Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosis<i>in vitro</i>

Guckian, Mary; Dransfield, Ian; Hay, Phillip; Dalgleish, Angus

doi:10.1046/j.1365-2249.2000.01332.x

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…Thus, dampening innate immunity without interfering with the development of the acquired immune response was associated with changes in the metabolic activity of Mtb but not with loss of control of bacillary growth. Previous reports have demonstrated the usefulness of TNF-α inhibition by CC-3052 treatment, both in acute and chronic HIV-1 infection in vitro [122] , [123] . In addition, the safe administration of several PDE4i has been demonstrated in clinical trials for the treatment of other inflammatory diseases, including asthma and chronic obstructive pulmonary disease [124] – [126] .…”

Section: Discussionmentioning

confidence: 97%

Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Subbian¹,

Tsenova

O'Brien³

et al. 2011

PLoS Pathog

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Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment.

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Section: Discussionmentioning

confidence: 97%

Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Subbian¹,

Tsenova

O'Brien³

et al. 2011

PLoS Pathog

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“…cAMP is an important intracellular second messenger which, at increased levels, has anti-inflammatory and tissue protective effects. The specific PDE4i compound used in this study was CC-3052, which increases intracellular levels of cAMP, leading to down-regulation of TNF-α and other inflammatory cytokines in monocyte/macrophages [22] – [24] . CC-3052 is water soluble and has been shown to be non-toxic, non-mutagenic and non-teratogenic [23] .…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice

Koo¹,

Manca²,

Yang³

et al. 2011

PLoS ONE

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

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“…The SelCIDs™ (selective cytokine inhibitory drugs) consist of phosphodiesterase type 4 (PDE4) inhibitors [17]. The IMiDs™ (immunomodulatory drugs) are thought to be mechanistically similar to Thd, although with enhanced potency and therapeutic indices, and act via as yet © 2002 Blackwell Publishing Ltd, Clinical and Experimental Immunology , 130 :75-84 unknown mechanism(s) [18][19][20][21][22][23][24]. Both groups of compounds are potent inhibitors of monocyte/macrophage-derived TNF-α , although T cell co-stimulatory activity is limited to the IMiD group [17].…”

Section: Introductionmentioning

confidence: 99%

Thalidomide and its analogues have distinct and opposing effects on TNF-αand TNFR2 during co-stimulation of both CD4+ and CD8+ T cells

Marriott

Clarke

Dredge

et al. 2002

Clinical and Experimental Immunology

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148

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SUMMARYThalidomide (Thd) is clinically useful in a number of conditions where its efficacy is probably related to its anti-TNF -α activity. More recently, Thd has also been shown to co-stimulate T cells and second generation co-stimulatory (IMiD™) analogues are currently being assessed in the treatment of cancer patients. However, in contrast to their known suppressive effects during inflammatory stimuli, the effects of Thd/IMiDs on TNF-α and TNF receptors (TNFRs) during T cell co-stimulation are not known. We sought to determine the effect of Thd, two clinically relevant IMiDs (CC-4047, ACTIMID™ and CC-5013, REVIMID™) and a non-stimulatory SelCID analogue (CC-3052) on TNF-α production and on the expression and shedding of TNFRs during co-stimulation. We found that co-stimulation of PBMC with Thd/IMiDs, but not CC-3052, prevented α CD3-induced T cell surface expression of TNFR2 and thereby reduced soluble TNFR2 (sTNFR2) levels. However, there was no effect on total (surface/ intracellular) TNFR2 protein expression, suggesting inhibition of trafficking to the cell membrane. The extent of co-stimulation by Thd/IMiDs (assessed by CD69/CD25 expression and IL-2/sIL-2R α production) was similar for CD4 + and CD8 + T lymphocytes and correlated with TNFR2 inhibition. Costimulation, but not the early inhibitory effect on TNFR2, was IL-2-dependent and led to increased TNF-α production by both CD4 + and CD8 + T lymphocytes. The clinical relevance of this observation was confirmed by the elevation of serum TNF-α during REVIMID™ treatment of patients with advanced cancer. Together, these results suggest a possible role for TNF-mediated events during costimulation and contrast with the TNF inhibitory effects of Thd and its analogues during inflammatory stimuli.

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Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosisin vitro

Cited by 11 publications

References 53 publications

Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice

Thalidomide and its analogues have distinct and opposing effects on TNF-αand TNFR2 during co-stimulation of both CD4+ and CD8+ T cells

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