Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Am J Transplant ; 12(10): 2588-600, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22759274

ABSTRACT

Costimulatory molecules are a heterogenous group of cell surface molecules that act to amplify or counteract the initial activating signals provided to T cells from the T cell receptor following its interaction with an antigen/major histocompatibility complex, thereby influencing T cell differentiation and fate. Although costimulation was previously thought to be indispensable for T cell activation at all stages of development, it is now known that the requirements for costimulation, and the costimulatory molecules involved, vary according to the stage of T cell differentiation. The ability to influence T cell fate is of paramount interest in the field of transplantation as we seek therapeutic options that inhibit detrimental alloimmune responses whilst simultaneously promoting allograft tolerance. As with many immune mechanisms, there is a degree of functional overlap between certain costimulatory molecules, whereas some have diametrically opposite effects on different T cell subsets despite sharing common ligands. This is a critical point when considering these molecules as therapeutic targets in transplantation, as blockade of a costimulatory pathway, although desirable in itself, may prevent the ligation of an essential regulatory coinhibitory molecule. This review discusses the T helper cell lineages pertinent to transplantation and the costimulatory molecules involved in their differentiation.


Subject(s)
Cell Differentiation , T-Lymphocytes, Helper-Inducer/cytology , Cell Lineage , Humans , T-Lymphocytes, Helper-Inducer/immunology
2.
Am J Transplant ; 12(4): 856-66, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22390202

ABSTRACT

The addition of low, nondepleting doses of rabbit antithymocyte globulin (ATG) to human peripheral blood mononuclear cells has been shown to expand functional CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in vitro. This report is the first to elucidate the exact cellular mechanisms of ATG-mediated Treg expansion. CD4(+) T cells require monocytes, but not other antigen presenting cell subsets, to be present in coculture to expand Tregs. However, T cells do not require direct cell-cell contact with monocytes, suggesting the importance of soluble factors. Moreover, ATG initially "reprograms" CD4(+) T cells, but not monocytes, and induces STAT3 and STAT5 signaling in CD4(+) cells. These reprogrammed CD4(+) T cells subsequently secrete GM-CSF and IL-10 only in case of intact STAT3 signaling, which in turn promote the generation of tolerogenic CD14(+) CD11c(+) dendritic cells characterized by enhanced IL-10 and decreased IL-12 production. Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM-CSF and Bcl-2, but not TGF-ß, in peripheral blood mononuclear cells. These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram CD4(+) T cells in a STAT3-dependent but TGF-ß-independent manner, leading to the generation of monocyte-derived dendritic cells with a tolerogenic cytokine profile.


Subject(s)
Antilymphocyte Serum/pharmacology , CD4-Positive T-Lymphocytes/drug effects , Cell Proliferation/drug effects , Immunosuppressive Agents/pharmacology , Monocytes/drug effects , STAT3 Transcription Factor/metabolism , T-Lymphocytes, Regulatory/drug effects , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Flow Cytometry , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Monocytes/cytology , Monocytes/metabolism , RNA, Messenger/genetics , Rabbits , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effects , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
3.
Am J Transplant ; 10(10): 2355-62, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21143433

ABSTRACT

B7 ligands deliver both costimulatory and coinhibitory signals to the CD28 family of receptors on T lymphocytes, the balance between which determines the ultimate immune response. Although B7-H4, a recently discovered member of the B7 family, is known to negatively regulate T cell immunity in autoimmunity and cancer, its role in solid organ allograft rejection and tolerance has not been established. Targeting the B7-H4 molecule by a blocking antibody or use of B7-H4(-/-) mice as recipients of fully MHC-mismatched cardiac allografts did not affect graft survival. However, B7-H4 blockade resulted in accelerated allograft rejection in CD28-deficient recipients. B7-1/B7-2-double-deficient recipients are truly independent of CD28/CTLA-4:B7 signals and usually accept MHC-mismatched heart allografts. Blockade of B7-H4 in these mice also precipitated rejection, demonstrating regulatory function of this molecule independent of an intact CD28/CTLA-4:B7 costimulatory pathway. Accelerated allograft rejection was always accompanied by increased frequencies of alloreactive IFN-γ-, IL-4- and Granzyme B-producing splenocytes. Finally, intact recipient, but not donor, B7-H4 is essential for prolongation of allograft survival by blocking CD28/CTLA4:B7 pathway using CTLA4-Ig. These data are the first to provide evidence of the regulatory effects of B7-H4 in alloimmune responses in a murine model of solid organ transplantation.


Subject(s)
B7-1 Antigen/immunology , Graft Rejection/immunology , Heart Transplantation/immunology , Transplantation, Homologous/immunology , Abatacept , Animals , Antibodies, Blocking/immunology , Graft Survival/immunology , Immunoconjugates/pharmacology , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunology , V-Set Domain-Containing T-Cell Activation Inhibitor 1
SELECTION OF CITATIONS
SEARCH DETAIL
...