title: Pig islet xenograft rejection is markedly delayed in macrophage-depleted mice: a study in streptozotocin diabetic animals.
abstract: The present study aimed to evaluate the effect of depletion of macrophages and/or natural killer (NK) cells on islet xenograft rejection in the pig-to-mouse model. Five microliters (4,000 to 5,000 IEQ, islet equivalents) of adult pig islets were transplanted under the renal capsule of C57BL/6 mice with streptozotocin-induced diabetes. Macrophages were depleted by injection of liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP) intraperitoneally (i.p.) at a dose of 100 microl/ 10 g body weight (BW) 2 days before transplantation, and 50 microl/10 g BW weekly thereafter. NK cells were depleted by injection of the monoclonal antibody NK 1.1 (anti-NK 1.1 mAb) i.p. at a dose of 100 microg/mouse 1 day before transplantation, and then 25 microg per week thereafter. Islet graft survival was monitored by daily measurements of blood glucose. Graft survival was 8 +/- 1.2 days in untreated controls, 9 +/- 1.0 days with anti-NK 1.1 mAb alone, 22 +/- 4.9 days with Lip-Cl2MDP alone (P<0.01 vs. controls), and 26 +/- 3.8 days with Lip-Cl2MDP plus anti-NK 1.1 mAb (P<0.01 vs. controls). In the last group, two of six animals were killed with functioning grafts 30 days after transplantation. In untreated controls, rejected xenografts were heavily infiltrated by F4/80+ macrophages and CD3+T cells. In Lip-Cl2MDP-treated groups, the number of F4/80+ macrophages was markedly reduced. On the periphery of xenografts, a small number of CD3+T cells were observed. In conclusion, our results suggest that strategies targeting macrophages may facilitate islet xenograft survival. A role for NK cells cannot be excluded, but appears to be of minor importance.
authors.affiliation: Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden. guoshengwu@hotmail.com
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: O
authors.initials: O
authors.lastname: Korsgren
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Song
authors.forename: N
authors.initials: N
authors.lastname: van Rooijen
authors.forename: A
authors.initials: A
authors.lastname: Tibell
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004002:Clodronic Acid; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology*; D008081:Liposomes; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000145:classification / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D008081:Liposomes; D004002:Clodronic Acid