Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Aptamer-based therapeutics and their potential in radiopharmaceutical design

Aptamers, short, single stranded oligonucleotide entities, have been developed in the past 15 years against a plethora of targets and for a variety of applications. These range from inhibition of receptors and enzymes to the identification of small molecules in sensor applications, and from the development of targeted therapeutic to the design of novel diagnostic and imaging agents. Furthermore, aptamers have been designed for targets that cover a wide range of diseases, from HIV to tropical diseases, cancer and inflammation. Their easy development and flexibility of use and manipulation, offers further potential. In this paper we review their selection and consider some of the recent applications of aptamers in the design of radiopharmaceuticals for the targeted radiotherapy and medical imaging of disease

On the Aging Dynamics in an Immune Network Model

Recently we have used a cellular automata model which describes the dynamics of a multi-connected network to reproduce the refractory behavior and aging effects obtained in immunization experiments performed with mice when subjected to multiple perturbations. In this paper we investigate the similarities between the aging dynamics observed in this multi-connected network and the one observed in glassy systems, by using the usual tools applied to analyze the latter. An interesting feature we show here is that the model reproduces the biological aspects observed in the experiments during the long transient time it takes to reach the stationary state. Depending on the initial conditions, and without any perturbation, the system may reach one of a family of long-period attractors. The pertrubations may drive the system from its natural attractor to other attractors of the same family. We discuss the different roles played by the small random perturbations (noise) and by the large periodic perturbations (immunizations)

The Symmetrical Immune Network Theory and a New HIV Vaccine Concept

The symmetrical immune network theory is based on Jerne’s network hypothesis. An improved version of the theory is presented. The theory is characterized by symmetrical stimulatory, inhibitory and killing interactions between idiotypic and antiidiotypic immune system components. In this version killing is ascribed to IgM antibodies, while IgG antibodies are stimulatory. In the symmetrical immune network theory T cells make specific T cell factors, that have a single V region, and are cytophilic for non-specific accessory cells (A cells, including macrophages and monocytes) and play a role in the system switching between stable steady states. A recurring theme in the theory is the concept of co selection. Co-selection is the mutual positive selection of individual members from within two diverse populations, such that selection of members within each population is dependent on interaction with (recognition of) one or more members within the other population. Prior to exposure to an antigen, antigen-specific and antiidiotypic T cells are equally diverse. This equality is a form of symmetry. Immune responses with the production of IgG involve co selection of the antigen-specific and antiidiotypic classes with the breaking of this diversity symmetry, while induction of unresponsiveness involves co-selection without the breaking of diversity symmetry. The theory resolves the famous I-J paradox of the 1980s, based on co selection of helper T cells with some affinity for MHC class II and suppressor T cells that are anti-anti-MHC class II. The theory leads to three experimentally testable predictions concerning I-J. The theory includes a model for HIV pathogenesis, and suggests that polyclonal IgG from many donors given in immunogenic form may be an effective vaccine for protection against infection with HIV. Surprisingly, a mathematical model that simulates the autonomous dynamics of the system is the same as one that models a previously described neural network

Origin of lymph node-derived lymphocytes in human hepatic allografts

Hepatic allograft-derived lymph nodes were examined in the post-transplant period on order to determine the origin of lymphocytes and structural elements of the lymph node. Histologic assessment and immunohistochemical studies verified that T-cell infiltration of donor lymph nodes by recipient-derived lymphocytes occurred early in the post-transplant period. These T cells bore T-cell activation markers, e.g. TAC receptor and HLA-DR antigens. In addition, functional analysis demonstrated alloreactive T cells in secondary proliferation assays. The pattern of alloreactivity in these assays was dependent upon the phenotypic make-up (and therefore origin) of the lymphocytes within the lymph node. A gradual shift in predominance of donor-derived lymphocytes to recipient-derived lymphocytes occurred, but even late in the post-transplant course the stromal elements and a residium of lymphocytes within the lymph nodes continued to bear donor HLA antigens. The possible role of these 'passenger' lymphocytes in allograft immunity is discussed