title: Inhibition of rejection in murine islet xenografts by CTLA4Ig and CD40LIg gene transfer.
abstract: BACKGROUND
  Costimulatory signals play a vital role in T cell activation. Blockade of costimulatory pathway by CTLA4Ig or CD40LIg have enhanced graft survival in experimental transplantation models yet mechanisms remain undetermined. We investigated the effects of CTLA4Ig and CD40LIg gene transfer on islet xenografts rejection in rats.
  
  
  METHODS
  Human islets were infected with recombinant adenoviruses containing CTLA4Ig and CD40LIg genes and implanted beneath the kidney capsule of diabetic rats. Levels of blood sugar, morphological changes, and survival of grafts were recorded. Expressions of CTLA4Ig, CD40LIg and insulin were detected by immunohistochemical staining and cytokines levels were quantified by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  Blood glucose levels in transplant rats decreased to normal level on the 2nd day post transplantation. The mean blood glucose in the control group, CTLA4Ig transfected group, CD40LIg transfected group and CTLA4Ig + CD40LIg cotransfected group increased on days 8, 24, 21, 68, post transplantation respectively. The grafts in control group, CTLA4Ig transfected group, CD40LIg transfected group and CTLA4Ig + CD40LIg cotransfected group survived for (8 ± 1), (29 ± 4), (27 ± 3), and (74 ± 10) days, respectively. Survival in CTLA4Ig + CD40LIg cotransfected group was significantly longer. Survivals of CTLA4Ig transfected group and CD40LIg transfected group were significantly longer than control group. In control animals, serum interleukin-2 and tumor necrosis factor α concentration significantly increased within seven days post transplantation. Haematoxylin eosin staining of grafts showed live islets in situ of transplant rats without inflammatory cell infiltration. Immunohistochemical staining confirmed the expression of insulin at islets in all experimental groups.
  
  
  CONCLUSIONS
  Transfer of CTLA4Ig and CD40LIg genes, especially the cotransfer of both, inhibits rejection of murine islet xenografts. Downregulated expressions of Th1 cells related cytokines might be related to the beneficial effects.
authors.affiliation: Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Wang
authors.forename: Bin-Sheng
authors.initials: BS
authors.lastname: Fu
authors.forename: Gen-Shu
authors.initials: GS
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Chen
mesh_terms: D000069594:Abatacept; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000628:therapy; D006085:Graft Survival / Q000235:genetics / Q000502:physiology; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods*
chemical_list: C526581:CD40LIg fusion protein; D018796:Immunoconjugates; D007328:Insulin; D011993:Recombinant Fusion Proteins; D000069594:Abatacept