Histamine Protects T Cells and Natural Killer Cells Against Oxidative Stress

Hansson, Markus; Hermodsson, Svante; Brüne, Martin; Mellqvist, Ulf‐Henrik; Naredi, Peter; Betten, Åsa; Gehlsen, Kurt R.; Hellstrand, Kristoffer

doi:10.1089/107999099313073

Cited by 86 publications

(86 citation statements)

References 33 publications

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“…Our data support a novel treatment strategy involving the blocking of phagocyte-generated ROS by histamine, thereby protecting NK and T cells from apoptosis and, thus, synergising with IL-2 in inducing NK-and T-cell activation Asea et al, 1996;Hansson et al, 1999). Clearly, with regard to the 'good guys', treatment with IL-2/HDC resulted in significantly higher numbers of intratumoural NK and CD8 þ T cells during treatment compared with baseline.…”

Section: Discussionsupporting

confidence: 60%

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

et al. 2006

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Histamine (HDC) inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer (NK) and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). We have explored this potential mechanism clinically in two randomised phase II trials in metastatic renal cell carcinoma (mRCC). In parallel with the clinical trial in Denmark (n ¼ 63), we obtained serial blood samples and tumour biopsies searching for a potential histamine effect in situ. At baseline and on-treatment weeks 3 and 8, we monitored the 'good guys' (i.e. NK and T cells) and 'bad guys' (i.e. monocytes/macrophages and neutrophils) simultaneously in blood (n ¼ 59) and tumour tissue (n ¼ 44). Patients with high number of monocytes and neutrophils in peripheral blood had very poor survival, with apparently no benefit from either IL-2 alone or IL-2/HDC treatment. Blood monocytes (r ¼ À0.36, P ¼ 0.01) and neutrophils (r ¼ À0.46, P ¼ 0.001) were negatively correlated with cytotoxicity, whereas blood NK cells were positively correlated with cytotoxicity (r ¼ 0.39, P ¼ 0.002). Treatment with IL-2 alone resulted in a significantly higher number of circulating monocytes (P ¼ 0.037) and intratumoral macrophages (P ¼ 0.005) compared with baseline. In contrast, IL-2/HDC resulted in an unchanged number of circulating monocytes and intratumoral macrophages, and in addition, a significantly increased number of intratumoral CD56 þ NK cells (P ¼ 0.008) and CD8 þ T cells (P ¼ 0.019) compared with baseline. The study provides evidence that circulating monocytes and neutrophils are powerful negative prognostic factors for IL-2-based immunotherapy and establishes a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC.

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Section: Discussionsupporting

confidence: 60%

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

et al. 2006

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“…These SV-IV-induced immunosuppressive findings are in line with the protective effect of SV-IV on Raji, K562, and Daudi target cells against the NK cytotoxicity (see Results). In this setting it appears also relevant: 1) the SV-IV ability to activate mast cell degranulation with release of immunosuppressive and antiapoptotic histamine and TGF- (Hansson et al, 1999;Metafora et al, manuscript in preparation); 2) the SV-IV ability to protect mouse zygote growth up to blastocyst stage in the semi-solid Fell and Robison culture medium nonpermissive for fertilized egg early development (Morelli et al, 2007). 3) other data showing the critical role of oxidative stress in jeopardizing embryo survival during early development (Guerin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Anti-apoptotic seminal vesicle protein IV inhibits cell-mediated immunity

Fuggetta

Lanzilli

Cottarelli

et al. 2008

Journal of Reproductive Immunology

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“…While the Fas/FasL pathway appears to participate in inducing apoptosis of CD4+ T cells in HIV (Badley et al, 1998) and of CD8+ T cells in cancer (Saito et al, 2000;Dworacki et al, 2001;Hoffmann et al, 2002), it is clearly not the only mechanism responsible for elimination of activated T cells. Among other factors that have been suggested are TNF/TNF-R, TRAIL/TRAIL-R (Srivastava, 2001), tumour-derived soluble factors (Taylor et al, 2001), and reactive oxygen metabolites (Hansson et al, 1999;Schmielau and Finn, 2001). In the case of patients with breast cancer we evaluated, utilisation of sFasL present in the plasma suggests its engagement in Fasmediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer

et al. 2003

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Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ra, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3 + T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (Po0.05). In patients, 18711% (mean7s.d.) of CD3 + cells bound Annexin V, compared to 976% in NC (Po0.0004). Percentages of CD3 + Fas + and CD3 + CD25 + cells were higher in the peripheral circulation of patients than NC (Po0.0001 and o0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3 + Fas + T cells. Most T cells undergoing apoptosis were CD3 + CD25 À in patients, and the proportion of CD3 + CD25 À Annexin V + cells was significantly increased in patients compared to NC (Po0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas -ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.

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Histamine Protects T Cells and Natural Killer Cells Against Oxidative Stress

Cited by 86 publications

References 33 publications

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

Anti-apoptotic seminal vesicle protein IV inhibits cell-mediated immunity

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer

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