Modulation Of Neutrophil Motility By Curcumin: Implications For Inflammatory Bowel Disease.
Source: Inflammatory Bowel Diseases
BACKGROUND:<br>Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration.<br><br>METHODS:<br>We investigated the effect of curcumin on mouse and human neutrophil polarization and motility in vitro and in vivo.<br><br>RESULTS:<br>Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1β, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis. Curcumin-mediated inhibition of PMN motility could be attributed to a downregulation of PI3K activity, AKT phosphorylation, and F-actin polymerization at the leading edge. The inhibitory effect of curcumin on neutrophil motility was further demonstrated in vivo in a model of aseptic peritonitis.<br><br>CONCLUSIONS:<br>Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis.<br><br>
Allogeneic Effector/Memory Th 1 Cells Impair Fox P3+ Regulatory T Lymphocytes And Synergize With Chaperone Rich Cell Lysate Vaccine To Treat Leukemia.
Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.<br><br>
Personalized Dendritic Cell Based Tumor Immunotherapy.
Advances in the understanding of the immunoregulatory functions of dendritic cells (DCs) in animal models and humans have led to their exploitation as anticancer vaccines. Although DC-based immunotherapy has proven clinically safe and efficient to induce tumor-specific immune responses, only a limited number of objective clinical responses have been reported in cancer patients. These relatively disappointing results have prompted the evaluation of multiple approaches to improve the efficacy of DC vaccines. The topic of this review focuses on personalized DC-based anticancer vaccines, which in theory have the potential to present to the host immune system the entire repertoire of antigens harbored by autologous tumor cells. We also discuss the implementation of these vaccines in cancer therapeutic strategies, their limitations and the future challenges for effective immunotherapy against cancer.<br><br>
Killer Dendritic Cells And Their Potential For Cancer Immunotherapy.
Source: Cancer Immunology, Immunotherapy : Cii
Known for years as the principal messengers of the immune system, dendritic cells (DC) represent a heterogeneous population of antigen presenting cells critically located at the nexus between innate and adaptive immunity. DC play a central role in the initiation of tumor-specific immune responses as they are endowed with the unique ability to take up, process and present tumor antigens to naïve CD4(+) or CD8(+) effector T lymphocytes. By virtue of the cytokines they produce, DC also regulate the type, strength and duration of T cell immune responses. In addition, they can participate in anti-tumoral NK and NKT cell activation and in the orchestration of humoral immunity. More recent studies have documented that besides their primary role in the induction and regulation of adaptive anti-tumoral immune responses, DC are also endowed with the capacity to directly kill cancer cells. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. First, the direct killing of malignant cells by DC may foster the release and thereby the immediate availability of specific tumor antigens for presentation to cytotoxic or helper T lymphocytes. Second, DC may participate in the effector phase of the immune response, potentially augmenting the diversity of the killing mechanisms leading to tumor elimination. This review focuses on this non-conventional cytotoxic function of DC as it relates to the promotion of cancer immunity and discusses the potential application of killer DC (KDC) in tumor immunotherapy.<br><br>