Role of CD4+CD25+ regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.1

Oluwole, Olakunle O.; DePaz, H.A; Adeyeri, Ayotunde O.; Jin, Mei; Hardy, Mark A.; Oluwole, Soji F.

doi:10.1097/01.tp.0000062842.47597.13

Cited by 27 publications

(13 citation statements)

References 24 publications

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“…Consequently one should be able to identify them in naïve animals. Reports that naïve mice contain preexisting alloreactive natural CD4+CD25+ Tregs capable of ameliorating lethal graft-versus-host disease induced by mismatched bone marrow and splenic T cells [38][39][40], inhibiting rejection of skin grafts [31] and promoting tolerance to cardiac grafts [41] support this possibility. However, alloreactive natural Tregs have not been observed in all systems [33][34][35][36]42].…”

Section: Discovery Of Natural Cd4+cd25+ Tregs As Inhibitors Of Autoimmentioning

confidence: 90%

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Field

Kulhánková²,

Nasr³

2007

Immunol Res

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The natural CD4+CD25+ T regulatory (Treg) lymphocyte has emerged as a critical cell for controlling immune responses to self, foreign proteins, and pathogens. Identified initially by the constitutive expression of CD4 and CD25, natural Tregs suppress a variety of immune cells and responses, including CD4+CD25- proliferation and IL-2 production, and CD8 cell proliferation, IFNgamma production and CTL activity. Although natural Tregs require activation with specific antigen to attain their suppressive phenotype, once activated they execute inhibition in an antigen specific as well as non-specific (bystander) fashion. Treg suppression depends on IL-2, CD25, and cell:cell contact. The use of live cell imaging in vivo and in vitro to visualize the dynamic cell:cell interactions involving natural Tregs as well as the CD4+CD25+ Treg inhibitory hybridoma RD6 has refined the mechanistic models of contact dependent Treg suppression.

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Section: Discovery Of Natural Cd4+cd25+ Tregs As Inhibitors Of Autoimmentioning

confidence: 90%

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Field

Kulhánková²,

Nasr³

2007

Immunol Res

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“…These range from clonal deletion/anergy to active suppression, depending on the type of graft and rat/mouse strain combinations used (3,4). A limited number of studies, including a recent report by our laboratory, have implicated immunoregulatory cells as the key component of tolerance mechanisms in this model (5)(6)(7). The phenotype of these cells and their mechanisms of action, however, remain to be elucidated.…”

mentioning

confidence: 87%

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

et al. 2005

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“…The role of DCs in the ex vivo expansion of donor-specific T regs only recently has begun to be elucidated (11). Early studies have reported that the injection of donor MHC class I allopeptide-pulsed host DCs prolong the survival of rat islet allografts (32) and have implicated CD4 ϩ CD25 ϩ T regs in the salutary effect on graft survival (33). The system we describe here, in which we use DCs and TGF-␤1 to differentiate large numbers of antigen-specific CD4 ϩ CD25 ϩ Foxp3 ϩ T regs, also may provide a clinically applicable tool for cell therapy in transplant tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells with TGF-β1 differentiate naïve CD4⁺CD25⁻T cells into islet-protective Foxp3⁺regulatory T cells

Luo

Tarbell

Yang

et al. 2007

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

214

168

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CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells (T regs) are important for preventing autoimmune diabetes and are either thymic-derived (natural) or differentiated in the periphery outside the thymus (induced). Here we show that ␤-cell peptide-pulsed dendritic cells (DCs) from nonobese diabetic (NOD) mice can effectively induce CD4 ؉ CD25 ؉ Foxp3 ؉ T cells from naïve islet-specific CD4 ؉ CD25 ؊ T cells in the presence of TGF-␤1. These induced, antigen-specific T regs maintain high levels of clonotype-specific T cell receptor expression and exert islet-specific suppression in vitro. When cotransferred with diabetogenic cells into NOD scid recipients, T regs induced with DCs and TGF-␤1 prevent the development of diabetes. Furthermore, in overtly NOD mice, these cells are able to significantly protect syngeneic islet grafts from established destructive autoimmunity. These results indicate a role for DCs in the induction of antigen-specific CD4 ؉ CD25 ؉ Foxp3 ؉ T cells that can inhibit fully developed autoimmunity in a nonlymphopoenic host, providing an important potential strategy for immunotherapy in patients with autoimmune diabetes.antigen-presenting cells ͉ autoimmunity ͉ type 1 diabetes ͉ nonobese diabetic (NOD) mice T he nonobese diabetic (NOD) mouse models the pathogenesis of human type 1 diabetes and allows the study of potential therapeutics (1). In NOD mice, the thymic-derived CD4 ϩ CD25 ϩ regulatory T cells (T regs) expressing the transcription factor Foxp3 suppress autoimmunity and delay the development of diabetes (2). Considerable effort has focused on expanding the small numbers of these so-called ''natural'' CD4 ϩ CD25 ϩ T regs in the NOD and other models (3-6). Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that can effectively expand and sustain antigen-specific CD4 ϩ CD25 ϩ T regs (3, 4). However, in humans, only the infrequent cells with high CD25 expression have regulatory function (7). Alternatively, the more abundant CD4 ϩ CD25 Ϫ T cells can be differentiated into CD4 ϩ CD25 ϩ T regs that express Foxp3 by stimulation with mitogenic antibodies in the presence of TGF-␤1, although it is not known whether these induced cells are functionally identical to T regs that develop in the thymus (8). Such ''induced T regs'' with islet specificity can prevent diabetes in lymphopoenic models (9), but their ability to induce tolerance at late pathogenic stages of autoimmunity, such as in already-diabetic NOD mice, has not been fully addressed.A separate issue that remains to be addressed is the requirement for APCs in the induction of T regs with TGF-␤1. The use of DCs instead of mitogenic stimuli to differentiate T regs de novo from CD4 ϩ CD25 Ϫ T cells has numerous potential advantages, including selection and maintenance of antigen specificity (10, 11); provision of paracrine TGF-␤1 (12-14), which is known to play an important role in T reg homeostasis by its ability to induce Foxp3 (8, 15); and/or provision of costimulatory signals such as CD80/86 for CTLA-4 ligation, which is necessary f...

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Role of CD4+CD25+ regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.1

Abstract: This study suggests that CD4+CD25+ regulatory T cells specific for the induction of transplant tolerance are similar in origin, phenotype, and function to those involved in the maintenance of self-tolerance and the prevention of autoimmunity.

Cited by 27 publications

References 24 publications

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Dendritic cells with TGF-β1 differentiate naïve CD4⁺CD25⁻T cells into islet-protective Foxp3⁺regulatory T cells

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Role of CD4+CD25+ regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.1

Abstract: This study suggests that CD4+CD25+ regulatory T cells specific for the induction of transplant tolerance are similar in origin, phenotype, and function to those involved in the maintenance of self-tolerance and the prevention of autoimmunity.

Cited by 27 publications

References 24 publications

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Dendritic cells with TGF-β1 differentiate naïve CD4+CD25−T cells into islet-protective Foxp3+regulatory T cells

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Dendritic cells with TGF-β1 differentiate naïve CD4⁺CD25⁻T cells into islet-protective Foxp3⁺regulatory T cells