Monocyte-Derived Dendritic Cell Precursors Facilitate Tolerance to Heart Allografts After Total Lymphoid Irradiation1

Hayamizu, Keisuke; Huie, Philip; Sibley, Richard K.; Strober, Samuel

doi:10.1097/00007890-199811270-00004

Cited by 64 publications

(30 citation statements)

References 24 publications

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“…Moreover, blockade of costimulation can markedly enhance the ability of DC to induce apoptosis in alloactivated T cells (55). The tolerogenic potential of these costimulator-deficient DC (24,26,30,(33)(34)(35)(36)(37)(38) raises the possibility that manipulation of FL-mobilized donor DC progenitors or immature DC in transplant recipients may promote donor-specific unresponsiveness. However, a therapeutic effect of FL-BM cells (alone or with tacrolimus) on allograft survival could not be demonstrated in the present study.…”

Section: Discussionmentioning

confidence: 99%

Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus

Morelli

Antonysamy²,

Takayama³

et al. 2000

The Journal of Immunology

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Flt3 ligand (FL) is a potent hemopoietic growth factor that strikingly enhances stem cells and dendritic cells (DC) in vivo. We examined the impact of infusing FL-mobilized bone marrow (BM) cells on microchimerism and anti-donor reactivity in normal and tacrolimus-immunosuppressed, noncytoablated allogeneic recipients. BM from B10 (H2b) mice given FL (10 μg/day; days 0–8; FL-BM) contained a 7-fold higher incidence of potentially tolerogenic immature CD11c+ DC (CD40low, CD80low, CD86low, MHC IIlow) that induced alloantigen-specific T cell hyporesponsiveness in vitro. C3H (H2k) mice received 50 × 106 normal or FL-BM cells (day 0) and tacrolimus (2 mg/kg/day; days 0–12). On day 15, enhanced numbers of donor (IAb+) cells were detected in the thymi and spleens of FL-BM recipients. Tacrolimus markedly enhanced microchimerism, which declined as a function of time. Ex vivo splenocyte proliferative and CTL responses and Th1 cytokine (IFN-γ) production in response to donor alloantigens were augmented by FL-BM infusion, but reduced by tacrolimus. Systemic infusion of purified FL-BM immature DC, equivalent in number to that in corresponding whole BM, confirmed their capacity to sensitize, rather than tolerize, recipient T cells in vivo. In vitro, tacrolimus suppressed GM-CSF-stimulated growth of myeloid DC from normal BM much more effectively than from FL-BM without affecting MHC class II or costimulatory molecule expression. Infusion of normal B10 BM cells at the time of transplant prolonged C3H heart allograft survival, whereas FL-BM cells did not. A therapeutic effect of tacrolimus on graft survival was observed in combination with normal, but not FL-BM cells. These findings suggest the need for alternative immunosuppressive strategies to calcineurin inhibition to enable the engraftment, survival, and immunomodulatory function of FL-enhanced, immature donor DC.

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Section: Discussionmentioning

confidence: 99%

Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus

Morelli

Antonysamy²,

Takayama³

et al. 2000

The Journal of Immunology

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“…They migrate in vivo to T cell areas of secondary lymphoid tissue, where they persist for weeks in allogeneic recipients (20,21). These liver-derived DC progenitors (DCp) can prolong allograft survival (22), a property shared with immature myeloid DC propagated from rodent BM (23)(24)(25).…”

mentioning

confidence: 99%

Effects of Liver-Derived Dendritic Cell Progenitors on Th1- and Th2-Like Cytokine Responses In Vitro and In Vivo

Khanna¹,

Morelli²,

Zhong³

et al. 2000

The Journal of Immunology

174

112

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There is evidence that donor-derived dendritic cells (DC), particularly those at a precursor/immature stage, may play a role in the immune privilege of liver allografts. Underlying mechanisms are poorly understood. We have examined the influence of in vitro generated mouse liver-derived DC progenitors (DCp) on proliferative, cytotoxic, and Th1/Th2 cytokine responses induced in allogeneic T cells. Liver DCp, propagated in GM-CSF from C57B10 mice (H2b), induced only minimal proliferation, and weak cytotoxic responses in allogeneic (C3H; H2k) T cells compared with mature bone marrow (BM)-derived DC. Flow-cytometric analysis of intracellular cytokine staining revealed that mature BM DC, but not liver DCp, elicited CD4+ T cell production of IFN-γ. Intracellular expression of IL-10 was very low in both BM DC- and liver DCp-stimulated CD4+ T cells. Only stimulation by liver DCp was associated with IL-10 secretion in primary MLR. Notably, these liver DCp cocultured with allogeneic T cells stained strongly for IL-10. Following local (s.c.) injection in allogeneic recipients, both BM DC and liver DCp homed to T cell areas of draining lymph nodes and spleen, where they were readily detected by immunohistochemistry up to 2 wk postinjection. Liver DCp induced clusters of IL-10- and IL-4-secreting mononuclear cells, whereas Th2 cytokine-secreting cells were not detected in mice injected with mature BM DC. By contrast, comparatively high numbers of IFN-γ+ cells were induced by BM DC. Modulation of Th2 cytokine production by donor-derived DCp may contribute to the comparative immune privilege of hepatic allografts.

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“…45 In addition, there is evidence that immature or costimulatory molecule-deficient DC can induce allospecific T cell hyporesponsiveness, 16,21 and prolong pancreatic islet, 17 or cardiac graft survival. [18][19][20][21] However, the efficacy of this approach to the prevention of transplant rejection is transient, due probably to the eventual up-regulation of costimulatory pathway interaction between the adoptively transferred DC and host T cells. In an attempt to overcome this limitation, we sought to block functional expression of CD80/CD86 costimulatory signals by transgene expression at the sites of interaction between allogeneic DC and host T cells in vivo, using CTLA4Ig-transduced DC as potential tolerogenic APC.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15] Recently, it has been shown that costimulatory molecule-deficient, immature DC can induce Ag-specific T cell anergy, 16 and prolong allograft survival. [17][18][19] This tolerogenic effect can be potentiated by the costimulation blocking agent anti-CD40 ligand (CD154) mAb, 20 or by administration of T cell-directed monoclonal antibody (mAb). 21 Alternative approaches to the potentiation of DC tolerogenicity include exposure of the cells to the anti-inflammatory cytokines interleukin (IL)-10 22,23 or transforming growth factor ␤ (TGF-␤), 20 or to the fusion protein cytotoxic T lymphocyte Ag-immunoglobulin (CTLA4Ig).…”

Section: Introductionmentioning

confidence: 99%

Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro

et al. 2000

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Dendritic cells (DC) are highly specialised, bone marrow (BM)-derived antigen-presenting cells (APC) that initiate and regulate immune responses. They provide costimulatory signals (in particular, CD40 and the CD28 ligands CD80 and CD86) necessary for naive T cell activation. Functional expression of CD80 and CD86 is blocked by the fusion protein cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4Ig), that promotes tolerance induction in animals. Here, replicating mouse (B10; H2 b ) myeloid DC progenitors, were retrovirally transduced to express CTLA4Ig using the centrifugal enhancement method. Gene product was detected by immunocyto-or histochemistry. Maximal DC transduction efficiency was 62%. Compared with control, zeomycin-resistance gene (Zeo)-transduced DC, CTLA4Ig-expressing cells showed markedly impaired capacity to stimulate naive allogeneic (C3H; H2 k ) T cell proliferation and cytotoxic T lymphocyte (CTL) generation. Their ability to induce alloantigen-specific T cell hyporesponsiveness was

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Monocyte-Derived Dendritic Cell Precursors Facilitate Tolerance to Heart Allografts After Total Lymphoid Irradiation1

Abstract: The intravenous injection of donor dendritic cell precursors derived from blood monocytes facilitates long-term acceptance of heart allografts.

Cited by 64 publications

References 24 publications

Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus

Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus

Effects of Liver-Derived Dendritic Cell Progenitors on Th1- and Th2-Like Cytokine Responses In Vitro and In Vivo

Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro

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