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Spontaneous Renal Allograft Acceptance Associated with "Regulatory" Dendritic Cells and IDO¹

Charles H. Cook^2,*,, Alice A. Bickerstaff^*, Jiao-Jing Wang^*, Tibor Nadasdy, Patricia Della Pelle, Robert B. Colvin and Charles G. Orosz^*

^* Department of Surgery, Department of Anesthesiology, and Department of Pathology, The Ohio State University, Columbus, OH 43210; and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114

MHC-mismatched DBA/2 renal allografts are spontaneously accepted by C57BL/6 mice by poorly understood mechanisms, but both immune regulation and graft acceptance develop without exogenous immune modulation. Previous studies have shown that this model of spontaneous renal allograft acceptance is associated with TGF-β-dependent immune regulation, suggesting a role for T regulatory cells. The current study shows that TGF-β immune regulation develops 30 days posttransplant, but is lost by 150 days posttransplant. Despite loss of detectable TGF-β immune regulation, renal allografts continue to function normally for >200 days posttransplantation. Because of its recently described immunoregulatory capabilities, we studied IDO expression in this model, and found that intragraft IDO gene expression progressively increases over time, and that IDO in "regulatory" dendritic cells (RDC) may contribute to regulation associated with long-term maintenance of renal allografts. Immunohistochemistry evaluation confirms the presence of both Foxp3⁺ T cells and IDO⁺ DCs in accepted renal allografts, and localization of both cell types within accepted allografts suggests the possibility of synergistic involvement in allograft acceptance. Interestingly, at the time when RDCs become detectable in spleens of allograft acceptors, 30% of these mice challenged with donor-matched skin allografts accept these skin grafts, demonstrating progression to "true" tolerance. Together, these data suggest that spontaneous renal allograft acceptance evolves through a series of transient mechanisms, beginning with TGF-β and T regulatory cells, which together may stimulate development of more robust regulation associated with RDC and IDO.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health RO1 AI053094 (to C.H.C.) and a grant from the Roche Organ Transplant Foundation (to R.B.C.).

² Address correspondence and reprint requests to Dr. Charles H. Cook, The Ohio State University, 410 West Tenth Ave, N747 Doan Hall, Columbus, OH 43210. E-mail address: charles.cook{at}osumc.edu

³ Abbreviations used in this paper: DTH, delayed-type hypersensitivity; T_reg, regulatory T cell; GIC, graft-infiltrating cell; DC, dendritic cell; RDC, regulatory DC; IVC, inferior vena cava; 1-MT, 1-methyl-D-tryptophan.