceramides / Q000008:administration & dosage; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019707:Receptors, Chemokine / Q000032:analysis; D013868:Thioinosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
D000906:Antibodies; D001786:Blood Glucose; D039481:CD11b Antigen; D015704:CD4 Antigens; D005699:Galactosylceramides; C503133:Gr-1 protein, mouse; D007166:Immunosuppressive Agents; D033703:Nucleoside Transport Proteins; D019707:Receptors, Chemokine; C444719:adenosine transporter; C493154:alpha-galactosylceramide; D013868:Thioinosine; D004176:Dipyridamole; D007371:Interferon-gamma; C001789:4-nitrobenzylthioinosine; D000241:Adenosine