The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis

Lubahn, Cheri; Schaller, Jill; Bellinger, Denise L.; Sweeney, Sarah; Lorton, Dianne

doi:10.1016/j.bbi.2004.02.004

Cited by 43 publications

(59 citation statements)

References 27 publications

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“…In contrast, selective denervation of the lymph nodes that drain the hind limbs (the popliteal and inguinal) prior to immunization to induce experimental arthritis exacerbates the disease [364]. This latter finding is consistent with a protective role of the SNS, likely afforded by shifting the immune response toward a humoral response based on circulating and immune organ cytokine profiles [334,365] or by preventing the autoreactive immune cell populations from homing to the joint.…”

Section: Sympathetic Regulation Of Autoimmune Diseasessupporting

confidence: 72%

“…Treating rats with α-or α 2 -antagonists from adjuvant challenge through severe disease increases disease severity [363,365,366]. However, it α-, α 1 -or α 2 -AR antagonist treatment begins at disease onset, disease pathology is significantly ameliorated ( [365,366] Lorton and Lubahn, unpublished observations). Based on these data, both α 1 and α 2 -AR mediate sympathetic influences on disease outcome.…”

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

“…The effects of treatment with drugs that interact with α-AR on disease pathology are dependent on time of treatment relative to disease course [365]. Treating rats with α-or α 2 -antagonists from adjuvant challenge through severe disease increases disease severity [363,365,366]. However, it α-, α 1 -or α 2 -AR antagonist treatment begins at disease onset, disease pathology is significantly ameliorated ( [365,366] Lorton and Lubahn, unpublished observations).…”

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

“…However, studies from our laboratories suggest that differences in outcome may be due to the timing of adrenergic drug treatment relative to the adjuvant challenge and the disease course. Treatment of AA rats with terbutaline, a β 2 -AR agonist, started at the time of adjuvant injection to induce disease, exacerbated disease severity; however, a directionally opposite effect of terbutaline treatment occurs when treatment begins at the time of disease onset significantly reduced disease severity [365]. Collectively, these findings suggest that at different time frames across the development and progression of AA, the SNS may differentially modulates afferent phase of the immune response and chronic inflammation once the disease has been established.…”

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

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Sympathetic modulation of immunity: Relevance to disease

Bellinger

Millar

Perez

et al. 2008

Cellular Immunology

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226

185

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Optimal host defense against pathogens requires cross-talk between the nervous and immune systems. This paper reviews sympathetic-immune interaction, one major communication pathway, and its importance for health and disease. Sympathetic innervation of primary and secondary immune organs is described, as well as evidence for neurotransmission with cells of the immune system as targets. Most research thus far as focused on neural-immune modulation in secondary lymphoid organs, and have revealed complex sympathetic modulation resulting in both potentiation and inhibition of immune functions. SNS-immune interaction may enhance immune readiness during disease-or injury-induced 'fight' responses. Research also indicate that dysregulation of the SNS can significantly affect the progression of immune-mediated diseases. However, a better understanding of neural-immune interactions is needed to develop strategies for treatment of immune-mediated diseases that are designed to return homeostasis and restore normal functioning neural-immune networks.

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Section: Sympathetic Regulation Of Autoimmune Diseasessupporting

confidence: 72%

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

Section: Sympathetic Regulation Of Autoimmune Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

Sympathetic modulation of immunity: Relevance to disease

Bellinger

Millar

Perez

et al. 2008

Cellular Immunology

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226

185

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An opposing time‐dependent immune‐modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen–induced arthritis

Härle¹,

Möbius²,

Carr³

et al. 2005

Arthritis & Rheumatism

145

141

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Objective. The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen-induced arthritis (CIA).Methods. We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin-10 (IL-10), IL-4, tumor necrosis factor ␣ (TNF␣), and interferon-␥ (IFN␥) were determined.Results. Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL-10 and IL-4 and unchanged levels of TNF␣ and IFN␥ compared with those from untreated animals. This indicates an immune-stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNF␣ and IFN␥ compared with those from nonsympathectomized controls with CIA. This indicates an immune-depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01).Conclusion. The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.Since the work of Selye in the 1940s (1), the sympathetic nervous system (SNS) together with the hypothalamic-pituitary-adrenal axis has been thought to play an important supportive role in the fight-or-flight response during stressful events. In linking this important concept to inflammatory diseases, several groups of investigators working from 1960 to the late 1980s delineated a proinflammatory role of the SNS for the early inflammatory response (for review, see ref.2). Indeed, the SNS seems to be a critical proinflammatory component of neurogenic inflammation, which is particularly evident during the first hours after induction of joint inflammation (3), when the SNS mediates an increase in vessel leakage, plasma extravasation, migration of leukocytes to inflamed tissue. This is accompanied by stimulation of sensory nerve fibers (2).At the beginning of the 1980s, with the introduction of in vitro immune cell culture assays that could continue for several days and with the detection of Sup...

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An early sympathetic nervous system influence exacerbates collagen‐induced arthritis via CD4+CD25+ cells

Härle¹,

Pongratz²,

Albrecht³

et al. 2008

Arthritis & Rheumatism

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Objective. Activation of the sympathetic nervous system (SNS) ameliorates collagen-induced arthritis (CIA) in the late phase of the disease but aggravates it in the presymptomatic phase. The aim of the present study was to determine whether CD4؉CD25؉ T cells are influenced by the SNS of mice and play a diseasemodifying role in the early symptomatic phase of the disease.Methods. We tested the effects of the SNS on arthritis by transferring CD4؉CD25؉ T cells from sympathectomized mice immunized with type II collagen and from immunized, SNS-intact animals (controls). We further characterized transferred cells by studying forkhead box P3 (FoxP3) expression, cell proliferation, and cytokine secretion.Results. Using anti-dopamine-␤-hydroxylase antibodies for systemic sympathectomy, we noticed a timedependent disease amelioration (strongest when sympathectomy was performed 7 days before immunization, with no effect 30 days after immunization). When CD4؉CD25؉ T cells from immunized and sympathectomized animals were transferred into mice with CIA (on day 32), disease severity was reduced compared with that in controls. However, the number of CD4؉CD25؉FoxP3؉ cells and the FoxP3 expression level in CD4؉CD25؉ cells were not changed by sympathectomy. In a mixed assay of donor CD4؉CD25؊ and CD4؉CD25؉ cells, proliferation was reduced when cells from sympathectomized animals were studied. In the same assay, secretion of tumor necrosis factor, interleukin-17 (IL-17), IL-10, and IL-4 (not interferon-␥) was markedly reduced when cells were taken from sympathectomized animals. Culture of CD4؉CD25؉ cells with norepinephrine (10 ؊5 M) for 24 hours before transfer worsened the arthritis.Conclusion. The SNS increases disease severity in the early phase of symptomatic CIA by stimulating several proinflammatory aspects of CD4؉CD25؉ T cells.

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The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis

Cited by 43 publications

References 27 publications

Sympathetic modulation of immunity: Relevance to disease

Sympathetic modulation of immunity: Relevance to disease

An opposing time‐dependent immune‐modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen–induced arthritis

An early sympathetic nervous system influence exacerbates collagen‐induced arthritis via CD4+CD25+ cells

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