Activation of Transplant Immunity: Effect of Donor Leukocytes on Thyroid Allograft Rejection

Talmage, David W.; Dart, G; Radovich, Jevrosima; Lafferty, Kevin J.

doi:10.1126/science.1082167

Cited by 150 publications

(81 citation statements)

References 12 publications

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“…For transplanted tissues such as skin, donor DC migrate from the graft via the dermal lymphatic vessels into draining lymph nodes (12). Improvement in graft survival following depletion of leukocytes from thyroid, pancreatic islet, skin, or kidney allografts supports the concept that trafficking and maturation of donor DC in recipient lymphoid organs lead to the activation of naive, alloreactive Th0 lymphocytes, and thus provides the primary stimulus for acute allograft rejection (18,43,44). By contrast, in the absence of immune suppression, liver allografts (that possess comparatively large numbers of passenger leukocytes) can induce donor-specific tolerance in fully MHC-mismatched mouse and certain rat strain combinations, and in a high proportion of outbred pigs (19,(45)(46)(47).…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…30,31 The evidence Implicating these antigen-presenting cells in primary T-cell alloimmunity 22,30,32 has prompted efforts to eliminate them before transplantation. 33,34 .…”

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confidence: 99%

Cell migration, chimerism, and graft acceptance

et al. 1992

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The chimeric nature of the transplanted liver was first shown in our long-surviving human recipients of orthotopic hepatic allografts in 1969. 1 When liver grafts were obtained from cadaveric donors of the opposite sex, karyotyping studies showed that hepatocytes and endothelium of major blood vessels retained their donor specificity, whereas the entire macrophage system, including Kuppfer cells, was replaced with recipient cells. 2 Where donor cells that had left the liver had gone was unknown, but their continued presence was confirmed by the acquisition and maintenance in recipient blood of new donor-specific immunoglobulin (Gm) types 1,3 and red-blood-cell alloantibodies, if donors with ABO non-identity were used. 4 Davies et al 5 attributed the secretion of new soluble HLA class I antigens of donor type to transplanted hepatocytes. However, these HLA molecules come from bone-marrow-derived macrophages and/or dendritic cells, 6 and probably have the same origin from migrated donor cells as the additional Gm types and red-cell antibodies.Although this early evidence of systemic mixed allogeneic chimerism was circumstantial, we have recently shown with both anatomical and molecular techniques the presence, in clinically stable patients, of peripherally located donor cells many years after liver replacement. For instance, in patients with type IV glycogen storage disease, a disorder in which an insoluble amylopectin-like polysaccharide accumulates throughout the body because of a deficiency in a branching enzyme, we found resorption of extrahepatic amylopectin after liver replacement. 7 This process could not be explained until the migrated donor cells, which had acted as enzyme couriers, were identified by both HLA monoclonal antibodies (fig 1) and polymerase chain reaction (PCR) studies (fig 2) in the biopsied myocardium and skin of 2 patients, 33 and 91 months after hepatic transplantation.Recent experiments in rats have shown the timing and extent of seeding from the hepatic allograft to both non-lymphoid and lymphoid organs (fig 3). 8 A similar pattern of distribution was found after successful rat-to-mouse bone-marrow transplantation. 9 This similarity between liver transplantation and bone-marrow transplantation has not been reported before. The prompt development, and then the persistence, of this systemic chimerism may help to explain the resistance of the liver to cellular 10 and humoral 11 rejection, as well as its tolerogenicity to other organs from the same donor. 12 The chimeric structure of the transplanted liver was thought to be a unique feature of this organ for many years until we identified lymphoid and dendritic cell replacement under FK 506 immunosuppression in rat 13 and human 14 intestinal allografts; a similar finding has been reported in swine. 15 In our experiments with rats, the two-way traffic was the same, irrespective of whether bowel was transplanted alone or as a part of a multivisceral graft that also contained Correspondence to

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“…M ore than 20 years ago, Lafferty and colleagues and, subsequently, Lechler and Batchelor demonstrated that the main immunogenic stimulus leading to graft rejection was provided by the migrant population of allogeneic "passenger" dendritic cells (DC) 3 present in the allografted tissue (1)(2)(3)(4). If the graft was depleted of these cells, rejection was less strong or was absent, and graft survival was extended.…”

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confidence: 99%

Acute Rejection in the Absence of Cognate Recognition of Allograft by T Cells

Braun¹,

Grandjean

Feunou³

et al. 2001

The Journal of Immunology

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We studied the effects of the indirect pathway of allograft recognition using T cells from TCR transgenic Marilyn mice, which recognize the male Ag H-Y in an I-Ab-restricted fashion. The T cells are not alloreactive to the H-2k haplotype, because they are not activated when adoptively transferred into recombinase-activating gene-2−/− common γ-chain−/− double-mutant H-2k male or female mice. However, skin from H-2k males, but not from H-2k females, is acutely rejected by recombinase-activating gene-2−/− transgenic female recipients. In vitro, Marylin spleen cells primed by H-2k skin grafting proliferated and secreted both IL-4 and IFN-γ in response to H-2k male stimulators. However, the removal of H-2b APC from the responding population abolished the response. Taken together, these results show that the indirect recognition that triggers rejection in this model is due to the recognition of H-Y Ag shed from H-2k male allograft and presented by the recipient’s own I-Ab APC to transgenic T cells. This study demonstrates unequivocally the capacity of naive CD4+ T cells to promote the rejection of allografts through mechanisms that involve indirect destruction of grafted tissues.

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Activation of Transplant Immunity: Effect of Donor Leukocytes on Thyroid Allograft Rejection

Cited by 150 publications

References 12 publications

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

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

Cell migration, chimerism, and graft acceptance

Acute Rejection in the Absence of Cognate Recognition of Allograft by T Cells

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