Interleukin-2 restores the depressed allogeneic cell-mediated lympholysis and natural killer cell activity in patients with systemic lupus erythematosus

Tsokos, George C.; Smith, Paula; Christian, Carole; Lipnick, Robert; Balow, James E.; Djeu, Julie Y.

doi:10.1016/0090-1229(85)90186-2

Cited by 28 publications

(7 citation statements)

References 27 publications

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“…Regarding the latter possibility, lupus patients do appear to be more susceptible to viral infections, including reactivation of varicella zoster virus (VZV), a possible consequence of aberrant cytotoxic T cell function (4 -6). This latter idea finds support in the observations that patients with lupus have decreased cytotoxic T cell responses to mitogens and against allogenic and xenogenic targets (7,8), indicating a global impairment in cytotoxic T cell function that may increase the risk of infection. Despite the facts that patients with SLE have increased incidence of EBV infection and potentially impaired cytotoxic T cell function, the specific cellular control of latent EBV infection in SLE has been less well characterized, apart from observations 20 years ago that lupus patients had decreased cytotoxic responses directed against EBV-infected B cells (9).…”

supporting

confidence: 50%

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Kang

Quan

Nolasco

et al. 2004

The Journal of Immunology

226

187

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EBV infection is more common in patients with systemic lupus erythematosus (SLE) than in control subjects, suggesting that this virus plays an etiologic role in disease and/or that patients with lupus have impaired EBV-specific immune responses. In the current report we assessed immune responsiveness to EBV in patients with SLE and healthy controls, determining virus-specific T cell responses and EBV viral loads using whole blood recall assays, HLA-A2 tetramers, and real-time quantitative PCR. Patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, a finding not explained by disease activity or immunosuppressive medications. The frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ was higher in patients with SLE than in controls. By contrast, the frequency of EBV-specific CD69+ CD8+ T cells producing IFN-γ in patients with SLE appeared lower than that in healthy controls, although this difference was not statistically significant. These findings suggest a role for CD4+ T cells in controlling, and a possible defect in CD8+ T cells in regulating, increased viral loads in lupus. These ideas were supported by correlations between viral loads and EBV-specific T cell responses in lupus patients. EBV viral loads were inversely correlated with the frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ and were positively correlated with the frequencies of CD69+ CD8+ T cells producing IFN-γ and with EBV-specific, HLA-A2 tetramer-positive CD8+ T cells. These results demonstrate that patients with SLE have defective control of latent EBV infection that probably stems from altered T cell responses against EBV.

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supporting

confidence: 50%

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Kang

Quan

Nolasco

et al. 2004

The Journal of Immunology

226

187

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“…Other cellular sources of suppression were not investigated in this study. We have previously shown that IL-2 can consistently augment the diminished allogeneic cytotoxic and NK cell responses of MNC of SLE patients in vitfo (21). Previously, our explanation for this enhancement would have included the induction of y IFW, since it can enhance cytotoxic response (27,28) and IL-2 induces the release of y I F N by normal MNC (22).…”

Section: Discussionmentioning

confidence: 92%

“…However, findings in the present study suggest that the IL-2-induced enhancement of cytotoxic responses is not the result of augmented y I F N release. The possibility that deficient y I F N production by MNC from patients with SLE is secondary to the faihre of IL-2 to bind to its surface receptor can be excluded by the fact that IL-2 can enhance the cytotoxic responses of these cells (21). Furthermore, MNC from patients with SLE express normal levels of IL-2 receptors after stimulation with PHA (unpublished observations).…”

Section: Discussionmentioning

confidence: 95%

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Deficient γ‐interferon production in patients with systemic lupus erythematosus

Tsokos

Boumpas

Smith

et al. 1986

Arthritis & Rheumatism

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We examined the ability of peripheral mononuulear cells (MNC) from patients with systemic lupus erflhematosus (SLE) to produce y-interferon ( y-IFN) in vitro. MNC from patients with SLE produced varying amounts of y-IFN upon mitogenic stimulation. However, they produced distinctly decreased amounts of y-WN upon in vitro stimulation with interleukin-2 (IL-2). Deficient production seemed to be primary, rather than secondary to either excessive monocytic suppresion or failure of IL-2 to bind to the MNC surface membranes. y-IFN-specific RNA transcription, as determined by slot-blot analysis, was severely decreased in MNC that had been stimulated with phytohemagglutinin or IL-2. These findings suggest that MNC of patients with SLE have defects in the IL-2 signal transduction which is required for production of y-IFN.Systemic lupus erythematosus (SLE) is the prototype human autoimmune disease and is characterized by multiple abnormalities of both humoral and cellular immune responses (1). Cellular cytotoxic re-

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“…Nevertheless, defective cytotoxic T lymphocyte (CTL) responses are a longstanding observation [5–7] and perhaps the least disputed T cell abnormality in lupus [8]. Depressed in vitro effector CTL function likely reflects a more proximal defect in T cell production of IL-2 because (1) exogenous IL-2 corrects depressed allogeneic in vitro CTL in human lupus [9] and (2) defective in vitro IL-2 production is a frequent [10,11] but not uniform [12] observation in lupus patients.…”

Section: Defective Cytotoxic T Cell and Il-2 Responses Are Frequent Amentioning

confidence: 99%

Defectivein vitroIL-2 production in lupus is an early but secondary event paralleling disease activity: Evidence from the murine parent-into-F1 model supports staging of IL-2 defects in human lupus

Via

Shearer

2009

Autoimmunity

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T cell defects are a well described feature of both human and murine lupus however their exact significance is unclear. Evidence from an induced model of lupus, the P → F1 model of chronic lupus-like GVHD demonstrates that a secondary inducible T cell defect in in vitro IL-2 and CTL responses occurs early in the course of lupus-like disease and well in advance of clinical disease. Defective Th cell function was probed using a novel approach categorizing the response to two stimuli:1) the MHC self restricted response, termed self + X; and 2) the allogeneic response. Using this approach, lupus mice exhibited similar in vitro Th cell pattern i.e. and absent S + X response but preserved allogeneic (termed −/+). In contrast, human lupus patients exhibited three possible response patters, +/+, −/+ or −/− with more severe in vitro T cell impairment correlated with more severe disease. Similarly, patients with other T cell mediated conditions i.e. HIV infection or renal allograft recipients, also exhibited more severe in vitro T cell impairment with greater disease activity or greater immunosuppression respectively. The similar Th response patterns in human and murine T cell mediated conditions indicates that the underlying mechanisms involved are not disease specific but instead reflect common immune responses and validate the use of the P → F1 model for future studies of T cell mediated conditions. These results support the use of prospective monitoring of IL-2 responses in lupus patients. Successful adaptation of this approach to the clinical setting could allow not only earlier therapeutic intervention and reduced organ damage but also earlier tapering of pharmacological agents and reduced untoward effects.

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Interleukin-2 restores the depressed allogeneic cell-mediated lympholysis and natural killer cell activity in patients with systemic lupus erythematosus

Cited by 28 publications

References 27 publications

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Deficient γ‐interferon production in patients with systemic lupus erythematosus

Defectivein vitroIL-2 production in lupus is an early but secondary event paralleling disease activity: Evidence from the murine parent-into-F1 model supports staging of IL-2 defects in human lupus

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