title: Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.
abstract: BACKGROUND
  Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.
  
  
  RESULTS
  The DNA demethylating agent Zebularine, previously demonstrated to induce expression of the genes for the immunosuppressive enzymes indolamine-2,3-deoxygenase-1 (IDO1) and kynureninase of the kynurenine pathway, is tested for capacity to suppress rejection of allotransplants. Allogeneic pancreatic islets from Lewis rats were transplanted under the kidney capsule of Fischer rats previously made diabetic by a streptozotocin injection (40 mg/kg). One group was treated with Zebularine (225 mg/kg) daily for 14 days from day 6 or 8 after transplantation, and a control group received no further treatment. Survival of the transplants was monitored by blood sugar measurements. Rats, normoglycemic for 90 days after allografting, were subjected to transplant removal by nephrectomy to confirm whether normoglycemia was indeed due to a surviving insulin producing transplant, or alternatively was a result of recovery of pancreatic insulin production in some toxin-treated rats. Of 9 Zebularine treated rats, 4 were still normoglycemic after 90 days and became hyperglycemic after nephrectomy. The mean length of normoglycemia in the Zebularine group was 67±8 days as compared to 14±3 days in 9 controls. Seven rats (2 controls and 5 Zebularine treated) were normoglycemic at 90 days due to pancreatic recovery as demonstrated by failure of nephrectomy to induce hyperglycemia.
  
  
  CONCLUSIONS
  Zebularine treatment in vivo induces a long-lasting suppression of the immune destruction of allogeneic pancreatic islets resulting in protection of allograft function for more than 10 weeks after end of treatment.
authors.affiliation: Institute of Clinical Sciences, Department of Neurosurgery, the Rausing Laboratory, Lund University, Lund, Sweden.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Nittby
authors.forename: Peter
authors.initials: P
authors.lastname: Ericsson
authors.forename: Karolina
authors.initials: K
authors.lastname: Förnvik
authors.forename: Susanne
authors.initials: S
authors.lastname: Strömblad
authors.forename: Linda
authors.initials: L
authors.lastname: Jansson
authors.forename: Zhongtian
authors.initials: Z
authors.lastname: Xue
authors.forename: Gunnar
authors.initials: G
authors.lastname: Skagerberg
authors.forename: Bengt
authors.initials: B
authors.lastname: Widegren
authors.forename: Hans-Olov
authors.initials: HO
authors.lastname: Sjögren
authors.forename: Leif G
authors.initials: LG
authors.lastname: Salford
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000601:surgery*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside