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Biomedical subjects

Dominik Wodarz

Publications and source records attributed to Dominik Wodarz.

29 records · Page 2Linked to original sources
PubMed2003

Evolution of immunological memory and the regulation of competition between pathogens.

Memory is a central characteristic of immune responses. It is defined as an elevated number of specific immune cells that remain after resolution of infection and can protect the host against reinfection. The evolution of immunological memory is subject to debate. The advantages of memory discussed so far include protection from reinfection, control of chronic infection, and the transfer of immune function to the next generation. Mathematical models are used to identify a new force that can drive the evolution of immunological memory: the duration of memory can regulate the degree of competition between different pathogens. While a long duration of memory provides lasting protection against reinfection, it may also allow an inferior pathogen species to persist. This can be detrimental for the host if the inferior pathogen is more virulent. On the other hand, a shorter duration of memory ensures that an inferior pathogen species is excluded. This can be beneficial for the host if the inferior pathogen is more virulent. Thus, while in the absence of pathogen diversity memory is always expected to evolve to a long duration, under specific circumstances, memory can evolve toward shorter durations in the presence of pathogen diversity.

Biological Evolution↗
PubMed2003

A dynamical perspective of CTL cross-priming and regulation: implications for cancer immunology.

Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such as viral infections and tumors. At the same time, they can cause disease when induced inappropriately. Which factors regulate CTL and decide whether they should remain silent or react is open to debate. The phenomenon called cross-priming has received attention in this respect. That is, CTL expansion occurs if antigen is recognized on the surface of professional antigen presenting cells (APCs). This is in contrast to direct presentation where antigen is seen on the surface of the target cells (e.g. infected cells or tumor cells). Here we introduce a mathematical model, which takes the phenomenon of cross-priming into account. We propose a new mechanism of regulation which is implicit in the dynamics of the CTL: According to the model, the ability of a CTL response to become established depends on the ratio of cross-presentation to direct presentation of the antigen. If this ratio is relatively high, CTL responses are likely to become established. If this ratio is relatively low, tolerance is the likely outcome. The behavior of the model includes a parameter region where the outcome depends on the initial conditions. We discuss our results with respect to the idea of self/non-self discrimination and the danger signal hypothesis. We apply the model to study the role of CTL in cancer initiation, cancer evolution/progression, and therapeutic vaccination against cancers.

Animals↗
PubMed2003

Boosting immunity by antiviral drug therapy: a simple relationship among timing, efficacy, and success.

Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

Antiviral Agents↗
PubMed2003

Gene therapy for killing p53-negative cancer cells: use of replicating versus nonreplicating agents.

Research has focused on the use of viral vectors to attack p53-negative cancer cells. Such agents may be nonreplicating, whereas others are replicating. This paper uses mathematical models to study the conditions under which therapy can lead to tumor remission. It is found that the optimal characteristics of the vector can be quite different depending on whether the virus replicates or not. If it does not replicate, the rate of virus-induced tumor cell killing should be maximized. If the virus does replicate, the rate of virus-induced cell killing should be kept small. If the virus is too lytic in cancer cells, viral spread is compromised, resulting in persistence of both virus and tumor. This has important implications for choosing the correct techniques to evaluate replicating viruses in culture. A low multiplicity of infection must be used for evaluation, because this mimicks the spread of the virus through an established tumor. If a high multiplicity of infection is used, the virus that appears most efficient in this evaluation can be least efficient at eradicating the cancer in vivo. Theoretical results are discussed in the context of experimental data.

Animals↗
PubMed2003

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses.

This paper investigates the role of CTL and antibody responses in hepatitis C virus (HCV) dynamics and pathology. Mathematical models suggest that a strong CTL response is required for resolution of HCV infection and that a weak CTL response can result in persistent infection. According to the model, establishment of persistent infection is accompanied mainly by an ongoing antibody response, while CTLs are not maintained at high levels. In the model, this outcome correlates with absence of pathology. Persistent infection in the face of an ongoing antibody response can result in evolution of antigenic escape. According to the model, evolution towards escape from antibodies can shift the balance of immune responses so that the weak CTL levels become increasingly more dominant relative to antibodies. This shift results in onset of liver pathology as the virus evolves towards increased levels of antigenic escape. Therefore, the relative balance of the immune response can be a decisive factor that determines whether patients are asymptomatic or whether pathology is observed. Virus evolution can shift this balance towards pathology over time. Theoretical results are discussed in the context of published data.

Acute Disease↗
PubMed2003

Quantitative analysis of long-term virus-specific CD8+-T-cell memory in mice challenged with unrelated pathogens.

The consequences for the long-term maintenance of virus-specific CD8+-T-cell memory have been analyzed experimentally for sequential respiratory infections with readily eliminated (influenza virus) and persistent (gammaherpesvirus 68 [gammaHV68]) pathogens. Sampling a broad range of tissue sites established that the numbers of CD8+ T cells specific for the prominent influenza virus D(b)NP(366) epitope were reduced by about half in mice that had been challenged 100 days previously with gammaHV68, though the prior presence of a large CD8+ D(b)NP366+ population caused no selective defect in the gammaHV68-specific CD8+ K(b)p79+ response. Conversely, mice that had been primed and boosted to generate substantial gammaHV68-specific CD8+ D(b)p56+ populations did not show any decrease in prevalence for this set of CD8+ memory cytotoxic T lymphocytes (CTL) at 200 days after respiratory exposure to an influenza A virus. However, in both experiments, the total magnitude of the CD8+-T-cell pool was significantly diminished in those that had been infected with gammaHV68 and the influenza A virus. The broader implications of these findings, especially under conditions of repeated exposure to unrelated pathogens, are explored with a mathematical model which emphasizes that the immune effector and memory "phenome" is a function of the overall infection experience of the individual.

Animals↗
PubMed2003

Mathematical models of HIV and the immune system.

I describe how mathematical models have been used to elucidate the principles which govern HIV and immune system dynamics in relation to antiviral drug therapy. The review starts by introducing a basic model of virus infection and demonstrates how it was used to study HIV dynamics and to measure crucial parameters which lead to a new understanding of the disease process. Since this analysis indicates that eradication of the virus is not feasible during the lifetime of the patient, I continue to discuss mathematical models with the aim to explore how drug therapy can be used to induce long-term immunological control of the infection.

Allergy and Immunology↗
PubMed2002

Mathematical models of HIV pathogenesis and treatment.

We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long-term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long-term non-progression.

Algorithms↗
PubMed2002

The importance of lytic and nonlytic immune responses in viral infections.

Antiviral immune effector mechanisms can be divided broadly into lytic and nonlytic components. We use mathematical models to investigate the fundamental question of which type of response is required to combat different types of viral infection. According to our model, the relative roles of the two types of component depend on the cytopathicity of the virus relative to its rate of replication. If the viral cytopathicity is low relative to the rate of viral replication, the model predicts that a combination of lytic and nonlytic effector mechanisms is likely to be required to resolve the disease, particularly if the virus replicates at a fast rate. By contrast, if viral cytopathicity is high relative to the replication rate of the virus, then lytic and nonlytic mechanisms can, in principle, resolve the infection independently. We discuss our findings in the context of specific viral infections and use our model to interpret empirical data.

Animals↗
PubMed2002

Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice.

The primary influenza A virus-specific CD8(+)-T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A(b+/+) and CD4(+)-T-cell-deficient I-A(b-/-) mice. Comparable levels of virus-specific cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4(+) subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A(b-/-) mice. Thus, though the capacity to mediate the CD8(+)-T-cell effector function is broadly preserved in the absence of concurrent CD4(+)-T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.

Animals↗