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1.
Front Immunol ; 9: 1381, 2018.
Article in English | MEDLINE | ID: mdl-29967616

ABSTRACT

During an immune response, naïve CD4+ T cells proliferate and generate a range of effector, memory, and regulatory T cell subsets, but how these processes are co-ordinated remains unclear. A traditional model suggests that memory cells use mitochondrial respiration and are survivors from a pool of previously proliferating and glycolytic, but short-lived effector cells. A more recent model proposes a binary commitment to either a memory or effector cell lineage during a first, asymmetric cell division, with each lineage able to undergo subsequent proliferation and differentiation. We used improved fixation and staining methods with imaging flow cytometry in an optimized in vitro system that indicates a third model. We found that cell fates result from stochastic decisions that depend on GITR co-stimulation and which take place before any cell division. Effector cell commitment is associated with mTORC2 signaling leading to uropodium development, while developing memory cells lose mitochondria, have a nuclear localization of NFκB and depend on TGFß for their survival. Induced, T helper subsets and foxp3+ regulatory T cells were found in both the effector and memory cell lineages. This in vitro model of T cell differentiation is well suited to testing how manipulation of cytokine, nutrient, and other components of the microenvironment might be exploited for therapeutic purposes.

2.
Front Immunol ; 7: 124, 2016.
Article in English | MEDLINE | ID: mdl-27148253

ABSTRACT

Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity, and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3(+) Treg. Here, we show that both in vitro and in vivo generated antigen-specific Foxp3(+) Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model.

3.
Immunology ; 140(4): 391-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23952610

ABSTRACT

The mammalian target of rapamycin (mTOR) pathway is an important integrator of nutrient-sensing signals in all mammalian cells, and acts to coordinate the cell proliferation with the availability of nutrients such as glucose, amino acids and energy (oxygen and ATP). A large part of the immune response depends on the proliferation and clonal expansion of antigen-specific T cells, which depends on mTOR activation, and the pharmacological inhibition of this pathway by rapamycin is therefore potently immunosuppressive. It is only recently, however, that we have started to understand the more subtle details of how the mTOR pathway is involved in controlling the differentiation of effector versus memory CD8(+) T cells and the decision to generate different CD4(+) helper T-cell subsets. In particular, this review will focus on how nutrient sensing via mTOR controls the expression of the master transcription factor for regulatory T cells in order to maintain the balance between tolerance and inflammation.


Subject(s)
CD8-Positive T-Lymphocytes/enzymology , Signal Transduction , T-Lymphocytes, Helper-Inducer/enzymology , T-Lymphocytes, Regulatory/enzymology , TOR Serine-Threonine Kinases/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Cell Hypoxia , Energy Metabolism , Humans , Immune Tolerance , Immunologic Memory , Inflammation/enzymology , Inflammation/immunology , Lymphocyte Activation , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology
4.
Article in English | MEDLINE | ID: mdl-23732858

ABSTRACT

Transplantation tolerance is a continuing therapeutic goal, and it is now clear that a subpopulation of T cells with regulatory activity (Treg) that express the transcription factor foxp3 are crucial to this aspiration. Although reprogramming of the immune system to donor-specific transplantation tolerance can be readily achieved in adult mouse models, it has yet to be successfully translated in human clinical practice. This requires that we understand the fundamental mechanisms by which donor antigen-specific Treg are induced and function to maintain tolerance, so that we can target therapies to enhance rather than impede these regulatory processes. Our current understanding is that Treg act via numerous molecular mechanisms, and critical underlying components such as mTOR inhibition, are only now emerging.


Subject(s)
T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance/immunology , Animals , Autoimmunity , Biomarkers , Epigenomics , Forkhead Transcription Factors/physiology , Graft Rejection/immunology , Graft vs Host Disease/prevention & control , Humans , Immune Tolerance/physiology , Immunity, Heterologous/physiology , Transcription Factors/metabolism
6.
J Immunol ; 189(8): 3947-56, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22988034

ABSTRACT

CD4(+)Foxp3(+) regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-ß-dependent manner. Foxp3(+) Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGF-ß signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-ß and Foxp3 to the transcriptome of TGF-ß-induced Treg and showed that TGF-ß elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4(+) T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF-ß and Foxp3 in induced tolerance, in which TGF-ß stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance.


Subject(s)
Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/genetics , T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance , Animals , Cell Line, Tumor , Forkhead Transcription Factors/deficiency , Graft Survival/genetics , Graft Survival/immunology , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Knockout , Mice, Transgenic , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/physiology , Transplantation Tolerance/genetics
7.
J Exp Med ; 208(10): 2043-53, 2011 Sep 26.
Article in English | MEDLINE | ID: mdl-21875958

ABSTRACT

A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4(+)Foxp3(+) cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3(hCD2) mice to isolate and ablate Foxp3(+) T reg cells with an anti-hCD2 antibody, we show for the first time that CD4(+)Foxp3(+) cells are crucial for infectious tolerance induced by nonablative anti-T cell antibodies. In tolerant animals, Foxp3(+) T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3(+) T reg cells. Finally, Foxp3(+) cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3(+) cells sustain tolerance by converting naive T cells into the next generation of Foxp3(+) cells. Empowering Foxp3(+) regulatory T cells in vivo offers a tractable route to avoid and correct tissue immunopathology.


Subject(s)
Forkhead Transcription Factors/immunology , T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance/immunology , Adoptive Transfer , Animals , Antibodies/immunology , Female , Forkhead Transcription Factors/genetics , Homeodomain Proteins/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Knockout , Self Tolerance/immunology , Skin Transplantation/immunology
8.
Curr Opin Immunol ; 23(5): 660-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21839624

ABSTRACT

TGF-ß is a cytokine required for the induction and maintenance of transplantation tolerance in animal models. TGF-ß mediates anti-inflammatory effects by acting on many immune cell-types. Central for transplantation tolerance is the role for TGF-ß in the induction of Foxp3 and regulatory capacity in CD4(+) T cells. Recently, however, the general anti-inflammatory role of TGF-ß in CD4(+) T cell polarization was questioned by the discovery that, in the presence of inflammatory cytokines such as IL-6 or IL-1, TGF-ß drives the differentiation of Th17 cells associated with transplant rejection. A better understanding of the factors determining TGF-ß production and activation, Foxp3 induction and Treg stability is vital for the development of tolerogenic strategies in transplantation.


Subject(s)
Adaptive Immunity , Forkhead Transcription Factors/immunology , Graft Rejection/prevention & control , Organ Transplantation , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Transforming Growth Factor beta , Transplantation Tolerance , Animals , Antigens, CD/immunology , Cell Differentiation/drug effects , Cell Differentiation/immunology , Forkhead Transcription Factors/genetics , Graft Rejection/immunology , Humans , Interleukin-1/immunology , Interleukin-6/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mice , Mice, Knockout , T-Lymphocytes, Regulatory/cytology , Th17 Cells/cytology , Transforming Growth Factor beta/deficiency , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/pharmacology
9.
Eur J Immunol ; 41(10): 2955-65, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21770045

ABSTRACT

Levels of anti-inflammatory extracellular adenosine are controlled by the sequential action of the ectonucleotidases CD39 and CD73, whose expression in CD4(+) T cells has been associated with natural regulatory T cells (nTregs). We here show that CD73 expression on activated murine CD4(+) T cells is induced by TGF-ß independently of Foxp3 expression, operates at the transcriptional level and translates into gain of functional capacity to generate adenosine. In the presence of AMP, CD73 induced by TGF-ß generates adenosine able to suppress proliferation of activated CD4(+) T cells in vitro. These effects are contextual and opposed by proinflammatory cytokines. CD73 is also upregulated by TGF-ß in CD8(+) T cells, DCs and macrophages, so providing an amplification mechanism for adenosine generation in tissue microenvironments. Together, these findings expose a novel anti-inflammatory role for TGF-ß.


Subject(s)
5'-Nucleotidase/metabolism , Adenosine/metabolism , CD4-Positive T-Lymphocytes/metabolism , Inflammation Mediators , Leukocytes/metabolism , Lymphocyte Activation , Transforming Growth Factor beta/metabolism , 5'-Nucleotidase/biosynthesis , Adenosine Monophosphate/metabolism , Animals , Antigens, CD/biosynthesis , Antigens, CD/metabolism , Antigens, Surface , Apyrase/biosynthesis , Apyrase/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/chemistry , Cell Proliferation , Cytokines/immunology , Cytokines/metabolism , Dendritic Cells/chemistry , Forkhead Transcription Factors/biosynthesis , Macrophages/chemistry , Mice , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/immunology
10.
Front Immunol ; 2: 9, 2011.
Article in English | MEDLINE | ID: mdl-22566800

ABSTRACT

A major limitation to the translation of tolerogenic therapies to clinical transplantation is a lack of biomarkers that can be used as surrogate measures for predicting the successful induction of immune tolerance which would allow for the safe withdrawal of immunosuppression. We have used three different mouse models of donor specific tolerance to skin grafts together with quantitative RT-PCR to search for potential biomarkers of tolerance using criteria based on the presence or activity of regulatory T cells and antigen presenting cells (APCs) within grafts or lymphoid organs. We find that significant differences in gene expression between tolerated and rejecting grafts are observed primarily within the grafted skin and not systemically or in the draining lymph node. The pattern of gene expression within long-term surviving tolerated grafts appear very similar to syngeneic grafts, with both having low levels of T cell and APC infiltration and a bias toward relative over-expression of "regulatory-associated" genes, while allografts destined for rejection show an overall increase in both "regulatory" and "effector" cell associated transcripts. We also, however, find an increase in a large number of regulatory genes, of both innate and T cell origin, even after grafting syngeneic skin. Taken together, these findings suggest that there may be no tissue biomarkers uniquely able to predict donor antigen specific tolerance per se, but that patterns of gene expression within tolerated grafts may be similar to those found in self tissues recovering from an inflammatory insult.

12.
Curr Opin Immunol ; 22(5): 655-61, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20833524

ABSTRACT

T cells constantly monitor energy status and nutrient levels in order to adjust metabolic pathways according to their nutritional status and other environmental stimuli. It is increasingly evident that the regulation of cellular metabolism is tightly coupled to T cell differentiation that ultimately determines the cellular fate. The mammalian target of Rapamycin (mTOR) pathway has emerged as a key player in sensing these nutritional/energetic signals and in addition, acts as a major integrator of growth factor induced signals, so placing mTOR at the core of a signalling network controlling metabolism and cellular fate. The mTOR pathway has been shown to play an important role in determining the differentiation of CD4(+) T cells into inflammatory and regulatory subsets, in the induction of anergy, in the development of CD8(+) memory T cells and the regulation of T cell trafficking.


Subject(s)
Cell Differentiation/immunology , Signal Transduction/immunology , T-Lymphocytes/cytology , TOR Serine-Threonine Kinases/metabolism , Animals , Chemotaxis, Leukocyte/immunology , Humans , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/immunology
13.
Stem Cells ; 28(10): 1905-14, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20737577

ABSTRACT

We have previously reported that ESC-derived tissues are subject to some level of immune privilege, which might facilitate induction of immune tolerance. Herein, we further demonstrate that fully allogeneic ESC-derived tissues are accepted with a regimen of coreceptor blockade even in recipients known to be relatively resistant to such a tolerizing protocol. Moreover, ESC-derived tissues could be spontaneously accepted across a class I major histocompatibility complex disparity. We further show that CD4(+)FoxP3(+) regulatory T cells (Treg) appear to be essential for this natural "privileged" state as their ablation with an anti-CD25 mAb results in rejection of ESC-derived tissue. This same treatment exposes activation of macrophages and effector CD8(+) T cells, suggesting that these cells are subject to regulatory T cell control. Thus, spontaneous acceptance of ESC-derived tissues mimics the acquired immune privilege induced by coreceptor blockade and is determined by Treg-mediated suppression.


Subject(s)
Embryonic Stem Cells/cytology , Major Histocompatibility Complex/immunology , T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line , Female , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Polymerase Chain Reaction , T-Lymphocytes, Regulatory/metabolism , Transplantation, Homologous/immunology
14.
Immunol Rev ; 236: 203-18, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20636819

ABSTRACT

A variety of different molecular mechanisms have been proposed to explain the suppressive action of regulatory T cells, including the production of anti-inflammatory cytokines, negative costimulatory ligands, indoleamine 2,3-dioxygenase-mediated tryptophan catabolism, CD73-mediated adenosine generation, and downregulation of antigen-presenting cells. Until now it has been unclear how important each of these different mechanisms might be and how they are coordinated. In this review, we examine the hypothesis that it is the interaction between regulatory T cells and dendritic cells that creates a local microenvironment depleted of essential amino acids and rich in adenosine that leads to the amplification of a range of different tolerogenic signals. These signals are all eventually integrated by mammalian target of rapamycin inhibition, which enables the induction of new forkhead box protein 3-expressing Tregs. If correct, this provides a molecular explanation for the in vivo phenomena of linked suppression and infectious tolerance.


Subject(s)
Cell Communication/immunology , Dendritic Cells/immunology , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Forkhead Transcription Factors/metabolism , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Models, Immunological , T-Lymphocytes, Regulatory/metabolism
15.
Eur J Immunol ; 40(6): 1728-37, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20373289

ABSTRACT

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-beta and 1alpha,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(+) 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.


Subject(s)
Dendritic Cells/immunology , Immune Tolerance/immunology , Animals , Antigen Presentation/immunology , Cell Separation , Female , Flow Cytometry , Lymphocyte Activation/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology
17.
J Immunol ; 183(7): 4197-204, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19752228

ABSTRACT

In the aftermath of thymic negative selection, natural and adaptive regulatory T cells (Tregs) must acknowledge peripheral, "danger-free" self-Ag to ensure their sustained activity. In this paper, we show that natural and adaptive Tregs or T cells transduced with cDNA for Foxp3, just like Th1 cells, express members of the MS4A family of transmembrane molecules. Naive T cells transduced with MS4A4B become able to respond to lower levels of Ag. Using two family members, MS4A4B and MS4A6B, as baits in a yeast split-ubiquitin Treg library screen, we demonstrate their interaction with each other and with GITR, Orai1, and other surface receptors. Interaction of 4B with GITR augments GITR signaling and T cell IL-2 production in response to triggering with GITR ligand or anti-GITR Abs. This interaction provides a mechanism whereby MS4A family members, through lateral coassociation with costimulatory molecules, may amplify Ag signals. We propose that T cells preoccupied with immune defense use this MS4A family to enhance sensitivity to extrinsic Ag stimulation, ensuring its elimination, while Tregs use these adaptors to allow low level Ag signals to sustain regulatory function.


Subject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , Adaptor Proteins, Signal Transducing/genetics , Lymphocyte Activation/immunology , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Adaptor Proteins, Signal Transducing/physiology , Amino Acid Sequence , Animals , CHO Cells , Cell Line , Cricetinae , Cricetulus , Gene Expression Profiling , Glucocorticoid-Induced TNFR-Related Protein , Humans , Lymphocyte Activation/genetics , Membrane Proteins/physiology , Mice , Mice, Inbred CBA , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Receptors, Nerve Growth Factor/physiology , Receptors, Tumor Necrosis Factor/physiology , Up-Regulation/genetics , Up-Regulation/immunology
18.
Proc Natl Acad Sci U S A ; 106(29): 12055-60, 2009 Jul 21.
Article in English | MEDLINE | ID: mdl-19567830

ABSTRACT

Infectious tolerance describes the process of CD4(+) regulatory T cells (Tregs) converting naïve T cells to become additional Tregs. We show that antigen-specific Tregs induce, within skin grafts and dendritic cells, the expression of enzymes that consume at least 5 different essential amino acids (EAAs). T cells fail to proliferate in response to antigen when any 1, or more, of these EAAs are limiting, which is associated with a reduced mammalian target of rapamycin (mTOR) signaling. Inhibition of the mTOR pathway by limiting EAAs, or by specific inhibitors, induces the Treg-specific transcription factor forkhead box P3, which depends on both T cell receptor activation and synergy with TGF-beta.


Subject(s)
Amino Acids, Essential/metabolism , Immune Tolerance/immunology , Protein Kinases/metabolism , Signal Transduction/immunology , Adoptive Transfer , Amino Acids, Essential/deficiency , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Epitopes/immunology , Forkhead Transcription Factors/metabolism , Immune Tolerance/drug effects , Lymphocyte Activation/drug effects , Mice , Phosphoinositide-3 Kinase Inhibitors , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , Skin Transplantation/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/enzymology , T-Lymphocytes, Regulatory/immunology , TOR Serine-Threonine Kinases , Transforming Growth Factor beta/metabolism
19.
J Exp Med ; 206(7): 1535-47, 2009 Jul 06.
Article in English | MEDLINE | ID: mdl-19528258

ABSTRACT

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other ("linked") epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10(+) T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti-IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.


Subject(s)
Asthma , Epitopes/immunology , Immune Tolerance/immunology , Interleukin-10/immunology , Peptides , Allergens/immunology , Animals , Asthma/immunology , Asthma/therapy , Bronchial Hyperreactivity/immunology , Cats , Desensitization, Immunologic , Disease Models, Animal , Double-Blind Method , Forkhead Transcription Factors/immunology , Genes, MHC Class II , Glycoproteins/genetics , Glycoproteins/immunology , HLA-DR1 Antigen/immunology , Humans , Lung/cytology , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptides/immunology , Peptides/therapeutic use , Placebos , Randomized Controlled Trials as Topic , Receptors, Interleukin-10/immunology , Th2 Cells/immunology , Transforming Growth Factor beta/immunology
20.
Immunotherapy ; 1(3): 447-60, 2009 May.
Article in English | MEDLINE | ID: mdl-20635961

ABSTRACT

Rodent models of transplantation and autoimmune disease have demonstrated that it is possible to induce lifelong and specific immunological tolerance to both self and graft antigens in the absence of any continued immunosuppression. If this situation could be achieved clinically, it would avoid many of the longer-term complications of immunosuppression, such as the increased risk of infection, cancer and other side effects, such as nephrotoxicity. In this review, we shall consider the interplay between regulatory T cells, dendritic cells and the tissue itself, and the resulting local protective mechanisms that are coordinated to maintain the tolerant state and an acquired local immune privilege. The current status of attempts to apply tolerogenic approaches to the clinical treatment of autoimmune diseases and to induce either tolerance to organ grafts or sufficient immune regulation so that conventional immunosuppression can be minimized will also be considered.


Subject(s)
Autoimmune Diseases/immunology , Dendritic Cells/immunology , Immunosuppression Therapy , Organ Transplantation , T-Lymphocytes, Regulatory/immunology , Animals , Cell Communication , Disease Models, Animal , Humans , Immune Tolerance/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Organ Transplantation/trends
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