Publications (33)63.69 Total impact
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Article: Neem leaf glycoprotein overcomes indoleamine 2, 3 dioxygenase mediated tolerance in dendritic cells by attenuating hyperactive regulatory T cells in cervical cancer stage IIIB patients.
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ABSTRACT: Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2, 3 dioxygenase (IDO) expression. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co-culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP.Human immunology 04/2013; · 2.55 Impact Factor -
Article: Neem leaf glycoprotein activates CD8(+) T cells to promote therapeutic anti-tumor immunity inhibiting the growth of mouse sarcoma.
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ABSTRACT: In spite of sufficient data on Neem Leaf Glycoprotein (NLGP) as a prophylactic vaccine, little knowledge currently exists to support the use of NLGP as a therapeutic vaccine. Treatment of mice bearing established sarcomas with NLGP (25 µg/mice/week subcutaneously for 4 weeks) resulted in tumor regression or dormancy (Tumor free/Regressor, 13/24 (NLGP), 4/24 (PBS)). Evaluation of CD8(+) T cell status in blood, spleen, TDLN, VDLN and tumor revealed increase in cellular number. Elevated expression of CD69, CD44 and Ki67 on CD8(+) T cells revealed their state of activation and proliferation by NLGP. Depletion of CD8(+) T cells in mice at the time of NLGP treatment resulted in partial termination of tumor regression. An expansion of CXCR3(+) and CCR5(+) T cells was observed in the TDLN and tumor, along with their corresponding ligands. NLGP treatment enhances type 1 polarized T-bet expressing T cells with downregulation of GATA3. Treg cell population was almost unchanged. However, T∶Treg ratios significantly increased with NLGP. Enhanced secretion/expression of IFNγ was noted after NLGP therapy. In vitro culture of T cells with IL-2 and sarcoma antigen resulted in significant enhancement in cytotoxic efficacy. Consistently higher expression of CD107a was also observed in CD8(+) T cells from tumors. Reinoculation of sarcoma cells in tumor regressed NLGP-treated mice maintained tumor free status in majority. This is correlated with the increment of CD44(hi)CD62L(hi) central memory T cells. Collectively, these findings support a paradigm in which NLGP dynamically orchestrates the activation, expansion, and recruitment of CD8(+) T cells into established tumors to operate significant tumor cell lysis.PLoS ONE 01/2013; 8(1):e47434. · 4.09 Impact Factor -
Article: Neem leaf glycoprotein is nontoxic to physiological functions of Swiss mice and Sprague Dawley rats: Histological, biochemical and immunological perspectives.
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ABSTRACT: We have evaluated the toxicity profile of a unique immunomodulator, neem leaf glycoprotein (NLGP) on different physiological systems of Swiss mice and Sprague Dawley rats. NLGP injection, even in higher doses than effective concentration caused no behavioral changes in animals and no death. NLGP injection increased the body weights of mice slightly without any change in organ weights. NLGP showed no adverse effect on the hematological system. Moreover, little hematostimulation was noticed, as evidenced by increased hemoglobin content, leukocyte count and lymphocyte numbers. Histological assessment of different organs like brain, liver, kidney, spleen and lymph nodes revealed no alterations in the organ microstructure of the NLGP treated mice and rats. Histological normalcy of liver and kidney was further confirmed by the assessment of liver enzymes like alkaline phosphatase, SGOT, SGPT and nephrological products like urea and creatinine. NLGP has no apoptotic effect on immune cells like T cells but induces proliferation of mononuclear cells collected from mice and rats. Number of CD4(+), CD8(+) T cells, DX5(+) NK cells, CD11b(+) macrophages and CD11c(+) dendritic cells is upregulated by NLGP without a significant change in CD4(+)CD25(+)Foxp3(+) regulatory T cells. Type 1 cytokines, like IFNγ also increased in serum with a decrease in type 2 cytokines. Total IgG content, especially IgG2a increased in NLGP treated mice. These type 1 directed changes help to create an anti-tumor immune environment that results in the restriction of carcinoma growth in mice. Accumulated evidence strongly suggests the non-toxic nature of NLGP. Thus, it can be recommended for human use in anti-cancer therapy.International immunopharmacology 11/2012; · 2.21 Impact Factor -
Article: IFNα2b augments immune responses of cisplatin+5-fluorouracil treated tongue squamous cell carcinoma patients--a preliminary study.
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ABSTRACT: Background & objectives: Interferon alpha 2b (IFNα2b) has been reported to regulate several immune functions efficiently to enhance the cytotoxic activity of NK and T cells towards various forms of tumours. The objective of the present study was to evaluate the efficacy of IFNα2b in overcoming disease induced and/or treatment associated imunosuppression of tongue squamous cell carcinoma (TSCC) patients undergoing chemotherapy for better clinical outcome. Methods: Seven TSCC patients under cisplatin + 5-fluorouracil chemotherapy in combination with IFNα2b were assessed for various immunohaematological parameters before treatment, after chemotherapy and after IFNα2b therapy. Results: Deterioration of the haematological and immune responses was detected in immunosuppressed TSCC patients after chemotherapy. IFNα2b treatment led to a recovery in these parameters in most of the patients. Greater number of T/NK cells and enhanced secretion of type 1 cytokines were also noted. Haematological complications were reduced after completion of the therapy. Immune- and haematostimulation were also observed in patients with partial response. No positive clinical response was detected in one patient. Interpretation & conclusions: IFNα2b appears to be an effective immunostimulator having clinical impact to combat the immunosuppression in TSCC patients. Successful immunostimulation by IFNα2b may help TSCC patients in clinical improvement. The findings of this preliminary study need to be confirmed on a large number of patients with TSCC.The Indian journal of medical research 07/2012; 136(1):54-9. · 1.84 Impact Factor -
Article: Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte/macrophage functions.
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ABSTRACT: We have shown that neem leaf glycoprotein (NLGP) inhibits the regulatory T cell (Tregs) induced suppression of tumoricidal functions of CD14(+)CD68(+) monocyte/macrophages (MO/Mφ) from human peripheral blood. Cytotoxic efficacy of MO/Mφ toward macrophage sensitive cells, U937, is decreased in presence of Tregs (induced), however, it was increased further by supplementation of NLGP in culture. Associated Treg mediated inhibition of perforin/granzyme B expression and nitric oxide release from MO/Mφ was normalized by NLGP. Altered status of signature cytokines, like, IL-12, IL-10, IL-6, TNFα from MO/Mφ under influence of Tregs is also rectified by NLGP. Tregs significantly enhanced the expression of altered marker, mannose receptor (CD206) on CD68(+) cells that was downregulated upon NLGP exposure. In addition to tumoricidal functions, antigen presenting ability of MO/Mφ is hampered by Treg induced downregulation of CD80, CD86 and HLA-ABC. NLGP upregulated these molecules in MO/Mφ even in the presence of Tregs. Treg mediated inhibition of MO/Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP, where participation of CCR5 was documented. Overall results suggest that Treg influenced pro-tumor MO/Mφ functions are rectified in a significant extent by NLGP to create an anti-tumor immune environment.International immunopharmacology 12/2011; 12(2):326-33. · 2.21 Impact Factor -
Article: Dysregulated CC receptor/ligand in monocytes/macrophages from tongue squamous cell carcinoma patients is partially rectified by interferon α-2b.
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ABSTRACT: In an aim to rectify dysregulated CC chemokine receptor (CCR5)/ligand (RANTES, MIP-1α, MIP-1β) status of monocytes/macrophages in tongue squamous cell carcinoma (TSCC; n = 12) patients, we have tested interferon α2b (IFNα2b), a novel immunomodulator with wide use in the management of several forms of cancer. IFNα2b can upregulate reduced CCR5 expression and increases the suppressed secretory status of its ligands, as evidenced from in vitro studies on monocytes/macrophages from the peripheral blood of TSCC patients as well as healthy individuals. Isolated monocytes of TSCC patients (n = 5) undergoing chemotherapeutic treatment along with IFNα2b immunotherapy demonstrated significant upregulation in CCR5 expression and secretion of corresponding ligands. These rectifications in receptor/ligand levels are reflected in improved CCR5-dependent migration of monocytes/macrophages after IFNα2b treatment. The rectified chemokine profile and cellular migration translate into better tumoricidal and antigen-presenting functions of these cells. Accordingly, enhanced T-cell-mediated tumor cell killing is demonstrated upon IFNα2b treatment. Translating dual benefits on monocyte/macrophage functions, IFNα2b may emerge as a potential form of immunotherapy for TSCC patients that may be combined with standard chemotherapy for better clinical outcome.Human immunology 10/2011; 73(1):38-47. · 2.55 Impact Factor -
Article: Defective dendritic cell generation from monocytes is a potential reason for poor therapeutic efficacy of interferon α2b (IFNα2b) in cervical cancer.
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ABSTRACT: Despite being a pleiotropic cytokine, the therapeutic potential of interferon α2b (IFNα2b) is debatable. Thus, the need for identifying predictive marker(s) for patients who are most likely to benefit from the treatment is pivotal for avoiding the exposure of nonresponsive patients to the toxicity of the treatment. To account for the attenuated efficacy of the drug, we have verified its dendritic cell (DC) maturating ability from monocytes of cervical cancer stage IIIB (CaCx-IIIB) patients. First, we evaluated the status of monocytes from CaCx-IIIB and healthy women by conducting flow cytometric studies of various activation markers and a cytokine analysis by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Immature DCs were then generated from these monocytes and matured with low-dose IFNα2b (1500 units/mL). A functional and phenotypic comparative analysis of these matured DCs was performed by flow cytometric, proliferative, cytotoxic, and enzyme-linked immunosorbent assays. Our study shows that monocytes isolated from CaCx-IIIB are impaired, and in vitro maturation with IFNα2b did not significantly improve the functional repertoire of DCs generated from these monocytes in comparison with healthy controls. This impairment of monocytes might be a plausible reason for the attenuated efficacy of this drug alone in treating CaCx-IIIB patients, and this imbalance of immune parameters associated with the stage of malignancy might be considered an effective marker to design a proper therapeutic regimen.Translational research : the journal of laboratory and clinical medicine. 10/2011; 158(4):200-13. -
Article: Neem leaf glycoprotein inhibits CD4+CD25+Foxp3+ Tregs to restrict murine tumor growth.
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ABSTRACT: The presence of Tregs in tumors is associated with compromised tumor-specific immune responses and has a clear negative impact on survival of cancer patients. Thus, downregulation of Tregs is considered as a promising cancer immunotherapeutic approach. We have reported previously that neem leaf glycoprotein (NLGP) prophylaxis restricts tumor growth in mice by immune activation. In continuation, here, involvement of NLGP in the modulation of Tregs in association with tumor growth restriction is investigated. NLGP downregulates CD4+CD25+Foxp3+ Tregs within tumors. NLGP-mediated downregulation of CCR4 along with its ligand CCL22 restricts Treg migration at the tumor site. NLGP is not apoptotic to Tregs but significantly downregulates the expression of Foxp3, CTLA4 and GITR. It also reverses the functional impairment of T-effector cells by Tregs, in terms of IFN-γ secretion, cellular proliferation and tumor cell cytotoxicity. NLGP also facilitates reconditioning of tumor microenvironment (hostile) by increasing IFN-γ and IL-12 but decreasing IL-10, TGF-β, VEGF and IDO, creating an antitumor niche. Interaction between Foxp3, p-NFATc3 and p-Smad2/3, needed for successful Treg function, is also inhibited by NLGP. All of these coordinated events might result in inhibition of Treg associated-tumor growth and therefore increased survivability of mice having NLGP treatment before or/and after tumor inoculation. Thus, the possibility of NLGP being an excellent tool as a T-cell anergy breaker by abrogating the suppressor functions of Tregs in cancer needs to be explored further in the clinic.Immunotherapy 08/2011; 3(8):949-69. · 1.85 Impact Factor -
Article: Neem leaf glycoprotein partially rectifies suppressed dendritic cell functions and associated T cell efficacy in patients with stage IIIB cervical cancer.
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ABSTRACT: Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.Clinical and vaccine immunology: CVI 02/2011; 18(4):571-9. · 2.37 Impact Factor -
Chapter: Chapter 2: Immunotherapeutic Targeting of Multiple Dysregulated Immune Functions in Cancer by Neem Leaf Glycoprotein
01/2011: pages (in press); -
Conference Proceeding: Immunotherapeutic targeting of multiple dysregulated immune functions in cancer by neem leaf glycoprotein.
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ABSTRACT: Non-specificity and collateral toxicity of conventional therapeutics attracts researchers to the immunotherapy for cancerous diseases. Several forms of non-toxic, biological therapeutics are housed under an umbrella of immunotherapy. In cancer, generally immunotherapy intervenes therapeutic modalities, instead of prophylactic setting, which initially aimed to activation and functional optimization of immune cells, like, macrophages, NK cells, T cells and dendritic cells. With advent of knowledge in last decade it has been well established that tumor instructed suppressor cells are dynamically active in cancer to paralyze host immune surveillance. And unfortunately, many promising prophylactic vaccine shows only modest efficacy when translated into therapeutic settings because of suppressor cells are either promoted or unaffected under influence of these vaccines. Accordingly, there is a definite need for an alternative candidate that might be able to stimulate immune effectors in concert with suppressing regulatory cells. In our continuous experimental effort with neem leaf glycoprotein (NLGP), a natural immunomodulator, we have experienced that NLGP can effectively break the T cell anergy in tumor condition and prevent the IDO mediated apoptosis of T cells. At the same time, T cells acquire greater cytotoxic efficacy to kill tumors utilizing IFNı dependent perforin-granzyme B pathway. NLGP also mobilizes activated T cells to tumor site by maintaining CXC receptor-ligand homeostasis. In such normalization of T cell functions, maturation of dendritic cells by NLGP and subsequent antigen delivery to T cells plays a critical role. NLGP matured DCs effectively prime antigen specific T cells by optimizing co-stimulatory signaling and histocompatibility in vivo to obtain robust anti-tumor response translated into tumor growth restriction in mice. Elevated level of suppressor regulatory T cells in cancer condition may interfere with NLGP rescued T cell functions. Fortunately, at the sametime, NLGP prevents the tumor promoted conversion of T cells to regulatory T cells, thereby, partially withdraws the suppression of regulatory T cells on T cells and other immune components. Additionally, NLGP efficiently facilitate the trafficking of APCs (DC and macrophages), while limiting the migration of regulatory cells towards tumor microenvironment by differentially regulating CCR7/CCR5 and CCR4 (counter-regulatory) expression, thereby, optimizing tumor cell lysis by T cells. Mechanism of targeting multiple dysregulated immune functions in cancer by a single non-toxic natural agent NLGP is discussed here.World Congress on Biotechnology, 21-23 March 2011, Hyderabad, India.; 01/2011 -
Article: Restoration of dysregulated CC chemokine signaling for monocyte/macrophage chemotaxis in head and neck squamous cell carcinoma patients by neem leaf glycoprotein maximizes tumor cell cytotoxicity.
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ABSTRACT: Previous studies have shown that the CC chemokine receptor CCR5 is downregulated on monocyte/macrophage (MO/Mphi) surfaces in head and neck squamous cell carcinoma (HNSCC) patients (stage IIIB). Ligands (RANTES, MIP-1alpha and MIP-1beta) of this chemokine receptor were also secreted in lesser quantity from MO/Mphi of HNSCC patients in comparison with healthy individuals. In an aim to restore this dysregulated receptor-ligand signaling, we have used neem leaf glycoprotein (NLGP), a novel immunomodulator reported from our laboratory. NLGP upregulated CCR5 expression, as evidenced from studies on MO/Mphi of peripheral blood from HNSCC patients as well as healthy individuals. Expression of RANTES, MIP-1alpha and MIP-1beta was also upregulated following NLGP treatment of these cells in vitro. Interestingly, NLGP has little effect on the expression of CCR5 and the ligand RANTES in oral cancer cells. This restored CCR5 receptor-ligand signaling seen in MO/Mphi was reflected in improved CCR5-dependent, p38 mitogen-activated protein kinase (MAPK)-mediated migration of MO/Mphi after NLGP treatment to a standard chemoattractant. NLGP also induces better antigen presentation and simultaneous costimulation to effector T cells by MO/Mphi by upregulating human leucocyte antigen (HLA)-ABC, CD80 and CD86. In addition, NLGP-treated MO/Mphi-primed T cells can effectively lyse tumor cells in vitro. The effects of NLGP on monocyte migration and T cell-mediated oral tumor cell killing were further demonstrated in transwell assays with or without CCR5 neutralization. These results suggest a new approach in cancer immunotherapy by modulating dysregulated CCR5 signals from MO/Mphi.Cellular & molecular immunology 09/2010; 7(5):396-408. · 2.99 Impact Factor -
Article: Neem leaf glycoprotein enhances carcinoembryonic antigen presentation of dendritic cells to T and B cells for induction of anti-tumor immunity by allowing generation of immune effector/memory response.
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ABSTRACT: Vaccination with neem leaf glycoprotein matured carcinoembryonic antigen (CEA) pulsed dendritic cells (DCs) enhances antigen-specific humoral and cellular immunity against CEA and restricts the growth of CEA(+) murine tumors. NLGP helps better CEA uptake, processing and presentation to T/B cells. This vaccination (DCNLGPCEA) elicits mitogen induced and CEA specific T cell proliferation, IFN gamma secretion and induces specific cytotoxic reactions to CEA(+) colon tumor cells. In addition to T cell response, DCNLGPCEA vaccine generates anti-CEA antibody response, which is principally IgG2a in nature. This antibody participates in cytotoxicity of CEA(+) cells in antibody-dependent manner. This strong anti-CEA cellular and humoral immunity protects mice from tumor development and these mice remained tumor free following second tumor inoculation, indicating generation of effector memory response. Evaluation of underlying mechanism suggests vaccination generates strong CEA specific CTL and antibody response that can completely prevent the tumor growth following adoptive transfer. In support, significant upregulation of CD44 on the surface of lymphocytes from DCNLGPCEA immunized mice was noticed with a substantial reduction in L-selectin (CD62L).International immunopharmacology 08/2010; 10(8):865-74. · 2.21 Impact Factor -
Chapter: Chapter 2: Neem leaf glycoprotein as a new vaccine adjuvant for cancer immunotherapy
01/2010: pages 21-45; -
Article: Neem leaf glycoprotein matures myeloid derived dendritic cells and optimizes anti-tumor T cell functions.
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ABSTRACT: In an objective to find out an effective, nontoxic dendritic cell (DC) maturating agent for human use, CD14(+) monocytes were differentiated with GMCSF/IL-4 and matured with neem leaf glycoprotein (NLGP). NLGP matured DCs (NLGP-DCs) show upregulated expression of CD83, CD80, CD86, CD40 and MHCs, in a comparable extent of control, LPS. NLGP-DCs secrete high amount of IL-12p70 with low IL-10. NLGP upregulates the expression of crucial transcription factor, ikaros, indicating maturation towards DC1 phenotype. Increased expression of CD28 and CD40L on T cells following co-culture with NLGP-DCs was noticed to promote DC-T interactions. As a result, T cells secrete high amount of IFN gamma with low IL-4 and generates anti-tumor type 1 immune microenvironment. Such NLGP-DCs present carcinoembryonic antigen (CEA) effectively to T cells to increase T cell mediated cytotoxicity of CEA(+) tumor cells in vitro and in vivo. With emergence of the NLGP as a promising DC maturating agent, NLGP-DCs can be used as a candidate vaccine tool for antigen specific cancer immunotherapy.Vaccine 12/2009; 28(5):1241-52. · 3.77 Impact Factor -
Article: Neem (Azadirachta indica) leaf preparation prevents leukocyte apoptosis mediated by cisplatin plus 5-fluorouracil treatment in Swiss mice.
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ABSTRACT: Neem (Azadirachta indica) is widely regarded as a wonder tree because of its diverse medicinal applications. We investigated the ability of neem leaf preparation (NLP) to protect against apoptosis of circulating blood cells induced by cisplatin and 5-fluorouracil (cis + 5-FU) in carcinoma-bearing mice. Apoptosis was studied by annexin V-propidium iodide method. Total white blood cell count was performed using 3% glacial acetic acid on hemocytometer. Cytotoxicity was determined by LDH release assay and T/NK cell status was determined by flow cytometry. In comparison to untreated control, during cis + 5-FU therapy, significant down-regulation of leukocyte apoptosis was noted in mice pretreated with NLP or granulocyte colony stimulating factor (GCSF) during cis + 5-FU therapy. This enhanced cytotoxicity may be associated with NLP-induced increase of the cytotoxic T and NK cell pool. Efficacy of NLP is comparable to GCSF in its ability to protect against leukocyte apoptosis induced by cis + 5-FU. NLP would be a better choice of treatment because GCSF is tumor promoting, angiogenic and expensive.Chemotherapy 05/2009; 55(3):137-44. · 1.82 Impact Factor -
Article: Association of early phase of colorectal carcinogenesis with STAT3 activation and its relevance in apoptosis regulation.
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ABSTRACT: Expression of STAT3/pSTAT3 in colorectal cancer (CRC) patients of Indian origin was studied to assess its significance in early detection and apoptosis regulation. Colorectal tissues with malignant lesions were STAT3/pSTAT3 positive in 66% of the cases and among these positive cases, well differentiated, moderately differentiated and poorly differentiated cancers were 86%, 60% and 0% respectively. All CRC specimens studied were immunoreactive with anti-carcinoembryonic antigen antibody. Cells purified from CRC tissues exhibited greater STAT3/pSTAT3 reactivity than peripheral blood mononuclear cells (PBMC) from healthy individuals, which served as control. apoptotic index (AI) was comparatively low in tissue specimens with STAT3/pSTAT3 expression. CRC cells with a comparatively less number of apoptotic cells, expressed a minimum number of Caspase-3 positive cells (4.73%), in comparison to healthy-PBMC (12.63%). CRC cells with high STAT3/pSTAT3 staining had cells with greater percentage of Bcl2 reactivity (23.05%), but less positivity with Caspase3 antibody (2.05%). Overall data suggests that CRC population was STAT3/pSTAT3 immunoreactive in a stage specific manner and STAT3 protects cancerous colorectal epithelial cells from apoptosis. Bcl-2, Cyclin D1 and Caspase-3 control the activity of apoptosis regulator, STAT3.Experimental and Molecular Pathology 04/2009; 87(1):36-41. · 2.42 Impact Factor -
Article: Induction of type 1 cytokines during neem leaf glycoprotein assisted carcinoembryonic antigen vaccination is associated with nitric oxide production.
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ABSTRACT: Involvement of the nitric oxide (NO) release in CEAM phi NLGP (carcinoembryonic antigen pulsed macrophages with neem leaf glycoprotein) vaccination and its relationship with vaccine induced type 1 immune response were aimed to study in the present communication. Vaccination with CEAM phi NLGP resulted in macrophage activation as evidenced by its increased number and expression of CD69 marker. Activated macrophages demonstrated upregulation in synthesis of IL-12 and downregulation in IL-10, along with excess IFN gamma production in splenic cells, as evidenced from mRNA analysis. Induction of such type 1 immunity was further confirmed by expression of type 1 specific transcription factor, T-bet and enhancement of intracellular glutathione content. Such vaccination also induced greater nitric oxide (NO) production from macrophages. Dependence of induced type 1 immune response on the NO release and vice versa was studied by in vitro neutralization of IFN gamma/IL-12 and in vivo inhibition of NO production by methylene blue. Obtained results clearly demonstrated the interdependence of two anti-tumor immune functions, namely, NO production and generation of type 1 immune response. Understanding of the mechanism of this NO related immune modulation would have great impact in proposing CEAM phi NLGP vaccine in clinic for the treatment of CEA+ tumors.International immunopharmacology 04/2009; 9(6):753-60. · 2.21 Impact Factor -
Article: Neem leaf glycoprotein induces perforin-mediated tumor cell killing by T and NK cells through differential regulation of IFNgamma signaling.
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ABSTRACT: We have demonstrated augmentation of the CD3-CD56+ natural killer (NK) and CD8+CD56_ T-cell-mediated tumor cell cytotoxicity by neem leaf glycoprotein (NLGP). These NK and T cells were isolated from the peripheral blood of head and neck squamous cell carcinoma patients with a state of immunosuppression. NLGP induces TCRalphabeta-associated cytotoxic T lymphocyte (CTL) reaction to kill oral cancer (KB) cells. This CTL reaction is assisted by NLGP-mediated up-regulation of CD28 on T cells and HLA-ABC, CD80/86 on monocytes. CTL-mediated killing of KB cells and NK-cell-mediated killing of K562 (erythroleukemic) cells are associated with activation of these cells by NLGP. This activation is evidenced by increased expression of early activation marker CD69 with altered expression of CD45RO/CD45RA. NLGP is a strong inducer of IFNgamma from both T and NK cells; however, IFNgamma regulates the T-cell-mediated cytotoxicity only without affecting NK-cell-mediated one. Reason of this differential regulation may lie within up-regulated expression of IFNgamma-receptor on T-cell surface, not on NK cells. This NLGP-induced cytotoxicity is dependent on up-regulated perforin/granzyme B expression in killer cells, which is again IFNgamma dependent in T cells and independent in NK cells. Although, FasL expression is increased by NLGP, it may not be truly linked with the cytotoxic functions, as brefeldin A could not block such NLGP-mediated cytotoxicity, like, concanamycin A, a perforin inhibitor. On the basis of these results, we conclude that NLGP might be effective to recover the suppressed cytotoxic functions of NK and T cells from head and neck squamous cell carcinoma patients.Journal of immunotherapy (Hagerstown, Md.: 1997) 02/2009; 32(1):42-53. · 3.20 Impact Factor -
Chapter: Suppression of Suppressors: Neem leaf glycoprotein Guided Crosstalk Between Regulatory T cells and T cells/NK Cells/ Macrophages in Cancer
01/2009: pages 153-157;
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2006–2013
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Chittaranjan National Cancer Institute
Calcutta, Bengal, India
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