Abstract
BackgroundDendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model.MethodsImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model.ResultsDonor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4+CD25+ T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to naïve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients.ConclusionCombined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.
Highlights
Organ transplantation is almost the only hope of complete cure for patients with organ failure
Characterization of Exosomes Derived from Dendritic cells (DCs) Eight days after culturing in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF) and recombinant interleukin-4 (IL-4), murine bone marrow (BM) cells developed a typical DC profile as reported by Lutz et al [16]
Mature DCs expressed high levels of major histocompatibility complex (MHC) class I, class II, and co-stimulatory CD80 and CD86 compared with immature DCs (imDCs)
Summary
Organ transplantation is almost the only hope of complete cure for patients with organ failure. The view that immature and mature DCs mediate different functional T-cell responses (i.e., tolerance versus priming) is very common, and the effect of immature DCs (imDCs) on inducing transplantation tolerance has been tested in many different animal transplantation models. Dendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. This effect is limited and does not induce immunological tolerance when imDex are administered alone. We tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model
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