Browsing by Author "P. Deepak"

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Autologous Hsp70 immunization induces anti-tumor immunity and increases longevity and survival of tumor-bearing mice
(SAP - Slovak Academic Press, spol. s.r.o., 2009) S. Kumar; P. Deepak; A. Acharya
Heat Shock proteins 70 (Hsp70) is a family of highly conserved molecules that maintain the function of crucial cellular pathways during stress. Hsp70 derived from tumor cells is bound with tumor antigenic peptides from the diverse antigen cytosolic pool. Tumor-derived Hsp70 preparations after ex vivo administration permit antigen presenting cells (APCs) to present tumor antigen to their cell surface and induce tumor specific immunity in many types of malignancies by directly eliciting cytotoxic T-lymphocytes (CTL) response. In the present investigation, we have demonstrated that immunization with tumor cell derived Hsp70 lead to an effective survival advantage in mice with minimal residual tumor cells from which Hsp70 is derived, by involvement of immune cell types in the rejection of tumor in the Hsp70 immunized tumor-bearing host mice and their post-immunization cytokine repertoire. It has been observed that autologous Hsp70 induces specific anti-tumor immunity and effectively eradicates tumors in the host mice, thereby enhancing survival of tumor-bearing host. Immunization with tumor-derived autologous Hsp70 effectively primed specific CTL response and increased tumor cell lysis independently of CD4+ T-lymphocytes. Increase in type I cytokines in the serum of Hsp70 immunized mice was also observed that indicates its adjuvant property in the host. Furthermore, Hsp70 immunized mice did not show any systemic disorder. Therefore, it could be assumed as safe and might be clinically useful for vaccination against malignant human tumors.
Gender variation in interleukin-13 production: A possible mechanism of differential in vivo growth of a T-cell lymphoma
(2008) P. Deepak; S. Kumar; A. Acharya
Interleukin (IL)-13 is a TH2 type of cytokine that plays a crucial role in the pathophysiology of different type of infections, autoimmune diseases and malignancies. It has been shown to dampen the TH1 type of immune responses and favours tumour growth. In the present investigation, we have determined IL-13 level in serum and ascitic fluid in both the sexes of BALB/c strain of mice bearing a T-cell lymphoma of spontaneous origin, designated as Dalton's Lymphoma (DL). Further, we have studied the involvement of gender hormones on the IL-13 level and NKT-cell production of IL-13. It has been observed that there exists a gender variation or gender dimorphism in the IL-13 production. IL-13 level in serum is directly correlated with in vivo progressive growth of DL cells. We observed a tendency in female DL-bearing mice to have higher serum IL-13 level and faster growth of DL cells. This study, therefore, indicates that sex hormones are directly involved in the differential production of IL-13 that may be a factor responsible, at least in part, for the differential in vivo progressive growth of a T-cell lymphoma. © 2008 The Authors.
Heat Shock Proteins (HSP): Future trends in cancer immunotherapy
(Biolife, 2006) P. Deepak; S. Kumar; Arbind Acharya
Heat Shock Proteins (HSPs) are a large family of highly conserved proteins involved in assisting protein folding and unfolding in the cells. HSPs are expressed constitutively as well as inducibly and, interacting with antigen presenting cells, induce the expression of various cytokines and chemokines as well as the maturation and migration of dendritic cells, thus acting themselves as cytokines. HSP-chaperoned antigenic peptides are also generated within the tumor cells. Such chaperoned peptides are released in the extra cellular medium with an association of HSPs by cell stress, death or tumor cell lyses. HSP-peptide complexes from extra cellular medium are taken up by antigen presenting cells through CD91 receptor and are represented or cross-presented by their MHC class I molecules for specific anti-tumor immune response. In addition, HSPs expressed on the cell surface of tumor cells stimulate αβ T-cells and γδ T-cells as well as natural killer (NK) cells that are first-line defense mechanisms. In this manner, HSPs have the ability to stimulate both arms of the effecter mechanism of the immune system. These unique immunological attributes of HSPs are presently becoming the basis for tumor immunotherapy. Tumor-derived HSP-peptide complexes have been demonstrated to serve as anti-tumor vaccines. To date various approaches of vaccination using HSPs have been developed and tested clinically. These HSP-based vaccine approaches can be combined with hyperthermia and CTLA-4 blockade to enhance their anti-tumor potentiality. Copyright © by BIOLIFE, s.a.s.
Hsp70 induces Th1 polarization through tumor-associated macrophages in a T-cell lymphoma
(SAP - Slovak Academic Press, spol. s.r.o., 2007) S. Kumar; P. Deepak; A. Acharya
Tumor progression produces immunoregulatory phenotype of macrophages in tumor bearing host (TBH), that mediate immunosuppression through increased production of soluble factors. These factors obviously suppress the T-cell responsiveness and underproduction of Th1-polarizing cytokines. Here, we reported that in vitro treatment of TAMs with autologous Hsp70 purified from DL-bearing mice reverse back the tumor induced macrophage suppressor activity, suggesting that Hsp70 can restore TAMs production of Th1-polarizing cytokines. LPS stimulation failed to overcome tumor-induced dysregulation of IL-1, IL-12, IL-15 and IFN-γ production. In contrary, Hsp70 significantly enhanced IL12, IL-15, IL-1 and IFN-γ production by TAMs in vitro and in vivo, but also enhanced the LPS and IFN-γ responsiveness of TAMs. These Th1 polarizing effects of cytokines of TAMs are dose dependent and reach the maximal values at 24 hrs of incubation. Though, we found a significant release of IFN-γ in TAMs without T-cells, and increased level of IFN-γ with T-cells suggests that Hsp70 stimulates T-cells. Summarizing, these data demonstrates that Hsp70 restore Th1 polarizing cytokines production in the TBH and thus ascribe a possibility to develop a novel immunotherapeutic regime by using TAMs that could contribute well to the correction of tumor induced immune dysfunction.
HSP70 modulates the enhanced production of reactive intermediate metabolites and a proinflammatory cytokine TNF-α in a T cell lymphoma
(Biolife, 2006) S. Kumar; P. Deepak; Arbind Acharya
Heat shock proteins are intracellular soluble proteins expressed consecutively in an cells. They are immunogenic proteins able to activate antigen-presenting cells by binding through the CD91 receptor and activate both CD4+ and CD8+ T-cells. Macrophage plays a pivotal role in innate immune response and secretes a number of regulatory molecules upon activation. In the present study, we investigate the activation of normal and tumor-associated macrophage to produce the effector molecules which have a role in immunomodulation, especially in the killing of the transformed or tumor cells. In vitro and in vivo treatment of NMO and TAMs (from T-Cell Lymphoma) with optimum dose 10 μg of hsp70 produce effector molecules such as nitric oxide (NO), hydrogen peroxide (H2O2) and tumor necrosis factor-α (TNF α). The results of our experiments reveal that the production of effector molecules is dose-dependent, and the result of immunoblots also confirms the increased expression of iNOS. These findings suggest that autologous hsp70 are highly immunogenic and potent activating agents for the enhanced production of effector molecules in NMO and TAMs in a T-cell lymphoma. Copyright © by Biolife, s.a.s.
IL-13 neutralization modulates function of type II polarized macrophages in vivo in a murine T-cell lymphoma
(Biolife, 2007) P. Deepak; S. Kumar; Arbind Acharya
IL-13 is a Th2 cytokine that suppresses the effector function and alters the phenotype and function of macrophages switching to alternatively activated or type II polarized macrophages. The type II polarized macrophages or M2 phenotype differ from normal macrophages greatly in terms of receptor expression, cytokine and NO production, that show tumor promoting function rather than tumoricidal function of classically activated macrophages. The chemokines CCL-22 and CCL-17 produced by either tumor cells or alternatively activated macrophages attract Th2 cells preferentially, which increase the local concentration of Th2 cytokines including IL-13 that further skewed the normal phenotype of macrophages at the site of the tumor micro-environment. Therefore, it is possible to restore the phenotype and function of alternatively activated macrophages by eliminating or blocking the activities of these cytokines. In the present investigation, we show that by blocking the activity/signaling of one of its major constituents IL-13, the iNOS expression and correspondingly NO production increases. The observation signifies its efficacy towards a novel approach for cancer therapy by modulating the function of tumor-associated macrophages (TAM) in vivo for the first time. Copyright © by Biolife, s.a.s.
IL-13 Rα2-mediated interleukin-13 neutralization represses in vivo progressive growth of a T-cell lymphoma
(2007) P. Deepak; K. Sanjay; A. Acharya
Dalton's lymphoma (DL) is a T-cell lymphoma of spontaneous origin, characterized by highly invasive and malignant nature, killing the host in a very short period of life span. DL-bearing host is reflected by very high titer of IL-13 in serum. Therefore, we hypothesized that over expression of IL-13 may greatly affect the growth of DL-cells in a tumor-bearing host. In this study, to assess the involvement of IL-13 in DL-cell progression, we have blocked the IL-13 activity/signalling by the systemic delivery of non-signaling decoy receptor IL-13 Rα2, and IL-13 level vs DL-cell proliferation were measured. We observed that systemic delivery of IL-13 Rα2 inhibits the DL-cell progression in much extent and enhances the survival and longevity of DL-bearing mice. Further, this study re-inforce the therapeutic advantage of IL-13 Rα2 in a T-cell lymphoma tumor system.
Interleukin-13 induces T helper type 2 immune responses in OVA-immunized BALB/c mice bearing a T cell lymphoma
(2012) P. Deepak; A. Acharya
T lymphocytes play a crucial role in the regulation of immune responses against the tumour cells. Tumour progression results in dysfunction and inhibition of T cells, which ultimately leads to impairment in the antitumour immune response. The impaired antitumour immune response in the host is represented by the decreased number of T cells and their incomplete and improper function. The immunosuppressive network in tumour-bearing host mediated by tumour cells also leads to the inequities of T cell subsets and imbalance of Th1/Th2 dichotomy. Therefore, in the present study, we sought to investigate the role of tumour progression in the development of T cell phenotype and the involvement of interleukin-13 thereof selecting Dalton's lymphoma (DL) as a tumour model. It was observed that a significant increase in the number of CD4 + T cell population, whereas a significant decline in the CD8 + T cells among lymphoid cell population of OVA-immunized DL-bearing BALB/c mice occurs. Similar observation was found following the administration of IL-13 to the normal healthy mice. It was further confirmed that expansion in Th2 type cells among CD4 + T cell population occurs following the progression of tumour and administration of IL-13 to normal healthy mice by an yet to define mechanism. Therefore, it can be concluded that IL-13 has immense role in polarizing the immune responses by inducing the differentiation of Th2 type of cells. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.
Interleukin-13-induced type II polarization of inflammatory macrophages is mediated through suppression of nuclear factor-κB and preservation of IκBα in a T cell lymphoma
(2007) P. Deepak; S. Kumar; A. Acharya
Spontaneously arising transplantable T cell lymphoma, designated as Dalton's lymphoma (DL), is characterized by a highly invasive and deleterious nature almost completely paralysing the host immune system. The level of interleukin (IL)-13 is elevated in serum and ascitic fluid of the DL-bearing host. IL-13 is a potent immunosuppressive cytokine and is an alternative activator of macrophages that suppresses the production of nitric oxide (NO) and expression of inducible nitric oxide synthase (iNOS), and proinflammatory cytokines. The expression of iNOS and proinflammatory cytokines are dependent largely upon the activation of nuclear factor-κB (NF-κB). Activation of NF-κB involves the degradation of cytoplasmic inhibitor IκBα, allowing the nuclear translocation of NF-κB and thereby transcription of the iNOS gene. Therefore, in this study we sought to determine whether the alternative activation or type II polarization of macrophages induced by IL-13 is mediated by the suppression of NF-κB and cytoplasmic preservation of IκBα. Western blot analysis and electrophoretic mobility shift assay (EMSA) indicate that tumour-associated macrophages (TAM) or polarized type II macrophages are due to preserved protein expression of IκBα, and therefore suppressed NF-κB nuclear translocation. These findings suggest that IL-13 may operate through the suppression of NF-κB activation and preservation of IκBα. © 2007 British Society for Immunology.
Morphological effects of autologous hsp70 on peritoneal macrophages in a murine T cell lymphoma
(IOS Press BV, 2013) P.K. Gautam; S. Kumar; P. Deepak; A. Acharya
Heat shock protein 70 is highly conserved cytosolic protein which have important role in growth, development, and apoptosis. Hsp70 is well-known activator of macrophages and enhances the release of specific and non-specific effector molecules that have major role in tumor destruction and immunopotentiation of host. However, morphological effects of hsp 70 has not been carried out, therefore, morphological effects of hsp 70 on murine peritoneal macrophages were examined by light microscopy and scanning electron microscopy. Thioglycolate-induced peritoneal macrophages were prepared from BALB/c mice and cultured for 24 h in the presence of the hsp70. Tumor-associated macrophages treated with 10 μg/ml were varied in shape, mostly spindle shaped, i.e., stretched bidirectionally; surface ruffles were increased and their lamellipodia was prominent which suggest that hsp 70 treatment not only enhances the functional state of the peritoneal macrophages but also initiate immense morphological changes leading to increased endothelium adherence, increased antigen uptake, and increased migration to the inflammatory site. © 2013 International Society of Oncology and BioMarkers (ISOBM).
Role of macrophage in tumor microenvironment: Prospect in cancer immunotherapy
(Biolife s.a.s., 2013) P.K. Gautam; P. Deepak; S. Kumar; A. Acharya
Current evidence suggests an increasing role of macrophages in inflammation and tumor progression. Most tumors contain an abundant number of macrophages as a major component of their leukocyte infiltrate, which co-exist with tumor cells at the tumor microenvironment. Upon activation with soluble tumor antigens, macrophages release a distinct repertoire of growth factor, cytokines, chemokines and enzymes that inhibit growth of the tumor. However, the anti-tumor immune response induced by macrophages does not always ensue. Tumor cells themselves are capable of down-regulating macrophage phenotype and functions and anti-tumor immune responses in the tumor-bearing host. The present review aims to elucidate the role of macrophages in tumor growth and progression, invasion, metastasis, and angiogenesis at the site of tumor growth. Moreover, the effect of tumor microenvironment on the phenotype and function of macrophages, which are altered due to the continuous exposure of various soluble and non-soluble tumor promoting factors secreted by tumor cells, and implication of macrophages in cancer immunotherapy have been discussed in detail. Copyright © by BIOLIFE, s.a.s.