Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4+ regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2Ek, to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-β. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-β. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-γ and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)+ CD25+ T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-β-dependent mechanism, and come to accumulate in tolerated grafts.

Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.

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Objective: To investigate the contribution of T lymphocytes and monocytes to cytokine production in systemic lupus erythematosus (SLE).Methods: Forty-five SLE patients and 19 healthy volunteers were included. Serum levels of tumor necrosis factor alpha (TNFa), interferon gamma (IFNc), interleukin (IL)-6, and IL10 were quantified by ELISA. The cytokine production capacities of peripheral blood mononuclear cells were assessed by culturing in vitro with PMA1Ionomycin or LPS. The intracellular cytokine expression was measured by flow cytometry in T lymphocytes and monocytes, respectively. The influence of the disease activity (measured as the SLE-disease activity index; SLEDAI) and the treatment the patients were receiving was evaluated.Results: Serum IL10, IL6, and TNFa levels were increased in patients (P ≤ 0.01), and a higher spontaneous (without stimuli) intracellular expression of IL10 in CD41 and CD81 T lymphocytes (P < 0.05) and of IL6 in monocytes (P 5 0.01) were found. After stimulation, patients presented a higher percentage of CD41 and CD81 T lymphocytes producing IL4 and IL10 (P ≤ 0.01), and of monocytes producing IL6 (P 5 0.04) and IL10 (P 5 0.008). The SLEDAI score was positively correlated with the percentage of CD41IL101 and CD81IL101 T lymphocytes (P < 0.01), and inversely correlated with CD81TNFa1 (P 5 0.02), CD41IFNg1 (P 5 0.04) and CD81 IFNg1 (P 5 0.002) T lymphocytes. Patients receiving high dose prednisone produced higher IL10, but they also were the patients with a more active disease.Conclusion: Monocytes and T lymphocytes (CD41 and CD81) contribute to an overproduction of IL6 and IL10 in SLE; this correlates with the disease activity but is independent of the treatment the patients are receiving. q 2009 Clinical Cytometry Society

Patients with a reduced percentage of EPCs showed pathological arterial stiffness and association with certain CV risk factors, suggesting that the measurement of circulating EPCs can be used as a biological marker to determine subclinical atherosclerosis in SLE.

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MetS may contribute to the development of atherosclerosis by significantly increasing inflammation levels and arterial stiffness and decreasing circulating EPCs. This finding would justify close monitoring of these patients.

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