Suppression Mediated by Anergic Cd4+ T Cells Requires Stimulation by MHC-Peptide Complexes and Can Be Induced in the Presence of Costimulation1

Witzke, Oliver; Wheeler, Paul R.; Barbara, Jeffrey A J; Gaspar, Manuela Carvalho; Morris, Peter J.; Wood, Kathryn J.

doi:10.1097/00007890-200108150-00004

Cited by 4 publications

(3 citation statements)

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“…In addition, the relationship of this activity to the generation of regulatory CD4 ϩ T cells or to the putative expansion and subsequent anergy of alloreactive CD4 ϩ T cells also remains to be determined. Of interest is the suggestion that anergic cells may mediate suppressive activity, but again the mechanisms by which this suppression are mediated are not known and may be complex (45).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Skin and Islet Allograft Survival in Mice Treated With Costimulation Blockade is Mediated by Different CD4+ Cell Subsets and Different Mechanisms

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Regulation of Skin and Islet Allograft Survival in Mice Treated With Costimulation Blockade is Mediated by Different CD4+ Cell Subsets and Different Mechanisms

et al. 2004

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“…Future studies are needed to elucidate whether the same patterns of the reparative processes observed in the mouse model could be triggered in the human endocrine pancreas, and how long after disease onset the reparative process can be induced. Once these parameters are defined, BMT and other approaches to impede autoimmunity already described [37][38][39][40][41], or yet to be found, may become new therapies for T1D.…”

Section: Figure 6 Dynamics Of Clinical and Pathological Features In mentioning

confidence: 99%

Recovery of the Endogenous β Cell Function in the NOD Model of Autoimmune Diabetes

et al. 2003

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In light of accumulating evidence that the endocrine pancreas has regenerative properties and that hematopoietic chimerism can abrogate destruction of β β cells in autoimmune diabetes, we addressed the question of whether recovery of physiologically adequate endogenous insulin regulation could be achieved in the nonobese diabetic (NOD) mice rendered allogeneic chimerae. Allogeneic bone marrow (BM) was transplanted into NOD mice at the preclinical and overtly clinical stages of the disease using lethal and nonlethal doses of radiation for recipient conditioning. Islets of Langerhans, syngeneic to the BM donors, were transplanted under kidney capsules of the overtly diabetic animals to sustain euglycemia for the time span required for recovery of the endogenous pancreas. Nephrectomies of the graft-bearing organs were performed 14 weeks later to confirm the restoration of endogenous insulin regulation. Reparative processes in the pancreata were assessed histologically and immunohistochemically. The level of chimerism in NOD recipients was evaluated by flow cytometric analysis. We have shown that as low as 1% of initial allogeneic chimerism can reverse the diabetogenic processes in islets of Langerhans in prediabetic NOD mice, and that restoration of endogenous β β cell function to physiologically sufficient levels is achievable even if the allogeneic BM transplantation is performed after the clinical onset of diabetes. If the same pattern of islet regeneration were shown in humans, induction of an autoimmunity-free status by establishment of a low level of chimerism, or other alternative means, might become a new therapy for type 1 diabetes.

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“…Our understanding of how this inhibition is achieved is complicated by there being a number of apparently separate mechanisms used, including ignorance, deletion, anergy, and regulation (previously called suppression) [13]. Recent investigation and comparison of anergy and induced regulatory cell formation is difficult to combine or summarize, as the systems and reagents used have varied considerably, but the one constant feature is the need for MHC/peptide contact [14][15][16][17][18][19][20]. Regulatory cells may be produced in the thymus and in the periphery, and can arise from conversion of non-inhibitory T cells [21][22][23].…”

Section: Inhibitory Mechanisms In T Cell Controlmentioning

confidence: 99%

The MHC-Based Suppression (MBS) Theory: Implications for Transplantation

Gray¹

2008

TOTRANSJ

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Abstract:Complex areas of scientific endeavor may sometimes benefit from a theoretical and/or reductionist approach to guide the direction of future experiments, perhaps best illustrated by the field of cosmology. The field of immunology in general, and transplantation immunology in particular, is certainly complex. This commentary draws attention to a theory that proposes an alternative role for MHC molecules, placing them central to the process of tolerance induction, with major implications for transplantation and all fields of immunology.Key Words: Immune tolerance, MHC-based suppression, peptide/MHC complex, peripheral tolerance, regulatory T cells, xenotransplantation. WHAT IS KNOWN ABOUT MHC MOLECULES?Originally named as human leukocyte antigens (HLA), later the term major histocompatibility (MHC) antigens came into common use. In this article, the term HLA will be used to indicate the human system, whilst the term MHC will be used only to indicate a deliberate widening to include other mammalian species, all of which have a superficially similar immune system. Many of the immunological mechanisms and concepts mentioned are arguably established facts and will not be referenced, unless the point being made is of particular importance for the concepts presented here. The term "cognate ligand " is used to mean the combination of MHC and bound peptide which binds fully to a particular T cell receptor. HLA -THE HUMAN MHCHLA molecules have been under intensive investigation for more than 25 years and a number of remarkable features have been discovered. Firstly, there are several molecular families -HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, HLA-DR, HLA-E, HLA-F, HLA-G, HLA-H -that are structurally related (Ig superfamily) membrane-bound molecules with 4 immunoglobulin-like domains, an anchoring transmembrane portion, and a groove on the exterior portion of the molecule which normally has a peptide bound to it. (Further discussion will be limited to the "classical" HLA genes and their products, whereas HLA-E, HLA-F, HLA-G, HLA-H, will not be discussed further here). HLA-A, HLA-B and HLA-C form a more closely-related sub-group, called HLA Class 1, that use a constant molecule, 2 microglobulin, as one of the four domains. HLA-DP, HLA-DQ, HLA-DR form a second structurally-related subgroup, known as MHC Class *Address correspondence to this author at the Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; Tel: 44(0)1865220145; Fax: 44(0)1865768876; E-mail: derek.gray@nds.ox.ac.uk II, that use two different double-Ig-like molecules to produce the 4-domain structure.Secondly, both MHC Class I and MHC Class II molecules exhibit genetically-coded (and therefore heritable) polymorphism that is so extensive that completely identical matching by non-related persons is rarely possible. Despite the polymorphism, all Type 1 and Type II MHC molecules are able to bind peptides derived from a wide range of proteins, holding them in the groove on the surface of the molecule, where they may be prese...

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Suppression Mediated by Anergic Cd4+ T Cells Requires Stimulation by MHC-Peptide Complexes and Can Be Induced in the Presence of Costimulation1

Cited by 4 publications

References 46 publications

Regulation of Skin and Islet Allograft Survival in Mice Treated With Costimulation Blockade is Mediated by Different CD4+ Cell Subsets and Different Mechanisms

Regulation of Skin and Islet Allograft Survival in Mice Treated With Costimulation Blockade is Mediated by Different CD4+ Cell Subsets and Different Mechanisms

Recovery of the Endogenous β Cell Function in the NOD Model of Autoimmune Diabetes

The MHC-Based Suppression (MBS) Theory: Implications for Transplantation

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