Interleukin 12 in Combination With Antmnterleukin 10 Reverses Graft Prolongation After Portal Venous Immunization

Gorczynski, Reg; Hozumi, Noriko; Wolf, Stanley F.; Chen, Z.

doi:10.1097/00007890-199512150-00024

Cited by 8 publications

(10 citation statements)

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“…Unresponsiveness to donor renal allografts following Ag-specific pv pre-or peritransplant immunization is associated with the preferential activation of type 2 rather than type 1 cytokine-producing cells (23,27). T cell activation depends not just upon the delivery of signals via the TCR (generally in the form of Ag-MHC), but also on the appropriate delivery of costimulatory signals from APCs (28), along with the cytokine milieu in which stimulation occurs.…”

Section: Discussionmentioning

confidence: 99%

Receptor Engagement on Cells Expressing a Ligand for the Tolerance-Inducing Molecule OX2 Induces an Immunoregulatory Population That Inhibits Alloreactivity In Vitro and In Vivo

Gorczynski

Yang

Clark

2000

The Journal of Immunology

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Increased survival of C57BL/6 renal allografts following portal vein donor-specific pretransplant immunization of C3H mice is associated with increased expression of the molecule OX2 seen on host dendritic cells, along with a marked polarization in cytokine production from lymphocytes harvested from the transplanted animals, with preferential production of IL-4, IL-10, and TGF-β on donor-specific restimulation in vitro, and decreased production of IL-2, IFN-γ, and TNF-α compared with non-portal vein-immunized control transplanted mice. The increased renal allograft survival and the altered cytokine production are abolished by infusion of anti-mouse OX2 mAb (3B6). Infusion of a soluble OX2:Fc immunoadhesin can itself produce significant prolongation of xeno- and allografts in mice. We have used FITC-conjugated OX2:Fc to characterize cells expressing a ligand (OX2L) for OX2, and provide evidence that subpopulations of LPS-stimulated splenic macrophages, Con A-activated splenic T cells, and the majority (>80%) of γδTCR+ T cells express this ligand. We show below that F4/80+, OX2L+ splenic macrophages, admixed with OX2:Fc, represent a potent immunosuppressive population capable of causing more profound inhibition of alloreactivity in vitro or in vivo than that seen using either OX2:Fc or OX2+ (or OX2L+) cells alone. Immunoregulation by this OX2L+ population occurs in an MHC-restricted fashion.

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Section: Discussionmentioning

confidence: 99%

Receptor Engagement on Cells Expressing a Ligand for the Tolerance-Inducing Molecule OX2 Induces an Immunoregulatory Population That Inhibits Alloreactivity In Vitro and In Vivo

Gorczynski

Yang

Clark

2000

The Journal of Immunology

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“…injection of minor HC-disparate cells is associated with decreased production of the Th1 cytokines (IFN␥ and IL-2) and that this enhances the production of the Th2 cytokines (IL-4 and IL-10). Furthermore, after treatment with anti-IL-10 antibody or IL-12, the prolongation of graft survival was found to be eliminated (27). Other researchers analyzing transplantation of vascularized grafts also have reported that recipients exhibiting accommodated grafts show a Th2-type cytokine response, whereas the recipients that have rejected grafts show a Th1-type cytokine response (8,9).…”

Section: Fig 3 Effects Of Donor T Cells On Skin Graft Survival Ratesmentioning

confidence: 98%

A strategy for organ allografts without using immunosuppressants or irradiation

Morita

Sugiura

Inaba

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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A strategy to achieve regular and long lasting organ and tissue allografts without using immunosuppressants and͞or irradiation has been established for mice. One hundred percent of skin allografts can be induced to survive >350 days after transplantation if spleen cells from the same donors are first injected into the portal vein of the recipients. The mechanisms underlying this long-term tolerance induction can be described as follows: (i) donor T cells from the spleen of the donor facilitate the acceptance of the allogeneic engraftment, (ii) donor-specific anergy is induced in the cytotoxic T-lymphocytes of the recipients, (iii) T helper type 2 cells become the dominant T cells in the recipients that are accepting the skin transplants, and (iv) a lasting chimerism (microchimerism) is established in these recipients. This strategy, perhaps with minor modifications, might permit one also to overcome major barriers to organ allografting in humans. If this were the case, it could represent production of long lasting immunologic tolerance without need for irradiation or cytotoxic chemo-preparative regimen and as such could greatly facilitate allotransplantation free of episodes of chronic or acute rejection or toxic and damaging preparatory regimens.

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“…Somewhat surprisingly, systemic injection or local high concentrations of IL-10 was found to accelerate graft rejection (51). In contrast, expression of viral IL-10 in nonvascularized cardiac allografts by retroviral transduction of the graft before transplantation resulted in graft prolongation (52), and neutralization of IL-10 by anti-IL-10 therapy abrogated skin graft prolongation induced by portal venous injection of allogeneic splenocytes (53). Moreover, high levels of IL-10 have been described as associated with tolerance to HLA-mismatched bone marrow stem cells (54), and in renal transplant patients with EBVinduced posttransplant lymphoproliferative disorder increased levels of IL-10 correlated with operational tolerance to the graft in aciclovir-treated patients (55).…”

Section: Cd45rbmentioning

confidence: 99%

IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo

Hara

Kingsley

Niimi

et al. 2001

The Journal of Immunology

716

523

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We present evidence that donor-reactive CD4+ T cells present in mice tolerant to donor alloantigens are phenotypically and functionally heterogeneous. CD4+ T cells contained within the CD45RBhigh fraction remained capable of mediating graft rejection when transferred to donor alloantigen-grafted T cell-depleted mice. In contrast, the CD45RBlow CD4+ and CD25+CD4+ populations failed to induce rejection, but rather, were able to inhibit rejection initiated by naive CD45RBhigh CD4+ T cells. Analysis of the mechanism of immunoregulation transferred by CD45RBlow CD4+ T cells in vivo revealed that it was donor Ag specific and could be inhibited by neutralizing Abs reactive with IL-10, but not IL-4. CD45RBlow CD4+ T cells from tolerant mice were also immune suppressive in vitro, as coculture of these cells with naive CD45RBhigh CD4+ T cells inhibited proliferation and Th1 cytokine production in response to donor alloantigens presented via the indirect pathway. These results demonstrate that alloantigen-specific regulatory T cells contained within the CD45RBlow CD4+ T cell population are responsible for the maintenance of tolerance to donor alloantigens in vivo and require IL-10 for functional activity.

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Interleukin 12 in Combination With Antmnterleukin 10 Reverses Graft Prolongation After Portal Venous Immunization

Cited by 8 publications

References 0 publications

Receptor Engagement on Cells Expressing a Ligand for the Tolerance-Inducing Molecule OX2 Induces an Immunoregulatory Population That Inhibits Alloreactivity In Vitro and In Vivo

Receptor Engagement on Cells Expressing a Ligand for the Tolerance-Inducing Molecule OX2 Induces an Immunoregulatory Population That Inhibits Alloreactivity In Vitro and In Vivo

A strategy for organ allografts without using immunosuppressants or irradiation

IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo

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