title: Monotherapy with anti-LFA-1 monoclonal antibody promotes long-term survival of rat islet xenografts.
abstract: Previously we demonstrated that anti-LFA-1 monoclonal (mAb) could promote long-term survival of discordant porcine islet xenografts in mice. The aim of this study, therefore, was to determine whether a shortterm administration of anti-LFA-1 mAb would promote long-term survival of concordant rat islet xenografts in mice, and whether combining short-term administration of anti-LFA-1 mAb therapy with an immunosuppressive drug, rapamycin, would facilitate islet xenograft survival. Streptozotocin-induced diabetic BALB/c mice were transplanted with 500 Wistar-Furth rat islets under the kidney capsule and were either left untreated or treated with short-term administration of rapamycin (0.2 mg/kg) alone, anti-LFA-1 mAb (0.2 mg/ dose) alone, or a combination of rapamycin and anti-LFA-1 mAb using the same doses. All untreated mice rejected their grafts by 24 days posttransplantation with a mean graft survival time of 18.8 +/- 2.5 days posttransplantation (n = 5). All mice treated with rapamycin alone had prolonged islet graft survival but eventually rejected their islet grafts by 81 days posttransplantation. In contrast, the majority of the mice (27/ 28) treated with anti-LFA-1 mAb alone maintained long-term normoglycemia (>100 days). Rapamycin in combination with anti-LFA-1 mAb proved equally effective with 29 of 30 mice maintaining normoglycemia for more than 100 days posttransplantation. Low levels of mouse anti-rat antibodies, as well as a decrease in the degree of mononuclear cell infiltration of the islet graft, closely correlated with long-term islet xenograft survival. These results demonstrate that monotherapy with anti-LFA-1 mAb is highly effective in promoting long-term survival of rat islet xenografts and that combination of anti-LFA-1 mAb with rapamycin does not facilitate nor abrogate the induction of long-term xenograft survival by anti-LFA-1 mAb therapy in BALB/c mice. Our study indicates that immunomodulation through mAb therapy could form a significant component of future antirejection therapies in clinical islet xenotransplantation.
authors.affiliation: Surgical-Medical Research Institute, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Tredget
authors.forename: Hossein
authors.initials: H
authors.lastname: Arefanian
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Gina R
authors.initials: GR
authors.lastname: Rayat
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011920:Rats, Inbred WF; D020123:Sirolimus / Q000494:pharmacology; D014183:Transplantation, Heterologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D020123:Sirolimus