Institute of Immunooncology

Buenos Aires, Argentina

Institute of Immunooncology

Buenos Aires, Argentina
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Massari N.A.,University of Buenos Aires | Massari N.A.,National University of Patagonia San Juan Bosco | Nicoud M.B.,University of Buenos Aires | Nicoud M.B.,Pontifical Catholic University of Argentina | And 9 more authors.
Oncotarget | Year: 2017

The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells. Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.


Martinel Lamas D.J.,University of Buenos Aires | Croci M.,Institute of Immunooncology | Carabajal E.,University of Buenos Aires | Crescenti E.J.V.,Institute of Immunooncology | And 6 more authors.
British Journal of Pharmacology | Year: 2013

Background and Purpose The presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. Experimental Approach Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg -1), clozapine (1 mg kg-1) and the experimental compound JNJ28610244 (10 mg kg-1). Results Data indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. Conclusions and Implications Histamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2013.170.issue-1 © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.


Prestifilippo J.P.,University of Buenos Aires | Carabajal E.,University of Buenos Aires | Croci M.,Institute of Immunooncology | Fernandez-Solari J.,University of Buenos Aires | And 5 more authors.
Inflammation Research | Year: 2012

Objective We have recently reported that experimental periodontitis (EP) reduced methacholine-induced submandibular gland (SMG) salivary secretion. The aim of the present study was to determine whether histamine could prevent SMG impairment produced by EP. Materials and Methods Bilateral EP was induced for 2 weeks and histamine treatment (0.1 mg/kg subcutaneously) was started 5 days before the end of the experimental period in male rats. The histamine effects on periodontitisaltered functional and histological parameters of SMG and on periodontal bone loss were evaluated. Results Histamine treatment partially reversed the methacholine-induced salivation reduction produced by EP while preventing SMG histological damage. Histamine's effect on SMG was associated with an increased proliferation rate (2.2 ± 0.3 vs. 0.2 ± 0.2 proliferative cells per field, P\0.001). Furthermore, histamine completely prevented enhanced EP-induced apoptosis (1.0 ± 0.4 vs. 60.9 ± 4.6 apoptotic cells per field, P\0.001). The protective effect exerted by histamine on SMG functionality is associated with attenuation of lingual and vestibular bone loss (0.66 ± 0.04 vs. 0.97 ± 0.06 mm; P\0.001). Conclusions Histamine is able to reduce periodontitisinduced damage to SMG and bone structure. copyright © Springer Basel AG 2012.


Medina V.A.,University of Buenos Aires | Medina V.A.,CONICET | Prestifilippo J.P.,University of Buenos Aires | Croci M.,Institute of Immunooncology | And 5 more authors.
International Journal of Radiation Biology | Year: 2011

Purpose: Xerostomia is a common, disturbing side-effect among patients treated with radiotherapy for head-and-neck cancer. The aim of the present work was to investigate whether histamine could prevent salivary gland dysfunction and histological alterations exerted by ionising radiation. Materials and methods: Forty-eight rats were divided into four groups. Histamine and histamine-5 Gy groups received a daily subcutaneous histamine injection (0.1 mg/kg) starting 24 h before irradiation. Histamine-5 Gy and untreated-5 Gy groups were irradiated with a single dose of whole-body Cesium-137 irradiation. Control and untreated-5 Gy groups were given daily saline injections. Three days post irradiation metacholine-induced salivary secretion was measured or animals were sacrificed and submandibular gland (SMG) removed, stained and histological characteristics were evaluated. Proliferation and apoptosis markers were studied by immunohistochemistry. Results: Radiation decreased salivary secretion by 40% in comparison to untreated rats, which was associated with loss of SMG mass, alteration of epithelial architecture, partial loss of secretor granular material, diminished proliferation and a remarkable apoptotic response. In contrast, histamine completely reversed the reduced salivation induced by radiation, conserved glandular mass with normal appearance and preserved the structural organisation of secretor granules. Radiation-induced toxicity is prevented by histamine essentially by suppressing apoptosis of ductal and acinar cells, reducing the number of apoptotic cells per field (19.0±3.8 vs. 106.0±12.0 in untreated animals, P < 0.001), and also by preventing the radiation-induced decrease in cell proliferation. Conclusions: Histamine prevents morphological and functional radiation-induced damage on SMG, representing a potential radioprotector for treatment of patients undergoing radiotherapy for head and neck malignancies. © 2011 Informa UK, Ltd.


Massari N.A.,University of Buenos Aires | Medina V.A.,University of Buenos Aires | Medina V.A.,CONICET | Cricco G.P.,University of Buenos Aires | And 9 more authors.
Journal of Dermatological Science | Year: 2013

Background: Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies. Objective: The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. Methods: Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis. Results: The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg-1, sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. Conclusions: We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma. © 2013 Japanese Society for Investigative Dermatology.


Crescenti E.J.V.,Institute of Immunooncology | Medina V.A.,University of Buenos Aires | Medina V.A.,CONICET | Sambuco L.A.,Institute of Immunooncology | And 13 more authors.
Biological Trace Element Research | Year: 2014

Scleroderma, sclerosis of the skin, is a severe autoimmune disease refractant to all kind of treatments. To study the in vivo effects of a combination of three oligoelements selenium (Se), zinc (Zn), and manganese (Mn) plus Lachesis muta venom (O-LM) on the bleomycin (BLM)-induced scleroderma mouse experimental model. C3H mice were randomly divided into four groups: control (phosphate-buffered saline (PBS)), O-LM, BLM, and BLM + O-LM. All administrations were performed subcutaneously into the back of mice. BLM was injected 5 days per week for three consecutive weeks and O-LM was administered simultaneously with BLM from the beginning of the experiments and lasted for 3 weeks after the final BLM or PBS injection (for O-LM and BLM + O-LM groups), when animals were sacrificed and histopathological, immunohistochemical, thiobarbituric acid reactive species (TBARS) evaluation, and autoantibodies detection were determined. O-LM significantly reduced BLM-induced enhanced dermal thickness (605 ± 47 vs. 956 ± 59 μm, P < 0.01), collagen deposition, and mast cells infiltration (43.1 ± 1.0 vs. 102 ± 14.1 mast cells, P < 0.05). O-LM administration significantly blocked BLM-induced oxidative damage and the enhanced immunoreactive fibroblasts for α-smooth muscle actin while reduced BLM-induced autoantibodies that strongly react mainly with skin and spleen. O-LM significantly reduced BLM-induced scleroderma through the modulation of antioxidant and immunological pathways. © 2013 Springer Science+Business Media New York.


Carabajal E.,University of Buenos Aires | Massari N.,University of Buenos Aires | Croci M.,Institute of Immunooncology | Martinel Lamas D.,University of Buenos Aires | And 7 more authors.
European Journal of Histochemistry | Year: 2012

The aim of this study was to improve knowl-edge about histamine radioprotective potential investigating its effect on reducing ionising radiation-induced injury and genotoxic dam-age on the rat small intestine and uterus. Forty 10-week-old male and 40 female Sprague-Dawley rats were divided into 4 groups. Histamine and histamine-5Gy groups received a daily subcutaneous histamine injection (0.1 mg/kg) starting 24 h before irradiation. Histamine-5Gy and untreated-5Gy groups were irradiated with a dose of whole-body Cesium-137 irradiation. Three days after irradiation animals were sacrificed and tissues were removed, fixed, and stained with haematoxylin and eosin, and histological characteristics were evaluated. Proliferation, apoptosis and oxidative DNA markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate chromosomal damage. Histamine treatment reduced radia-tion-induced mucosal atrophy, oedema and vascular damage produced by ionising radia-tion, increasing the number of crypts per cir-cumference (239±12 vs 160±10; P<0.01). This effect was associated with a reduction of radi-ation-induced intestinal crypts apoptosis. Additionally, histamine decreased the frequen-cy of micronuclei formation and also signifi-cantly attenuated 8-OHdG immunoreactivity, a marker of DNA oxidative damage. Further-more, radiation induced flattening of the endometrial surface, depletion of deep glands and reduced mitosis, effects that were com-pletely blocked by histamine treatment. The expression of a proliferation marker in uterine luminal and glandular cells was markedly stim-ulated in histamine treated and irradiated rats. The obtained evidences indicate that hista-mine is a potential candidate as a safe radio-protective agent that might increase the thera-peutic index of radiotherapy for intra-abdomi-nal and pelvic cancers. However, its efficacy needs to be carefully investigated in prospec-tive clinical trials. © E. Carabajal et al., 2012.


Crescenti E.J.V.,Institute of Immunooncology | Medina V.A.,University of Buenos Aires | Croci M.,Institute of Immunooncology | Sambuco L.A.,Institute of Immunooncology | And 4 more authors.
Journal of Radiation Research | Year: 2011

In this study we first evaluated the general radioprotective efficacy of Se, Zn and Mn (4 μg/ml each) plus Lachesis muta venom (4 ng/ml) combination (O-LM) by determining survival on rats irradiated with lethal doses of gamma-rays. The aim of the second part of the study was to investigate the O-LM ability to prevent ionizing radiation-induced damage on small intestine, bone marrow and submandibular glands. Hence, histological characteristics and functional studies, together with proliferation and apoptotic marker levels on whole body irradiated rats with a 5 Gy dose were evaluated. Results show that all animals of the untreated group died after whole body irradiation with 8 and 10 Gy while 60 day-survival was more than 80% and 40% in O-LM-treated animals, respectively. Histopathological examinations revealed a high degree of small intestine and submandibular gland radioprotection 3 days post-irradiation. O-LM inhibited histological damage on small intestine, restoring the radiation-induced reduction in villous height and crypt number. O-LM prevented radiation-induced loss of salivary gland function and morphological alterations. These effects were associated to a complete inhibition of radiation-induced apoptosis. Furthermore, studies performed 30 days post-irradiation revealed that O-LM significantly improved bone marrow repopulation, increasing all medullar progenies to the extent of the non-irradiated animals, and completely prevented permanent submandibular gland alterations. Based on the present results and taking into account that O-LM is being safely administered in phase I clinical trial as an immunomodulator, we conclude that O-LM is a non-toxic promising approach to achieve radioprotection for patients undergoing radiotherapy.


PubMed | Institute of Immunooncology
Type: Journal Article | Journal: Biological trace element research | Year: 2014

Scleroderma, sclerosis of the skin, is a severe autoimmune disease refractant to all kind of treatments. To study the in vivo effects of a combination of three oligoelements selenium (Se), zinc (Zn), and manganese (Mn) plus Lachesis muta venom (O-LM) on the bleomycin (BLM)-induced scleroderma mouse experimental model. C3H mice were randomly divided into four groups: control (phosphate-buffered saline (PBS)), O-LM, BLM, and BLM+O-LM. All administrations were performed subcutaneously into the back of mice. BLM was injected 5 days per week for three consecutive weeks and O-LM was administered simultaneously with BLM from the beginning of the experiments and lasted for 3 weeks after the final BLM or PBS injection (for O-LM and BLM+O-LM groups), when animals were sacrificed and histopathological, immunohistochemical, thiobarbituric acid reactive species (TBARS) evaluation, and autoantibodies detection were determined. O-LM significantly reduced BLM-induced enhanced dermal thickness (60547 vs. 95659 m, P<0.01), collagen deposition, and mast cells infiltration (43.11.0 vs. 10214.1 mast cells, P<0.05). O-LM administration significantly blocked BLM-induced oxidative damage and the enhanced immunoreactive fibroblasts for -smooth muscle actin while reduced BLM-induced autoantibodies that strongly react mainly with skin and spleen. O-LM significantly reduced BLM-induced scleroderma through the modulation of antioxidant and immunological pathways.

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