Tolerance to solid organ transplants through transfer of MHC class II genes

Sonntag, Kai‐Christian; Emery, David W.; Yasumoto, Akihiko; Haller, Gary W.; Germana, Sharon; Sablinski, Tomasz; Shimizu, Akira; Yamada, Kazuhiko; Shimada, Hideaki; Arn, Scott; Sachs, David H.; LeGuern, Christian

doi:10.1172/jci11015

Cited by 72 publications

(42 citation statements)

References 33 publications

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“…In rodents, a variety of maneuvers can induce donor-specific allograft tolerance, including pretransplantation priming with donor MHC Ags (blood or splenocytes) (2) (1, 2, 7-10), transfected cells expressing donor MHC Ags (11,12), MHC gene transfer (13,14), or DNA vaccination (15).…”

mentioning

confidence: 99%

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

Jovanović

Dugast²,

Heslan³

et al. 2008

The Journal of Immunology

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In rats, tolerance to MHC-incompatible renal allografts can be induced by the administration of anti-donor class II Abs on the day of transplantation. In this study we explored the mechanisms involved in the maintenance phase of this tolerance by analyzing intragraft gene expression profiles by microarray in long-term accepted kidneys. Comparison of the gene expression patterns of tolerated to syngeneic kidneys revealed 5,954 differentially expressed genes (p < 0.05). Further analysis of this gene set revealed a key role for the wingless-type (WNT) signaling pathway, one of the pivotal pathways involved in cell regulation that has not yet been implicated in transplantation. Several genes within this pathway were significantly up-regulated in the tolerated grafts, particularly matrix metalloproteinase 7 (MMP7; fold change > 40). Analysis of several other pathway-related molecules indicated that MMP7 overexpression was the result of the noncanonical WNT signaling pathway. MMP7 expression was restricted to vascular smooth muscle cells and was specific to anti-class II Ab-induced tolerance, as it was undetectable in other models of renal and heart transplant tolerance and chronic rejection induced across the same strain combination. These results suggest a novel role for noncanonical WNT signaling in maintaining kidney transplant tolerance in this model, with MMP7 being a key target. Determining the mechanisms whereby MMP7 contributes to transplant tolerance may help in the development of new strategies to improve long-term graft outcome.

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mentioning

confidence: 99%

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

Jovanović

Dugast²,

Heslan³

et al. 2008

The Journal of Immunology

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“…Experimentally, a variety of maneuvers can induce donor-specific allograft tolerance, including pretransplantation priming with donor MHC Ags (blood or splenocytes) (1-3), transfected cells expressing donor MHC Ags (4), soluble MHC molecules or allopeptides (5), MHC gene transfer (6,7), or DNA vaccination (8). In addition, we have shown that injection of recipients with Abs directed against donor class II MHC can also induce specific tolerance to renal vascularized allografts in adult rats (9,10).…”

mentioning

confidence: 99%

Dominant Tolerance to Kidney Allografts Induced by Anti-Donor MHC Class II Antibodies: Cooperation between T and Non-T CD103+ Cells

Degauque

Lair

Dupont

et al. 2006

The Journal of Immunology

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Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection. The kidney grafts of tolerant animals display an accumulation of TCR Cβ, FoxP3, and IDO transcripts. Moreover, as compared with syngeneic recipients, tolerant recipients harbor a large infiltrate of MHC class II+ cells and CD103+ cells. In vitro, splenocytes from tolerant recipients exhibit decreased donor-specific proliferation, which is restored by depletion of non-T cells and partially restored by the blockade of IDO. Finally, splenocytes from tolerant recipients, but not purified T cell splenocytes, transfer donor-specific infectious tolerance without chronic rejection, after infusion into naive recipients, over two generations. However, splenocytes depleted of T cells or splenocytes depleted of CD103+ cells fail to transfer tolerance. Collectively, these data show that a single administration of anti-donor MHC class II alloimmune serum induces a tolerant state characterized by an infiltration of the kidney graft by regulatory T cells and CD103+ cells. These data also show that the transfer of tolerance requires the presence of both T cells and CD103+ dendritic cells. The precise mechanism of cooperation of these two cell subsets remains to be defined.

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“…These data suggest that unresponsiveness can be achieved in the absence of microchimerism detectable using this PCR assay. Sonntag et al 8 have also reported similar findings following retroviral transfer of MHC class II genes to recipient BM in a renal allograft model in miniature swine. Increasing the dose to 5 × 10 6 CBK BMCs in combination with YTA3.1 pretreatment, enabled us to detect K b mRNA at all time-points up until the time of transplantation in the periphery but less frequently in the thymus (Figure 3a).…”

Section: Discussionmentioning

confidence: 57%

“…3,4 The potential of syngeneic bone marrow cells (BMCs) bearing alloantigen to induce tolerance in animal models has previously been demonstrated in this and other laboratories using transgenic or gene therapy strategies. [4][5][6][7][8] Most gene therapy protocols involving BMCs have employed replication-defective recombinant Moloney murine leukaemia virus (MMLV)-based retroviruses due in part to their ability to stably integrate the transferred genes into the genome of the host cell. The ability of replication-defective, E1-deleted, recombinant adenovirus vectors to transduce whole bone marrow is less well characterised, but these vectors have been shown to be highly effective at transducing many cell types at different developmental stages.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo

2002

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Tolerance to solid organ transplants through transfer of MHC class II genes

Cited by 72 publications

References 33 publications

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

Dominant Tolerance to Kidney Allografts Induced by Anti-Donor MHC Class II Antibodies: Cooperation between T and Non-T CD103+ Cells

Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo

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