Prolonged survival of islet allografts in mice treated with rosmarinic acid and anti-CD154 antibody.
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.
Jung
Da Yeon
DY
Transplantation Research Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Kim
Eun Young
EY
Joo
Sung Yeon
SY
Park
Jae Berm
JB
Moon
Cheol
C
Kim
Sa Hyun
SH
Sim
Eun Young
EY
Joh
Jae Won
JW
Kwon
Choon Hyuck
CH
Kwon
Ghee Young
GY
Kim
Sung Joo
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D023201:CD40 Ligand / Q000276:immunology*; D002934:Cinnamates / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D053630:Depsides / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006085:Graft Survival / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014184:Transplantation, Homologous; D000097123:Rosmarinic Acid
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D002934:Cinnamates; D016207:Cytokines; D053630:Depsides; D005947:Glucose; D000097123:Rosmarinic Acid