Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts

Objective: Interleukin-10 is a pleiotrophic cytokine with variable effects on the alloimmune response, depending on the experimental model system. The purpose of this study was to determine the role of regulated interleukin-10 expression on the development of chronic rejection in heart transplantation, or cardiac allograft vasculopathy. Methods: Donor hearts from B6.C-H2(bm12) mice were transplanted into wild-type and interleukin-10 transgenic recipients. In interleukin-10 transgenic recipients, murine interleukin-10 cytokine is produced under the control of human interleukin-2 promoter. Donor hearts were sacrificed at days 7 and 24. No immunosuppression was used. Intimal proliferation was measured morphometrically. Intragraft cellular infiltrate was defined by both immunohistochemistry and flow cytometry. Intracellular cytokine staining assay was performed to determine both the type and source of intragraft cytokines. Results: Hearts transplanted into wild-type recipients developed severe cardiac allograft vasculopathy by 24 days. Intimal lesions were absent in the donor hearts transplanted into interleukin-10 transgenic recipients. The number of graft-infiltrating T lymphocytes and the percentage of interleukin-2/interferon-gamma producing T lymphocytes were markedly reduced in interleukin-10 transgenic recipients. Finally, the overexpression of interleukin-10 resulted in the decline of graft-infiltrating macrophages at all time points. Conclusions: Regulated expression of interleukin-10 inhibits cardiac allograft vasculopathy development via reduction of mononuclear cell recruitment and alteration of their cytokine profile. This strategy may prove beneficial in controlling the alloimmune response in solid organ transplants.