Divergent Role of Donor Dendritic Cells in Rejection versus Tolerance of Allografts

Abstract

Little is known about heart tissue/donor dendritic cells, which play a key role in mounting alloimmune responses. In this report, we focus on three primary features of donor dendritic cells: their generation, their trafficking after transplantation, and their role in regulating tolerance versus rejection. Using transgenic mice as donors of heart allografts enabled us to monitor trafficking of donor dendritic cells after transplantation. Donor dendritic cells rapidly migrated into secondary lymphoid tissues within 3 h of transplantation. We found that the chemokine receptor CX3CR1 regulates the generation of heart tissue dendritic cells constitutively. Compared with wild-type hearts, CX3CR1Ϫ/Ϫ hearts contained fewer dendritic cells, and heart allografts from CX3CR1 Ϫ/Ϫ donors survived significantly longer without immunosuppression. Unexpectedly, though, co-stimulatory blockade with anti-CD154 or CTLA4-Ig induced long-term survival for wild-type heart allografts but not for CX3CR1 Ϫ/Ϫ heart allografts. Increasing the dendritic cell frequency in CX3CR1 Ϫ/Ϫ hearts by treatment with Flt3L restored the anti-CD154 -induced prolongation of CX3CR1 Ϫ/Ϫ heart allograft survival. Compared with wild-type donors, depleting transgenic donors of dendritic cells before heart transplantation also markedly worsened chronic rejection under anti-CD154 treatment. These data indicate the importance of the CX3CR1 pathway in the generation of heart tissue dendritic cells and the divergent role of tissue/dendritic cells in rejection versus tolerance.

Essential Role of PDL1 Expression on Nonhematopoietic Donor Cells in Acquired Tolerance to Vascularized Cardiac Allografts

“…Moreover, donor APCs lacking PDL1 also affected the outcome of CTLA4-Ig treated animals preventing complete tolerance in most but not all recipients, suggesting a contributory role. This latter finding expands a prior observation that donor dendritic cells are important for tolerance development (15) and suggests that PDL1 on donor APCs might be involved in this process.…”

Ischemic Injury Enhances Dendritic Cell Immunogenicity via TLR4 and NF-κB Activation

“…1D). The frequency of IFN-g-producing cells was also assessed as an index of alloreactivity, as has been described previously (25,37). IFN-g production following coculture of allogeneic T cells and isc DCs was significantly upregulated by ELISPOT in a dose-dependent manner (n = 3 experiments; p = 0.026; Fig.…”

“…As the most potent APCs, DCs have the capability to determine the early fate of allografts following transplantation and potentially following ischemia. We have shown that donor DCs from cardiac allografts migrate to recipient lymphoid tissue as early as 3 h posttransplant (25), and it is well established that efficient DC migration results in T cell priming and proinflammatory cytokine production (13,27,30). Our goal was therefore to examine the specific effect of isc insult on DCs, whereby a finding of augmented allostimulatory function of DCs would implicate DCs in having a primary role in ischemiainduced allograft immunogenicity.…”

“…Bone marrow-derived DCs were generated as previously described with minor modifications (25,26). Briefly, the femurs and tibiae of C57BL/6 mice were flushed, and mononuclear cells were seeded in 100 3 20-mm bacteriological petri dishes at a density of 3 3 10 6 cells/ml in 10 ml RPMI 1640 complete medium (containing 10% FCS [Gemini Bio-products, West Sacramento, CA] and 1% L-glutamine and penicillin-streptomycin [both from Cambrex, East Rutherford, NJ]) supplemented with 20 ng/ml recombinant murine GM-CSF (PeproTech, Rocky Hill, NJ).…”

Bidirectional alloreactivity

“…52 In the case of cardiac transplants, the aforementioned DST+ anti-CD40L is effective in inducing allotolerance in wild-type mice, but not in CXC3R1 "null" mice naturally deficient in tissue-resident DC and macrophages. 53 Depletion of heart-resident tissue macrophages by peritransplant antibody treatment led to accelerated cardiac allograft vasculopathy in rats, 54 a phenomenon also seen in combined cardiac-bone marrow, but not in combined cardiac-liver transplantation, where vascular architecture and tissue resident macrophages were preserved long after transplant surgery. 55 Sustaining "tissue-appropriate" immunity immediately after transplantation is likely critical for long-term tolerance with excellent graft function.…”