title: Pig embryonic pancreatic tissue as a source for transplantation in diabetes: transient treatment with anti-LFA1, anti-CD48, and FTY720 enables long-term graft maintenance in mice with only mild ongoing immunosuppression.
abstract: OBJECTIVE
  Defining an optimal costimulatory blockade-based immune suppression protocol enabling engraftment and functional development of E42 pig embryonic pancreatic tissue in mice.
  
  
  METHODS
  Considering that anti-CD40L was found to be thrombotic in humans, we sought to test alternative costimulatory blockade agents already in clinical use, including CTLA4-Ig, anti-LFA1, and anti-CD48. These agents were tested in conjunction with T-cell debulking by anti-CD4 and anti-CD8 antibodies or with conventional immunosuppressive drugs. Engraftment and functional development of E42 pig pancreatic tissue was monitored by immunohistology and by measuring pig insulin blood levels.
  
  
  RESULTS
  Fetal pig pancreatic tissue harvested at E42, or even as early as at E28, was fiercely rejected in C57BL/6 mice and in Lewis rats. A novel immune suppression comprising anti-LFA1, anti-CD48, and FTY720 afforded optimal growth and functional development. Cessation of treatment with anti-LFA1 and anti-CD48 at 3 months posttransplant did not lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced diabetes.
  
  
  CONCLUSIONS
  This novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Tchorsh-Yutsis
authors.forename: Gil
authors.initials: G
authors.lastname: Hecht
authors.forename: Anna
authors.initials: A
authors.lastname: Aronovich
authors.forename: Elias
authors.initials: E
authors.lastname: Shezen
authors.forename: Yael
authors.initials: Y
authors.lastname: Klionsky
authors.forename: Chava
authors.initials: C
authors.lastname: Rosen
authors.forename: Rivka
authors.initials: R
authors.lastname: Bitcover
authors.forename: Smadar
authors.initials: S
authors.lastname: Eventov-Friedman
authors.forename: Helena
authors.initials: H
authors.lastname: Katchman
authors.forename: Sivan
authors.initials: S
authors.lastname: Cohen
authors.forename: Orna
authors.initials: O
authors.lastname: Tal
authors.forename: Oren
authors.initials: O
authors.lastname: Milstein
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000071178:CD48 Antigen; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000196:embryology; D016035:Pancreas Transplantation; D011409:Propylene Glycols / Q000276:immunology / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology / Q000627:therapeutic use; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000071178:CD48 Antigen; C000604065:CD48 protein, human; C000604066:Cd48 protein, mouse; C000604067:Cd48 protein, rat; D016169:Lymphocyte Function-Associated Antigen-1; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine