The Immune Response to Melanoma Is Limited by Thymic Selection of Self-Antigens

The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE−/− mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4+ and MAA-specific CD8+ T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8+ T cell frequencies in AIRE−/− mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8+ T cells were found in both AIRE−/− and AIRE+/+ mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies

Impact of the Food Additive Titanium Dioxide (E171) on Gut Microbiota-Host Interaction

The interaction between gut microbiota and host plays a central role in health. Dysbiosis, detrimental changes in gut microbiota and inflammation have been reported in non-communicable diseases. While diet has a profound impact on gut microbiota composition and function, the role of food additives such as titanium dioxide (TiO2), prevalent in processed food, is less established. In this project, we investigated the impact of food grade TiO2 on gut microbiota of mice when orally administered via drinking water. While TiO2 had minimal impact on the composition of the microbiota in the small intestine and colon, we found that TiO2 treatment could alter the release of bacterial metabolites in vivo and affect the spatial distribution of commensal bacteria in vitro by promoting biofilm formation. We also found reduced expression of the colonic mucin 2 gene, a key component of the intestinal mucus layer, and increased expression of the beta defensin gene, indicating that TiO2 significantly impacts gut homeostasis. These changes were associated with colonic inflammation, as shown by decreased crypt length, infiltration of CD8+ T cells, increased macrophages as well as increased expression of inflammatory cytokines. These findings collectively show that TiO2 is not inert, but rather impairs gut homeostasis which may in turn prime the host for disease development

T-cell mediated immune responses after murine cytomegalovirus infection

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The impact of regulatory T cells on carcinogen-induced sarcogenesis

Burnet proposed in the 1950's that the immune system is engaged in identifying and destroying abnormal cancerous cells. This process, termed immune surveillance, has been at the centre of intense debate for decades. Results using immunodeficient mice lend support to the immune surveillance hypothesis. We surmised that immune surveillance would be hampered by the inhibitory effect of naturally occurring FoxP3(+) regulatory T cells, a population of T cells shown to be present at an increased frequency in a variety of human tumours. The carcinogen, methylcholanthrene was injected subcutaneously into mice and the steady development of fibrosarcomas was observed over approximately 200 days. These fibrosarcomas were strikingly infiltrated with FoxP3(+) regulatory T cells implying that these cells impinge upon immune-mediated rejection of the tumour. This was confirmed by partial ablation of FoxP3(+) regulatory T-cell activity, which resulted in a marked reduction in tumour incidence. The reduction of tumour incidence was ablated in mice that lacked interferon gamma. These data offer strong support for the concept of immune surveillance and indicate that this process is limited by the inhibitory effect of FoxP3(+) regulatory T cells

Dynamics of killer T cell inflation in viral infections

Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is characterized by a phase of expansion and contraction after which it settles at a relatively stable memory level. Recently, experimental data from mice infected with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After acute infection had resolved, some antigen specific CTL started to expand over time despite the fact that no replicative virus was detectable. This phenomenon has been termed as ‘CTL memory inflation’. In order to examine the dynamics of this system further, we developed a mathematical model analysing the impact of innate and adaptive immune responses. According to this model, a potentially important contributor to CTL inflation is competition between the specific CTL response and an innate natural killer (NK) cell response. Inflation occurs most readily if the NK cell response is more efficient than the CTL at reducing virus load during acute infection, but thereafter maintains a chronic virus load which is sufficient to induce CTL proliferation. The model further suggests that weaker NK cell mediated protection can correlate with more pronounced CTL inflation dynamics over time. We present experimental data from mice infected with MCMV which are consistent with the theoretical predictions. This model provides valuable information and may help to explain the inflation of CMV specific CD8+T cells seen in humans as they age

Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs

Memory is a hallmark of immunity. Memory carried by antibodies is largely responsible for protection against reinfection with most known acutely lethal infectious agents and is the basis for most clinically successful vaccines. However, the nature of long-term B cell and antibody memory is still unclear. B cell memory was studied here after infection of mice with the rabies-like cytopathic vesicular stomatitis virus, the noncytopathic lymphocytic choriomeningitis virus (Armstrong and WE), and after immunization with various inert viral antigens inducing naive B cells to differentiate either to plasma cells or memory B cells in germinal centers of secondary lymphoid organs. The results show that in contrast to very low background levels against internal viral antigens, no significant neutralizing antibody memory was observed in the absence of antigen and suggest that memory B cells (i) are long-lived in the absence of antigen, nondividing, and relatively resistant to irradiation, and (ii) must be stimulated by antigen to differentiate to short-lived antibody-secreting plasma cells, a process that is also efficient in the bone marrow and always depends on radiosensitive, specific T help. Therefore, for vaccines to induce long-term protective antibody titers, they need to repeatedly provide, or continuously maintain, antigen in minimal quantities over a prolonged time period in secondary lymphoid organs or the bone marrow for sufficient numbers of long-lived memory B cells to mature to short-lived plasma cells

Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity.

Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector and regulatory T cells. However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T cell populations is not well understood. We found that antigen-specific T regulatory cells (Treg) were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of effector T cells. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified effector T cells over Tregs, dramatically increasing the antigen-specific T effector:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase effector T cell:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific effector T cells:Tregs in draining lymph nodes were associated with enhanced CD8+ T cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of pro-inflammatory Type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ effector T cell expansion over that of antigen-specific Tregs, tipping the effector T cell to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T cell populations, facilitating the rational design of more effective cancer vaccines

The Staphyloccous aureus Eap Protein Activates Expression of Proinflammatory Cytokines▿

The extracellular adhesion protein (Eap) secreted by the major human pathogen Staphylococcus aureus is known to have several effects on human immunity. We have recently added to knowledge of these roles by demonstrating that Eap enhances interactions between major histocompatibility complex molecules and human leukocytes. Several studies have indicated that Eap can induce cytokine production by human peripheral blood mononuclear cells (PBMCs). To date, there has been no rigorous attempt to identify the breadth of cytokines produced by Eap stimulation or to identify the cell subsets that respond. Here, we demonstrate that Eap induces the secretion of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) by CD14+ leukocytes (monocytes and macrophages) within direct ex vivo PBMC populations (note that granulocytes are also CD14+ but are largely depleted from PBMC preparations). Anti-intercellular adhesion molecule 1 (CD54) antibodies inhibited this induction and implicated a role for this known Eap binding protein in cellular activation. IL-6 and TNF-α secretion by murine cells exposed to Eap was also observed. The activation of CD14+ cells by Eap suggests that it could play a significant role in both septic shock and fever, two of the major pathological features of S. aureus infections

Traitements intensifs en médecine de famille : usage de pompes et systèmes de mesure en continu du glucose

Les dispositifs technologiques font partie de la médecine actuelle. Les pompes à insuline, la mesure en continu du glucose (MCG) ainsi que les pompes à morphine sont présentées ici pour aider le médecin de famille à gérer ces différentes situations intensives. Les pompes à insuline externes et la MCG ont révolutionné la prise en charge du diabète sucré. Pourtant, leur utilisation demande une forte implication du patient, soit l'opposé d'une gestion automatisée du diabète. Les pompes à morphine sont une grande aide lorsque le patient en fin de vie ne peut plus avaler de comprimés ou lorsque l'absorption orale est aléatoire. Cet article résume les principes de fonctionnement de ces dispositifs technologiques, les problématiques communes et les situations à risque pour la pratique du médecin de premier recours