Exp Mol Med.  2008 Feb;40(1):1-10. 10.3858/emm.2008.40.1.1.

Prolonged survival of islet allografts in mice treated with rosmarinic acid and anti-CD154 antibody

Affiliations
  • 1Transplantation Research Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. kmhyj111@hotmail.com
  • 2Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
  • 3Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.

Abstract

Pancreatic islet transplantation can correct the abnormal glucose metabolism of Type 1 diabetes. Although immunosuppressants greatly reduce the acute rejection rate in transplant patients, the long-term side effects can be debilitating. Therefore, researchers are seeking to develop new immunosuppressive regimens that induce maximal levels of immunosuppression with minor side effects. Rosmarinic acid (Ros A) is a secondary metabolite of certain herbs and has multiple biological activities, including anti-inflammatory effects. Here, we have investigated whether treatment of mice with a combination of Ros A and anti-CD154 monoclonal antibody (MR1) improves islet allograft survival in a murine model. After transplantation, the mice were treated with either Ros A, MR1, or both (the "double" treatment). Allograft survival was prolonged in the double-treated animals compared to animals that received only Ros A or MR1. As is the case with the single-treated animals at 15 days after transplantation, the double-treated recipients did not display a significant decrease in the expression of cytokines or the population of activated T cells. Infiltrating CD3+ T cells were reduced in the MR1- or double therapy relative to control or RosA group. However, at the same time point, double-treated graft showed fewer apoptotic cells and increased expression of insulin and glucagons, compared to the single-treatment groups. Furthermore, long-term (>150 days) allografts that were received with double therapy exhibited larger islet clusters and contained more insulin- and glucagon-positive cells, relative to the MR1-treated grafts. In conclusion, treatment with both Ros A and MR1 has a synergistic effect in murine islet allotransplantation.

Keyword

apoptosis; CD40 ligand; graft survival; immunosuppressive agents; islets of Langerhans transplantation; rosmarinic acid

MeSH Terms

Animals
Antibodies, Monoclonal/*pharmacology
Apoptosis/drug effects
CD40 Ligand/*immunology
Cinnamates/*pharmacology
Cytokines/biosynthesis
Depsides/*pharmacology
Diabetes Mellitus, Experimental
Flow Cytometry
Glucose/metabolism
Glucose Tolerance Test
Graft Survival/*drug effects
In Situ Nick-End Labeling
Injections, Intraperitoneal
Islets of Langerhans/drug effects/pathology
*Islets of Langerhans Transplantation
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Time Factors
Transplantation, Homologous
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