Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
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PMID:Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. 1993 64

Foot-and-mouth disease virus (FMDV) causes an acute, highly contagious disease of livestock. Though FMDV is very sensitive to interferon-alpha (IFN-alpha), IFN-beta, and IFN-gamma, the virus has evolved mechanisms to evade such innate responses. For instance, during acute infection, FMDV suppresses IFN-alpha production by skin and myeloid dendritic cells (DCs). We have previously reported that FMDV infection induces a transient lymphopenia and interruption of T-lymphocyte responses to mitogenic stimuli. To further understand the immunopathogenesis of FMD, we have now analyzed the serum IFN-alpha response in relation to lymphopenia, and the number and function of plasmacytoid DCs (pDCs) following infection of pigs with multiple serotypes of FMDV. Serum IFN-alpha peaked 2-3 d post-infection (PI), regardless of FMDV serotype. Lymphopenia coincided with peak viremia and the serum IFN-alpha response. Circulating pDC numbers and in-vitro pDC IFN-alpha secretion transiently declined by 48 h following infection. Infection of lymphocytes or pDCs was never detected regardless of the FMDV serotype inoculated or the age of the animal infected. These data indicate that, like other DC subsets, there is suppression of interferon production by pDCs, which abrogates this important innate response. Rapid induction of serum IFN-alpha, albeit short-lived, may contribute to the rapid resolution of FMDV viremia prior to induction of specific immunity.
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PMID:Loss of plasmacytoid dendritic cell function coincides with lymphopenia and viremia during foot-and-mouth disease virus infection. 2056 98

IFN-gamma regulates multiple processes in the immune system. Although its antimicrobial effector functions are well described, less is known about the mechanisms by which IFN-gamma regulates CD8(+) T cell homeostasis. With the help of adoptive T cell transfers, we show in this study that IFN-gammaR signaling in CD8(+) T cells is dispensable for expansion, contraction, and memory differentiation in response to peptide vaccination. In contrast, host IFN-gammaR signaling counterregulates CD8(+) T cell responses and the generation of effector memory T cell processes, which are partially regulated by CD11b(+) cells. Similar to vaccination-induced proliferation, host IFN-gammaR signaling limits the expansion of naive CD8(+) T cells and their differentiation into effector memory-like T cells in lymphopenic mice. In contrast to peptide vaccination, IFN-gammaR signaling in CD8(+) T cells contributes to memory fate decision in response to lymphopenia, an effect that is fully reversed by high-affinity TCR ligands. In conclusion, we show that host IFN-gammaR signaling controls the magnitude of CD8(+) T cell responses and subsequent memory differentiation under lymphopenic and nonlymphopenic conditions. In contrast, IFN-gammaR signaling in CD8(+) T cells does not affect cell numbers under either condition, but it directs memory fate decision in response to weak TCR ligands.
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PMID:IFN-gamma receptor signaling regulates memory CD8+ T cell differentiation. 2016 22

Immune recovery in lymphopenic hosts depends largely on homeostatic peripheral expansion, especially when thymopoiesis is insufficient, as is often the case in human adults. Although it has been well studied in mice, the study of homeostatic peripheral expansion of human T cells has been limited by the lack of an appropriate in vivo model. In this study, we use T cell-deficient humanized mice and an adoptive transfer approach to demonstrate that two distinct proliferative responses of autologous T cells occur in vivo in a lymphopenic setting. Human naive CD4 and CD8 T cells that undergo rapid proliferation acquire a memory-like phenotype and the ability to rapidly produce IFN-gamma, whereas those undergoing slow proliferation retain naive phenotypic and functional characteristics. Recovery of both populations depends on the extent of human non-T cell chimerism in the periphery of recipient humanized mice. Furthermore, memory conversion of CD4 and CD8 T cells correlates with the level of human CD14+ and CD19+ chimerism in recipient mice, respectively, suggesting that different types of APCs support memory conversion of CD4 and CD8 T cells. Because lymphopenia affects clinical outcomes, this model, which will allow detailed investigation of the effects of lymphopenia in patients, is of clinical significance.
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PMID:Homeostatic expansion and phenotypic conversion of human T cells depend on peripheral interactions with APCs. 2048 39


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