The Assessment of Transplantation Tolerance Induced by Anti-Cd4 Monoclonal Antibody in the Murine Model1

Accumulating evidence that dendritic cells (DC) are important regulators of peripheral immune tolerance has led to the concept that donor-derived DC may be useful for inducing donor-specific transplantation tolerance. Although in vitro studies in this field have been encouraging, in vivo results have been inconsistent. Recent evidence has suggested a critical role of lymphoid organs in tolerance induction. In this study, we use a novel gene transduction technique to show that engineered expression of CCR7 on immature DC can markedly increase DC homing to lymphoid organs, leading to increased interaction with Ag-specific T cells. Moreover, we show that a single infusion of DC coexpressing CCR7 and the immunomodulatory molecule viral IL-10 (vIL-10) markedly prolongs cardiac allograft survival (mean survival time >100 days); importantly, DC expressing either vIL-10 alone or CCR7 alone was not effective. These results demonstrate an important paradigm for immune modulation using DC.

Section: Discussionmentioning

confidence: 84%

Targeted Lymphoid Homing of Dendritic Cells Is Required for Prolongation of Allograft Survival

Garrod

Chang

Liu

et al. 2006

“…injection of 400 g/mouse of depleting anti-CD8 mAb (YTS169) (39) either alone or in combination with 400 g/mouse of depleting anti-CD4 mAb (YTS191.1) (40). One day later, spleen cells were obtained from these mice and passed through a nylon wool column to enrich the T cell population.…”

Section: Cd8mentioning

confidence: 99%

Donor Lymphocyte Infusion Induces Long-Term Donor-Specific Cardiac Xenograft Survival through Activation of Recipient Double-Negative Regulatory T Cells

Chen

Zhou

Torrealba

et al. 2005

Previous studies have shown that pretransplant donor lymphocyte infusion (DLI) can enhance xenograft survival. However, the mechanism by which DLI induces xenograft survival remains obscure. Using T cell subset-deficient mice as recipients we show that CD4+, but not CD8+, T cells are necessary to mediate the rejection of concordant cardiac xenografts. Adoptive transfer of naive CD4+ T cells induces rejection of accepted cardiac xenografts in CD4−/− mice. This rejection can be prevented by pretransplant DLI in the absence of any other treatment. Furthermore, we demonstrate that DLI activates αβ-TCR+CD3+CD4−CD8− double-negative (DN) regulatory T (Treg) cells in xenograft recipients, and that DLI-activated DN Treg cells can inhibit the proliferation of donor-specific xenoreactive CD4+ T cells in vitro. More importantly, adoptive transfer of DLI-activated DN Treg cells from xenograft recipients can suppress the proliferation of xenoreactive CD4+ T cells and their ability to produce IL-2 and IFN-γ in vivo. Adoptive transfer of DLI-activated DN Treg cells also prevents CD4+ T cell-mediated cardiac xenograft rejection in an Ag-specific fashion. These data provide direct evidence that DLI can activate recipient DN Treg cells, which can induce donor-specific long-term cardiac xenograft survival by suppressing the proliferation and function of donor-specific CD4+ T cells in vivo.

“…This hypothesis could also explain why donor reactive T cells can frequently be detected by in vitro analysis in animals that have accepted a resistant allograft (although at much reduced numbers compared with naive controls), and why animals tolerant of a primary graft that is relatively resistant to rejection often reject a skin graft from a genetically identical donor (25)(26)(27).…”

Section: Figure 2 Absolute Number Of Cd8mentioning

confidence: 99%

Differential Susceptibility of Heart, Skin, and Islet Allografts to T Cell-Mediated Rejection

Jones

Turvey

Maurik

et al. 2001

Self Cite

163

135

Although it is widely accepted that there is a hierarchy in the susceptibility of different allografts to rejection, the mechanisms responsible are unknown. We show that the increased susceptibility of H-2Kb+ skin and islet allografts to rejection is not based on their ability to activate more H-2Kb-specific T cells in vivo; heart allografts stimulate the activation and proliferation of many more H-2Kb-specific T cells than either skin or islet allografts. Rejection of all three types of graft generate memory cells by 25 days posttransplant. These data provide evidence that neither tissue-specific Ags nor, surprisingly, the number of APCs carried in the graft dictate their susceptibility to T cell-mediated rejection and suggest that the graft microenvironment and size may play a more important role in determining the susceptibility of an allograft to rejection and resistance to tolerance induction.