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Role of Donor-Derived Monocyte Chemoattractant Protein-1 in Murine Islet Transplantation

Bernd Schröppel^*,, Nan Zhang^,, Peng Chen^*, Dongmei Chen, Jonathan S. Bromberg^, and Barbara Murphy^*,

^* Division of Nephrology, Recanati/Miller Transplantation Institute, and Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York

Address correspondence to: Dr. Bernd Schröppel, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1243, New York, NY 10029-6574. Phone: 212-241-8004; Fax: 212-987-0389; E-mail: bernd.schroppel{at}mssm.edu

Monocyte chemoattractant protein-1 (CCL2/MCP-1) is a proinflammatory chemokine produced by several cell types, including pancreatic islets. High levels of donor-derived CCL2 have been associated with poor islet allograft outcome in patients with type 1 diabetes; however, the causal relationship is unknown. The constitutive and inducible expression of chemokines and their receptors by pancreatic islets in vitro were investigated, specifically the role of donor-derived CCL2 in marginal mass murine islet transplantation. The results showed that inflammatory cytokine stimulation of islets induced de novo expression of CCL2, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP-10 and increased expression of CXCL2/macrophage-inflammatory protein-2. CCL2 mRNA and protein were highly expressed within 2 d in cultures. Transplantation of islets with high levels of CCL2 into syngeneic recipients led to a significantly greater influx of CCR2+ cells and higher expression of monocyte/macrophage-associated inflammatory cytokines compared with low CCL2-donor islets. The level of pretransplantation CCL2 inversely correlated (P < 0.0001) with isograft function. In contrast, in CCR2–/– recipients, this correlation was not present. A direct toxic effect of CCL2 on islets was excluded by assessing cell viability and insulin release in vitro. In conclusion, CCL2 secreted by islets plays an important role in the immediate islet graft function. Strategies to decrease islet-derived CCL2 release may increase the success of islet transplantation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673