Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for Experimental Tuberculous Meningitis

Tsenova, Liana; Mangaliso, Bande; Muller, George W.; Chen, Yong; Freedman, Victoria H.; Stirling, David I.; Kaplan, Gilla

doi:10.1128/aac.46.7.2313.2002

Cited by 12 publications

(19 citation statements)

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“…demonstrated a correlation between levels of TNF‐α and the extent of cerebral pathology as measured by CSF leukocytosis, protein accumulation, meningeal inflammation, persistence of bacillary load, and clinical deterioration . TNF‐α antagonists such as thalidomide and analogues thereof, used in rabbit models of TBM, down‐regulated the production of TNF‐α and subsequently improved survival. This finding was not replicated in human studies where a clinical trial of thalidomide used in conjunction with standard antituberculous therapy and corticosteroids in children with TBM was stopped early due to adverse events associated with thalidomide use .…”

Section: Pathogenic and Pathophysiologic Mechanisms Within The Brain mentioning

confidence: 99%

The pathogenesis of tuberculous meningitis

Davis

Rohlwink

Proust

et al. 2019

Journal of Leukocyte Biology

139

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Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested. K E Y W O R D S mycobacterial, endothelial cells, granulocytes, microglia cells, monocytes/macrophages, myeloid cells, neutrophils, T Lymphocytes, Th17 cells at the site of infection activates macrophages and DCs to produce cytokines and antimicrobial factors that contribute to containment of the TB bacillus. 2 This inflammatory process results in the formation of a granuloma, which encapsulates the infected cells and retards the replication of TB bacilli and can lead to latent infection. However, in

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Section: Pathogenic and Pathophysiologic Mechanisms Within The Brain mentioning

confidence: 99%

The pathogenesis of tuberculous meningitis

Davis

Rohlwink

Proust

et al. 2019

Journal of Leukocyte Biology

139

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“…Conversely, the addition of thalidomide to anti‐TB drug therapy led to a reduction in TNF‐α levels, leukocytosis, brain pathology, and was associated with 100% survival of all rabbits. The thalidomide analogue, IMiD3, was also proven effective as adjunctive therapy using the same model (Tsenova et al. , 2002).…”

Section: Biologic Disease Modifying Agentsmentioning

confidence: 99%

Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view

Paige

Bishai²

2010

Cellular Microbiology

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SummaryGranuloma formation represents a pivotal point during human infection with Mycobacterium tuberculosis, for this structure may limit mycobacterial spread and prevent active disease, while at the same time allow for the survival and persistence of viable mycobacteria within the host. The current therapeutic regimens for treating tuberculosis disease have proven effective in developing countries. However, in countries with large populations, limited access to health care, and high incidence of HIV co-infection, tuberculosis disease continues to represent a major global health emergency. Particularly, the emergence of extensively and multidrug-resistant forms of tuberculosis underscores the need develop new treatment strategies. Recent mechanistic studies have identified bacterial virulence mechanisms that subvert host responses and lead to an inappropriate upregulation of host factors such as tumour necrosis factor-a (TNF-a) and matrix metalloproteinases (MMPs). Paradoxically, then, part of the mycobacterial virulence programme may be to promote granuloma development and maturation. These observations suggest that together with appropriate anti-microbials host-based therapeutics directed at TNF-a and MMP inhibition may counteract the microbial subterfuge, reduce the pro-granulomatous response, and offer an enhanced therapeutic effect. Hostdirected therapy that alters the immune response may offer an alternative approach towards reducing treatment duration, the risk of anti-microbial resistance and improving patient outcome.

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“…Additionally, it has been shown that in infected rabbits, inhibition of the TNF-a production by thalidomide treatment may block the development of meningitis. [3][4][5][6] In contrast to these beneficial immunomodulatory effects, we observed two cases of newly developed bacterial meningitis in patients who were treated with thalidomide; however the main pathogenetic mechanisms and the possible relation between thalidomide and the infections remain unclear. Similarly, in a recently published study, Facon et al 7 compared the results of melphalan and prednisone plus thalidomide with melphalan and prednisone alone in elderly patients with multiple myeloma, and two cases of bacterial meningitis were reported as an emergent complication in the patients who were treated with thalidomide.…”

Section: Discussionmentioning

confidence: 84%

“…TNF-a is a cytokine that has recently been determined to play a central role in the regulation of the host immune and inflammatory response to infection. 3,4 Besides its protective role, TNF-a production has been associated with the development of pathology in vivo, including tissue necrosis and cachexia.…”

Section: Discussionmentioning

confidence: 99%

“…The immunomodulatory effects of thalidomide are at least partially mediated through its ability to down-regulate the pathogenic over-production of tumor necrosis factor-alpha (TNF-a). 3 TNF-a is a cytokine that plays a central role in the regulation of the host immune and inflammatory response to infection. 4 Besides its protective role, TNF-a production has been associated with the development of pathology, including tissue necrosis.…”

Section: Introductionmentioning

confidence: 99%

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Two cases of bacterial meningitis accompanied by thalidomide therapy in patients with multiple myeloma: is thalidomide associated with bacterial meningitis?

Paşa

Altıntaş

Çil

et al. 2009

International Journal of Infectious Diseases

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Morbidity and mortality in multiple myeloma is often attributed to life-threatening infections. A defect in humoral immunity has been proposed for the predisposition to bacterial infections. Most of the infections are of bacterial origin, and the most serious are septicemia, meningitis, and pneumonia. Thalidomide is a drug with pleiotropic effects. The immunomodulatory effects of thalidomide are at least partially mediated through its ability to down-regulate the pathogenic over-production of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a cytokine that plays a central role in the regulation of the host immune and inflammatory response to infection. In the central nervous system, TNF-alpha is involved in induction of a fever response and triggers the release of other cytokines, and may also influence transport of compounds into the brain, leading to cerebrospinal fluid leukocytosis, increased protein influx, and lactate accumulation. Thalidomide has been shown to down-regulate the production of TNF-alpha. On the other hand, knowledge of the effects of thalidomide on granulocyte functions is limited. Thalidomide has been shown to attenuate neutrophil adhesion and chemotaxis. We present herein two cases of Streptococcus pneumoniae bacterial meningitis that developed soon after the initiation of thalidomide treatment, and discuss the effect of thalidomide on the immune system. Although, it is not clear whether thalidomide caused the development of the bacterial infections and meningitis, or what its pathogenetic mechanisms are, physicians should be alert for signs and symptoms of meningitis in patients with multiple myeloma who are treated with thalidomide, especially those in neutropenic states.

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Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for Experimental Tuberculous Meningitis

Cited by 12 publications

References 0 publications

The pathogenesis of tuberculous meningitis

The pathogenesis of tuberculous meningitis

Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view

Two cases of bacterial meningitis accompanied by thalidomide therapy in patients with multiple myeloma: is thalidomide associated with bacterial meningitis?

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