Monotherapy with anti-LFA-1 monoclonal antibody promotes long-term survival of rat islet xenografts

Eric B. Tredget, Hossein Arefanian, Ronald G. Gill, Ray V. Rajotte, Gina R. Rayat

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 short-term 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.

Original languageEnglish
Pages (from-to)599-608
Number of pages10
JournalCell Transplantation
Volume17
Issue number6
DOIs
Publication statusPublished - 3 Nov 2008

Keywords

  • Islet transplantation
  • Leukocyte function associated antigen-1 (LFA-1)
  • Rapamycin (sirolimus)
  • Rat islets
  • Type 1 diabetes mellitus (T1DM)
  • Xenograft

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