Spontaneous Renal Allograft Acceptance Associated with “Regulatory” Dendritic Cells and IDO

Abstract

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.

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

“…5C). Therefore, anergy may be the major mechanism for tolerance maintenance, as suggested in other models of tolerance (34).…”

Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IL-10–Dependent Regulatory Dendritic Cells by SOCS3 Activation

“…Several types of regDCs, with similar functions but different phenotypes (13)(14)(15)(16)(17)(18), can be induced by a cytokine mixture that includes GM-CSF, IL-10, and TGF-b in vitro; however, these induction conditions do not accurately mimic the microenvironment in vivo, which involves a complex orchestration and regulation of cytokine production and cell-cell interaction. Previous reports showed that BM-MSCs could influence DC differentiation (8,9), and Cao's group (19) showed that endothelial splenic stroma could induce the differentiation of CD11b high Ia low regDCs from bone marrow hematopoietic stem/progenitor cells (BM-HPCs), but the induction of regDCs in vivo remains controversial.…”

Tolerogenic Dendritic Cells for Therapy of Immune-Mediated Inflammatory Diseases

“…In animal models, the administration of 1-methyl-tryptophan, a small-molecule IDO inhibitor, into pregnant mice resulted in immediate rejection of an allogeneic fetus, confirming its role in maternal immune tolerance towards paternal alloantigens (Munn, Zhou et al 1998;Mellor and Munn 2004). In this manner, it has been shown that IDO not only contributes to maternal tolerance but can control allograft rejection (Grohmann, Orabona et al 2002;Cook, Bickerstaff et al 2008) and ameliorate autoimmune diseases as well Platten, Ho et al 2005). In addition, IDOmediated immunosuppression has been demonstrated to play a role in decreased immunosurveillance of tumor tissues and its inhibition by pharmacological agents such as 1-L-methyl-tryptophan (1-MT) results in improved anti-tumor responses (Hou, Muller et al 2007).…”

“…Attempts have been made also to apply DCs transduced with constructs for both IL-10 and TGF-, which led to increased graft survival compared to single cytokine-expressing DCs (Gorczynski, Bransom et al 2000). Several experimental data confirmed an essential role of IDO and DCs in immunoregulation of allo-responses (Hainz, Jurgens et al 2007;Cook, Bickerstaff et al 2008). In a rat kidney transplantation model, allograft tolerance was induced by administration of an anti-CD28 Ab (Haspot, Seveno et al 2005).…”