Killer cell dynamics. Mathematical and computational approaches to immunology. (Q852301): Difference between revisions

The immune system is one of the most complicated organs of higher organisms, whose function is to fight off pathogenic organisms that enter and grow within the host. This book concentrates on a particular branch of the immune system: killer T cells (CTL) which recognize infected cells and attack them, mostly in the context of viruses. The text focuses on important questions about the dynamics of immune responses: What are the principles that underlie the functioning of immune responses? How do immune responses successfully clear infections and when do they fail? How can weak immune responses be boosted by treatment? The purpose is to review how mathematical and computational approaches can be useful to understand the way killer T cell responses work to fight viral infections, demonstrating that such approaches are most valuable when coupled with experimental work. Such complex issues are analyzed with the help of classical mathematical models for population dynamics, which are applied to describe the in vivo interactions between viruses and the immune system. These models for competition and predator-prey interactions are formulated as nonlinear systems of ordinary differential equations for the population densities of viruses and CTL. They range from very simple and phenomenological to more complicated models that try to capture many biological details explicitly. This range also represents the development of these models over time, as more and more biological information has became available from experimental research. A given virus consists of many parts, called epitopes, that can all be recognized by several different CTL. Consequently there are multiple CTL clones that fight the same virus population, and the relative abundance of these different CTL is called immunodominance. On the other hand, specific immune system interactions should not be considered in isolation, but heterologous infections can activate and diminish previously established CTL memory in a nonspecific manner through bystander effects. Particular mathematical models for these interactions suggest that this negative effect is mediated directly through the new virus population and not through competition between the different CTL responses. Once the host has been exposed to too many infections, the overall capability of the CTL are reduced, until the CTL populations collapse and fail to fight any infection successfully. A major mechanism by which CTL fight viruses is the lysis or killing of infected cells which, if many cells are infected, can lead to a significant amount of tissue damage, called CTL induced pathology, even resulting in the death of the host. A mechanism other than lysis exists: CTL can secrete soluble factors that bind to infected cells, the so-called nonlytic activity. The relative role of lytic versus nonlytic activities can be analyzed through a mathematical model in which cytopathic and noncytophatic viruses are defined in terms of the values of the different parameters of the model. The relevance of both mechanisms for resolving the infection depends on the viral cytopathicity relative to the rate of viral replication, which can be characterized by a threshold value depending on some values of these parameters. On the other hand, the balance between lytic and nonlytic responses is influenced by the competition between CTL and B cells which produce antibodies and proliferate in response to stimulation by the same virus. This balance can in turn determine whether the immune system deals with a pathogen successfully, or whether pathology is observed. An application of mathematical models to HCV infection shows how the competition between CTL and antibodies might determine the course of infection and how escape from antibodies during chronic infection could shift the dynamics from an asymptomatic to a pathogenic state. Viruses have the ability to avoid clearance in a variety of ways, like mutations of epitopes or establishment of latent infections. An alternative strategy is to impair the functionality of the CTL response itself. A major mechanism by which this can be achieved is the infection and killing of the so-called CD4T helper cells (whose specific role in the immune system is described in Chapter 4). If CD4T cell help is impaired, the host fails the mount effective CTL or antibody responses against the pathogen. Mathematical models to describe this mechanism are reviewed in Chapter 11, together with applications to SIV/HIV infections. These models can be used to explore coceptual therapy regimes that can result in reversal of immune impairment and control of immunosuppresive infections. It is a particularly desirable outcome with persistant human infections, like HIV, because drug therapy results in severe side effects and is difficult to tolerate. The book ends with Chapter 13 introducing the evolutionary aspects of immunity. As it is a large subject which includes a variety of topics, the book concentrates on one particular aspect: the way the immune responses influence the coevolution between pathogens and their hosts' immune system in the context of immunological memory, which is a central characteristic of the immune system; a host is protected more efficiently against a second infection if it has previously been infected with the same pathogen and survived the infection. A simple mathematical model developed in Chapter 3 gives rise to the new finding that in addition to protection against secondary challenges, memory can be required for the resolution of primary infections. Impairment of memory can be a decisive defect in CTL responses that could account for persistent and productive infections, and which has been applied to HIV infections in Chapters 11 and 12. Summing up, the book provides an introduction to the field of mathematical immunology and an overview together a broad variety of immunological topics. This text is intended for an interdisciplinary audience, and it is written in a way such that experimental immunologists and virologists should be able to understand the arguments and to see the biological implications of the theory. An interesting text which might be a good complement to this book is that of \textit{M. A. Nowak} and \textit{R. M. May}, Virus dynamics. Mathematical principles of immunology and virology. (2000; Zbl 1101.92028).