Induction of<i>foxP3</i>+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants

Cobbold, Stephen; Castejón, Raquel; Adams, Elizabeth; Zélénika, Diana; Graça, Luís; Humm, Susan; Waldmann, Herman

doi:10.4049/jimmunol.172.10.6003

Cited by 390 publications

(365 citation statements)

References 59 publications

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“…To our knowledge, we show for the first time, that donor-specific hyporesponder patients have the higher presence of FOXP3 ϩ CD4 ϩ CD25 ϩ T cells in graft infiltrates. Therefore, our findings strongly support the notion that the Tregs population is playing an active role promoting graft acceptance (52,53). Besides, rather than just being a static immune condition, the achievement of donor-specific hyporesponsiveness had a beneficial functional translation showed by better graft function and more preserved graft parenchyma.…”

Section: Discussionsupporting

confidence: 73%

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Bestard¹,

Cruzado²,

Mestre³

et al. 2007

The Journal of Immunology

146

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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+HLADR+ T cells, combined with a sustained enhancement of CD4+CD25+high lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+CD25+high T cells, which showed donor-Ag specificity. FOXP3+CD4+CD25+high Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

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Section: Discussionsupporting

confidence: 73%

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Bestard¹,

Cruzado²,

Mestre³

et al. 2007

The Journal of Immunology

146

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“…2B). Foxp3 mRNA was detected within the spleens and grafts of the anti-CD4 tolerized Marilyn mice, as previously described for A1.RAG mice [26] (Fig. 2C).…”

Section: Searching For Molecular Patterns That Correlate With DC Tolesupporting

confidence: 62%

“…For Ab-induced tolerance, 1 mg of non-depleting anti-CD4 (YTS177.9.6) or IgG2a isotype control Ab was administered as a single dose on the day of grafting [26].…”

Section: Tolerance Induction and Skin Graftingmentioning

confidence: 99%

Tolerogenicity is not an absolute property of a dendritic cell

et al. 2010

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Pharmacological modulation is known to temper the immune capacity of DC, enhancing the notion that modulated Ag-bearing DC might be used therapeutically to induce tolerance. We have investigated phenotypic features shared by such DC, and queried their potential to tolerize in different settings. Immature, IL-10, TGF-b and 1a,25-dihydroxyvitamin D 3 -modulated BMDC all induced tolerance to male skin in female TCR transgenic A1.RAG mice, and the modulated DC also tolerized after exposure to the TLR4-ligand LPS. Transcript profiling revealed that this was achieved despite retaining much of the normal LPS-maturation response. No shared tolerance-associated transcripts could be identified. Equivalent BMDC could not tolerize in Marilyn TCR-transgenic mice. Simultaneous presentation of both A1.RAG and Marilyn peptide-Ag (Dby-H2E k and Dby-H2A b ) on immature (C57BL/6JxCBA/Ca) F1 BMDC also only achieved tolerance in A1.RAG mice. Both strains registered Ag, but Foxp3 1 Treg were only induced in A1.RAG mice. In contrast, Marilyn T cells showed greater proliferation and an inflammatory bias, in response to Ag presented by immature F1 BMDC in vitro. In summary, while pharmacological agents can skew DC to reinforce their immature tolerogenic phenotype, the outcome of presentation is ultimately an integrated response including T-cell-intrinsic components that can over-ride for immune activation.Key words: DC . TCR transgenic mice . Transplantation tolerance Supporting Information available online IntroductionDespite enthusiasm to exploit tolerogenic DC clinically [1][2][3], what constitutes a tolerogenic DC in vivo, and how it achieves tolerance, is still poorly understood. Immunological outcome was thought to be related directly to the maturation status of DC, with immature DC presenting for tolerance [4][5][6]; however, this simple view rapidly failed to account for accumulating experimental observations [7,8]. The functional diversity of DC has more recently been explained by the integration of multiple factors within a particular anatomical location causing the differentiation of appropriately tuned ''effector'' DC [9,10]. Although key co-inhibitory receptors, such as ILT3/4, PIR-B, PD-L1 and ICOSL, and immunoregulatory molecules, such as IDO and histone deacetylase HDAC11, have been variously implicated in driving tolerance [11][12][13][14][15][16], it is still not clear to what degree such molecules are universal players.A concern using immature DC in vivo is that they might become activated, particularly within the context of inflammation. If DC are to be used therapeutically, then the tolerant phenotype must be robust and stable. Numerous agents have been used to manipulate Ã These authors contributed equally to this study.ÃÃ These authors contributed equally to this study as senior authors. 1728DC in vitro to generate maturation-resistant cells for adoptive cell therapy [2,9]; however, attempts to induce tolerance to allografts in conventional models have generally failed unless combined with other immunosuppressive...

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“…In transplantation models, the presence of cells capable of functional regulation was demonstrated by the ability of tolerant skin to confer donor-specific suppression when retransplanted into RAG Ϫ/Ϫ mice (25). Subsequently, higher levels of FoxP3 mRNA, a marker of regulatory T cells, were observed in tolerized skin or heart grafts than in rejecting graft or isograft controls (42,43). This was more recently confirmed by observations by Chen et al (44) of increased numbers of CD4 ϩ FoxP3 ϩ T cells in the tolerant compared with rejected heart grafts.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Control of Alloreactive B Cell Responses by the Suppression of T Cell Help

Yin

et al. 2008

The Journal of Immunology

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Alloantibodies can play a key role in acute and chronic allograft rejection. However, relatively little is known of factors that control B cell responses following allograft tolerance induction. Using 3-83 Igi mice expressing an alloreactive BCR, we recently reported that allograft tolerance was associated with the sustained deletion of the alloreactive B cells at the mature, but not the immature, stage. We have now investigated the basis for the long-term control of alloreactive B cell responses in a non-BCR-transgenic model of C57BL/6 cardiac transplantation into BALB/c recipients treated with anti-CD154 and transfusion of donor-specific spleen cells. We demonstrate that the long-term production of alloreactive Abs by alloreactive B cells is actively regulated in tolerant BALB/c mice through the dominant suppression of T cell help. Deletion of CD25+ cells resulted in a loss of tolerance and an acquisition of the ability to acutely reject allografts. In contrast, the restoration of alloantibody responses required both the deletion of CD25+ cells and the reconstitution of alloreactive B cells. Collectively, these data suggest that alloreactive B cell responses in this model of tolerance are controlled by dominant suppression of T cell help as well as the deletion of alloreactive B cells in the periphery.

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Induction offoxP3+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants

Cited by 390 publications

References 59 publications

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Tolerogenicity is not an absolute property of a dendritic cell

Long-Term Control of Alloreactive B Cell Responses by the Suppression of T Cell Help

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