Evidence that macrophages are required for T-cell infiltration and rejection of fetal pig pancreas xenografts in nonobese diabetic mice

Transplantation. 1998 Dec 15;66(11):1407-16. doi: 10.1097/00007890-199812150-00002.


Background: Host macrophages are abundant within fetal pig pancreas xenografts undergoing rejection, but their role is unknown. Therefore, we examined the effect of host macrophage depletion on xenograft rejection.

Methods: Nonobese diabetic (NOD) mice were given clodronate-loaded liposomes intravenously to deplete macrophages. Controls received phosphate-buffered saline (PBS) or PBS-liposomes. General immune status was assessed after 2, 3, and 7 days by (1) fluorescence-activated cell sorter analysis of peripheral blood, spleen, and lymph node cells, (2) immunohistochemistry on spleens, and (3) mixed lymphocyte reaction. Organ-cultured fetal pig pancreas was transplanted under the kidney capsule of NOD mice 3 days after clodronate or PBS injection. Grafts were assessed histologically at 4, 5, 6, and 8 days after transplantation.

Results: Splenic macrophages and peripheral blood monocytes were depleted 2 days after clodronate treatment but had recovered within 11 days. T cell, B cell, and dendritic cell numbers were normal in spleen, peripheral blood, and lymph nodes of clodronate-treated mice, and T cells and antigen-presenting cells from these mice functioned normally in mixed lymphocyte reaction. Clodronate treatment markedly reduced graft infiltration by macrophages, T cells, and eosinophils at 4, 5, and 6 days after transplantation, and was associated with maintenance of endocrine cell viability and insulin expression. However, all grafts were rejected 8 days after transplantation, concordant with reappearance of splenic macrophages.

Conclusions: Short-term, specific depletion of macrophages markedly delayed cellular infiltration and rejection of xenografts. The results provide the first evidence that macrophages promote T-cell infiltration and rejection of fetal pig pancreas xenografts in NOD mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / physiology
  • Clodronic Acid / pharmacology
  • Female
  • Fetal Tissue Transplantation / immunology*
  • Graft Rejection
  • Graft Survival / drug effects
  • Liposomes
  • Macrophages, Peritoneal / physiology*
  • Mice
  • Mice, Inbred CBA
  • Mice, Inbred NOD
  • Pancreas Transplantation / immunology*
  • Pregnancy
  • Spleen / cytology
  • Swine / embryology*
  • T-Lymphocytes / physiology
  • Transplantation, Heterologous* / immunology


  • Liposomes
  • Clodronic Acid