Background: It has been reported that HO-1 is critical for tolerogenic dendritic cells (tolDCs) to suppress T cell responses and tolDCs will lost their immunoregulatory effects when HO-1 is blocked. Therefore, significant upregulation of HO-1 may markedly improve the tolerogenic capability of tolDCs.

Methods: Bone marrow-derived DCs (BMDCs) were generated from Balb/c mice with low doses of GM-CSF and IL-4. The adherent immature BMDCs were obtained as TolDCs. HO-1 high expression of TolDCs (HO-1^hi TolDCs) was induced with CoPP treatment. SnPP-treated TolDCs served as control cells. LPS was used to induce DC maturation. T cell proliferation was stimulated by anti-CD3/CD28 antibodies. Adoptive transfer of different types of Balb/c donor-derived DCs (5×10⁶) to C57BL/6 recipient mice was performed 7 days prior to cardiac transplantation.

Results: CoPP treatment dramatically elevated HO-1 expression in TolDCs, which rendered TolDCs refractory to LPS-induced maturation, enhanced the capability to suppress the anti-CD3/CD28 antibodies-induced CD4⁺ and CD8⁺ T cells proliferation, as well as induce more allogenic Tregs in vitro. Adoptive transfer of donor-derived untreated TolDCs significantly prolonged cardiac allograft survival compared to untreated control group (18.000±2.853 vs. 7.500±0.289 days). Interestingly, adoptive transfer of CoPP-treated TolDCs further extended the prolongation of allograft survival (36.778±6.974 days, P<0.01, vs. TolDCs group). In contrast, adoptive transfer of SnPP-treated TolDCs significantly shortened the allograft survival (9.143 ± 0.670 days).Conclusion: In vitro generated HO-1^hi-TolDCs have enhanced capacity to modulate alloimmune responses both in vitro and in vivo, thus may provide an antigen-specific and cost-effective novel strategy to induce transplant tolerance.

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