Chlorpromazine induces apoptosis in activated human lymphoblasts: A mechanism supporting the induction of drug‐induced lupus erythematosus?

Hieronymus, Thomas; Grötsch, Philipp; Blank, Norbert; Grünke, Mathias; Capraru, Dorin; Geiler, Thomas; Winkler, Silke; Kalden, Joachim R.

doi:10.1002/1529-0131(200009)43:9<1994::aid-anr10>3.0.co;2-7

Cited by 40 publications

(14 citation statements)

References 32 publications

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“…It is intriguing to speculate that the different lymphoblast responses to the anti‐apoptotic γc‐chain cytokines might contribute to the induction and/or perpetuation of autoimmunity. An increased rate of apoptosis could lead to an overflow of the phagocytic system with apoptotic cell bodies and contribute to the induction of autoimmunity 3, 7, 27, 28. This concept is strongly supported by the findings of van Deventer and coworkers 29, 30 who recently published observations of a strong induction of apoptosis in activated lamina propria lymphocytes after the treatment of Crohn's patients with infliximab.…”

Section: Discussionmentioning

confidence: 89%

Hyporesponsiveness to γc‐chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis

et al. 2002

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Pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) is unresolved. Dysregulation of programmed cell death is discussed as a pathogenetic factor. We have previously shown that increased in vitro apoptosis of cultured peripheral blood mononuclear cells (PBMC) is nonspecific for SLE. Importantly, however, in recent experiments with SLE PBMC from patients with infections and fever in vitro apoptosis was strongly accelerated. We therefore hypothesized that regulation of apoptosis might be disturbed in activated SLE lymphocytes. Thus, we generated phytohemagglutinine (PHA)/IL‐2 stimulated lymphoblasts in vitro. These lymphoblasts readily undergo apoptosis after culture in cytokine‐free medium, and can be rescued by addition of γc‐chain cytokines IL‐2, ‐4, ‐7, or ‐15. In lymphoblasts from 60 SLE patients tested in comparison to lymphoblasts from normal donors cultured in parallel, we found significant hyporesponsiveness to γc‐chain cytokines in SLE cells. Minor differences were also seen in lymphoblasts from patients with other systemic autoimmunopathies (mixed connective tissue disease, vasculitis, n=49)and in lymphoblasts from patients with other autoimmune diseases (mainly rheumatoid or reactive arthritis, myositis, n=44). In patients with high erythrocyte sedimentation rate (>25 mm/h), TNF‐α (>6.5 pg/ml) or IL‐12 (>4.7 pg/ml) serum levels or detectable IFN‐γ concentrations hyporesponsiveness to γc‐chain cytokines was even more pronounced in SLE lymphoblasts, but not in lymphoblasts from the other groups. Moreover, increased apoptosis was seen in lymphoblasts from SLE patients with decreased complement (C)4 or elevated dsDNA antibody levels. In conclusion, these data suggest that in SLE patients with increased inflammatory activity and/or Th1 dominance signaling through γc‐chain cytokine receptors is deteriorated, leading to facilitated apoptosis of activated lymphocytes and enlarged onflow of apoptotic material.

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Section: Discussionmentioning

confidence: 89%

Hyporesponsiveness to γc‐chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis

et al. 2002

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“…In addition, CPZ has been shown to affect the activities of a variety of T lymphocytes in vitro (17,19,21), although these inhibitory effects require concentrations of CPZ which are beyond those clinically relevant (i.e., in excess of 1 mg/liter) or fairly close to the highest concentration of CPZ in plasma that might result from its aggressive use (Ն0.5 mg/liter). Our previous study (32) and the present study show that an in vitro concentration of 0.1 mg of either CPZ or TZ per liter, which is equivalent to that anticipated to be present in the plasma of a patient treated with either phenothiazine, has no significant toxicity against macrophages or alpha-beta TCR ϩ , gamma-delta TCR ϩ , or CD14 ϩ macrophages.…”

Section: Discussionmentioning

confidence: 99%

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

Ordway

Viveiros

Leandro

et al. 2003

Antimicrob Agents Chemother

191

168

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The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro activities against antibiotic-sensitive and -resistant Mycobacterium tuberculosis. These compounds have not been used as anti-M. tuberculosis agents because their in vitro activities take place at concentrations which are beyond those that are clinically achievable. In addition, chronic administration of CPZ produces frequent severe side effects. Because CPZ has been shown to enhance the killing of intracellular M. tuberculosis at concentrations in the medium that are clinically relevant, we have investigated whether TZ, a phenothiazine whose negative side effects are less frequent and serious than those associated with CPZ, kills M. tuberculosis organisms that have been phagocytosed by human macrophages, which have nominal killing activities against these bacteria. Both CPZ and TZ killed intracellular antibiotic-sensitive and -resistant M. tuberculosis organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant M. tuberculosis isolates. Nevertheless, we must await the outcomes of clinical trials to determine whether TZ itself may be safely and effectively used as an antituberculosis agent.

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“…It has been found that chlorpromazine induces apoptosis in human lymphoblasts by stimulating proapoptotic signaling pathways [69]. This is in contrast to the mechanism proposed for TNFa induced autoimmunity, in which case a defect in apoptosis leads to the failure to eliminate autoreactive B and T cells, leading to a breakdown of central or peripheral tolerance.…”

Section: Other Agents and Autoimmunitymentioning

confidence: 92%

Drugs and autoimmunity – A contemporary review and mechanistic approach

Chang

Gershwin

2010

Journal of Autoimmunity

148

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Chlorpromazine induces apoptosis in activated human lymphoblasts: A mechanism supporting the induction of drug‐induced lupus erythematosus?

Cited by 40 publications

References 32 publications

Hyporesponsiveness to γc‐chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis

Hyporesponsiveness to γc‐chain cytokines in activated lymphocytes from patients with systemic lupus erythematosus leads to accelerated apoptosis

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

Drugs and autoimmunity – A contemporary review and mechanistic approach

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