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Biomedical subjects

Dominik Wodarz

Publications and source records attributed to Dominik Wodarz.

At least 19 recordsLinked to original sources
PubMed2006

Ecological and evolutionary principles in immunology.

Experimental immunology has given rise to detailed insights into how immune cells react to infectious agents and fight pathogens. At the same time, however, the interplay between infectious agents and immune responses can be viewed as an ecological system in vivo. This is characterized by complex interactions between species of immune cells and populations of pathogens. This review discusses how an understanding of the immune system can be aided by the application of ecological and evolutionary principles: competition, predation, and the evolution of viruses in vivo. These concepts can shed light onto important immunological concepts such as the correlates of efficient virus control, immunodominance, the relationship between viral evolution and the development of pathology, as well as the ability of the immune system to control immunosuppressive infections.

Allergy and Immunology↗
PubMed2005

Effect of the CTL proliferation program on virus dynamics.

Experiments have established that CTLs do not require continuous antigenic stimulation for expansion. Instead, responses develop by a process of programmed proliferation which involves approximately 7-10 antigen-independent cell divisions, the generation of effector cells and the differentiation into memory cells. The effect of this program on the infection dynamics and the advantages gained by the program have, however, not been explored yet. We investigate this with mathematical models. We find that more programmed divisions can make virus clearance more efficient because CTL division continues to occur independent from antigenic stimulation when virus load drops to low levels. This results in stronger effector activity at low virus loads, and in a higher chance of virus extinction. On the other hand, the more programmed divisions occur, the less efficient the response is at preventing high acute virus loads and thus acute symptoms. The reason is that the programmed divisions are independent from antigenic stimulation, and an increase in virus load does not speed up the rate of CTL expansion. We hypothesize that the 7-10 programmed divisions observed in vivo represent an optimal solution to this trade-off which maximizes the chances to clear, while preventing excessive acute pathology. If the CTLs fail to clear the virus, however, we find that the properties of the programmed proliferation model are very similar to those derived from models which assume continuous antigenic stimulation. We discuss these results in the context of data from murine virus infections and explore implications for virus dynamics in CD4 helper-deficient hosts.

Animals↗
PubMed2005

Drug resistance in cancer: principles of emergence and prevention.

Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.

Antineoplastic Agents↗
PubMed2005

Dynamical interactions between multiple cancers.

Multiple tumors in a patient have the possibility to interact with each other, through the competition for new blood supply which is required for growth and progression (angiogenesis). The multiple tumors can be independent, multiple primary cancers. Alternatively, they can be metastases which originate from one primary tumor. This paper uses mathematical models to investigate such dynamical interactions between multiple cancers. We start with a model which describes the growth of a single angiogenic tumor, and then generalize this model to include multiple tumors which compete for circulating endothelial progenitor cells in order to build new blood vessels. We explore under which conditions multiple tumors can coexist, and when one tumor can exclude other tumors from growing. Based on this framework, we discuss the circumstances under which independent multiple primary tumors can arise. We further discuss the inefficiency of metastatic cells to grow successfully, and suggest an explanation for the occurrence of multiple metastases with an unknown primary cancer.

Humans↗
PubMed2005

Does programmed CTL proliferation optimize virus control?

CD8 T-cell or cytotoxic T-lymphocyte responses develop through an antigen-independent proliferation and differentiation program. This is in contrast to the previous thinking, which was that continuous antigenic stimulation was required. This Opinion discusses why nature has chosen the proliferation program and how it compares to continuous stimulation. Although the two mechanisms should not lead to significantly different dynamics during chronic infection, they do make a difference in acute infection. We argue that programmed proliferation is better at clearance, whereas continuous stimulation is better at limiting acute symptoms. The 7-10 programmed cell divisions observed in vivo might be an optimization of this trade-off. We also discuss the conditions under which the program does or does not require CD4 T-cell help for clearance.

Animals↗
PubMed2005

Emergence and prevention of resistance against small molecule inhibitors.

Small molecule inhibitors target specific metabolic pathways in tumor cells and are a promising class of drugs for the treatment of cancers. The best known example is the treatment of chronic myeloid leukemia (CML) with Gleevec. This is a small molecule inhibitor of the Bcr-Abl kinase which has been shown to drive the initiation and progression of CML. While treatment of early stage CML with Gleevec has been quite successful, later stages of the disease (blast crisis) are not successfully treated due to the emergence of drug resistant cells. It is therefore important to understand the principles according to which drug resistant cells evolve, so that we can design treatment strategies which aim to prevent the rise of resistant cells. Such evolutionary dynamics can be studied with mathematical models, and this article reviews such an approach. We address three specific questions: (i) Do resistant cells emerge before or after the start of therapy? (ii) How does the turnover rate of cancer cells influence the evolution of drug resistant cells? (iii) Can combination therapy be used to prevent drug resistance? We apply our model to the treatment of CML with Gleevec, in order to demonstrate how this mathematical framework can be applied to the treatment of a specific cancer with small molecule inhibitors.

Antineoplastic Agents↗
PubMed2004

Contrasting B cell- and T cell-based protective vaccines.

A substantial research effort is devoted to the development of vaccines based on T cells. Such a vaccine would provide a means to protect against infection with HIV and stop the current pandemic. Here we investigate the possibility to develop a protective T cell-based vaccine. We do this by means of a mathematical model which describes the dynamics of a pathogen and the immune system in the early stages of infection. We compare an immune response that is near immediate--as is the case for a humoral response--with that of a response in which the effector cells have to be formed from precursor cells--as occurs in T cell responses. The latter applies to a T cell-based vaccine. A near immediate response is associated with a threshold number of effector cells above which an infection cannot take hold. For a T cell-based vaccine this threshold increases with the amount of antigen the immune system is exposed to. For small initial doses, as one would naturally expect to occur, this gives rise to impractically large thresholds. Thus, although a T cell vaccine might work against a high dose exposure, it might fail when exposed against to a low-dose exposure. This limits, we argue, the efficacy of T cell-based vaccines.

AIDS Vaccines↗
PubMed2004

Checkpoint genes, ageing, and the development of cancer.

Mathematical models are used to examine the relationship between checkpoint competence, ageing, and the development of cancer. The models take into account the dynamics of healthy tissue, the dynamics of initial tumor growth, and the interactions between healthy tissue and tumor cells. Two types of behavior are found. (i) A reduction of checkpoint competence results in reduced ageing of tissue, but in faster development and progression of tumors. (ii) Reduced checkpoint competence results both in reduced ageing of tissue, and in a reduced incidence of tumors. The tumors which do become established, however, are predicted to progress at an accelerated rate. The models define the conditions under which this counter-intuitive finding is observed. One reason could be the relationship between checkpoint activity and the ability of the tissue environment to exert inhibitory effects on tumor cells. Checkpoints induce senescence in tissue cells, and this compromises their ability to suppress tumor growth. Reduced checkpoint competence leads to reduced tissue senescence, and this results in higher amounts of tumor inhibition. The theoretical work is discussed with respect to data from p53 mutant mice, which show both types of relationships suggested by the models. The models help to identify differences in the experimental protocols which could explain the seemingly contradictory observations.

Aging↗
PubMed2004

On the emergence of multifocal cancers.

Several tumors can exist as multiple lesions within a tissue. The lesions may either arise independently, or they may be monoclonal. The importance of multiple lesions for tumor staging, progression, and treatment is subject to debate. Here we use mathematical models to analyze the emergence of multiple, clonally related lesions within a single tissue. We refer to them as multi-focal cancers. We find that multifocal cancers can arise through a dynamical interplay between tumor promoting and inhibiting factors. This requires that tumor promoters act locally, while tumor inhibitors act over a longer range. An example of such factors may be angiogenesis promoters and inhibitors. The model further suggests that multifocal cancers represent an intermediate stage in cancer progression as the tumor evolves away from inhibition and towards promotion. Different patterns of progression can be distinguished: (i) If tumor inhibition is strong, the initial growth occurs as a unifocal and self contained lesion; progression occurs through bifurcation of the lesion and this gives rise to multiple lesions. As the tumor continues to evolve and pushes the balance between inhibition and promotion further towards promotion, the multiple lesions eventually give rise to a single large mass which can invade the entire tissue. (ii) If tumor inhibition is weaker upon initiation, growth can occur as a single lesion without the occurrence of multiple lesions, until the entire tissue is invaded. The model suggests that the sum of the tumor sizes across all lesions is the best characteristic which correlates with the stage and metastatic potential of the tumor.

Journal Article↗
PubMed2004

Immune responses and the emergence of drug-resistant virus strains in vivo.

The treatment of viral infections using antiviral drugs has had a significant public health benefit in the setting of human immunodeficiency virus (HIV) infection, and newly developed drugs offer potential benefits in the management of other viral infections, including acute self-limiting infections such as influenza and picornaviruses (including the rhinoviruses that are responsible for a large proportion of 'common colds'). A serious concern with such treatments is that they may lead to the selection of drug-resistant strains. This has been a significant problem in the case of HIV infection. Existing mathematical-modelling studies of drug resistance have focused on the interactions between virus, target cells and infected cells, ignoring the impact of immune responses. Here, we present a model that explores the role of immune responses in the rise of drug-resistant mutants in vivo. We find that drug resistance is unlikely to be a problem if immune responses are maintained above a threshold level during therapy. Alternatively, if immune responses decline at a fast rate and fall below a threshold level during treatment (indicating impaired immunity), the rise of drug-resistant mutants is more likely. This indicates an important difference between HIV, which impairs immunity and for which immune responses have been observed to vanish during treatment, and viral infections such as influenza and rhinoviruses, for which such immune impairment is not present. Drug resistance is much more likely to be a problem in HIV than in acute and self-limiting infections.

Drug Resistance, Viral↗
PubMed2004

The optimal rate of chromosome loss for the inactivation of tumor suppressor genes in cancer.

Many cancers are characterized by chromosomal instability (CIN). This phenotype involves the deletion and duplication of chromosomes or chromosome parts and results in a high degree of aneuploidy. The role of CIN for cancer progression is a very important, yet unresolved question. It has been argued that CIN contributes to cancer initiation because chromosome loss can unmask a mutated tumor suppressor (TSP) gene. At the same time, CIN is costly for the cell because it destroys the genome and therefore compromises clonal expansion. Here, we use mathematical models to determine whether CIN can accelerate the generation and expansion of TSP(-/-) cells in the context of this tradeoff. Comparing cells with different degrees of CIN, we find that the emergence and growth of TSP(-/-) cells is optimized if the rate of chromosome loss is of the order of 10(-3) to 10(-2). This result is very robust, is independent of parameter values, and coincides with experimental measures using colon cancer cell lines. However, if we consider all of the steps in the pathway, including the generation of the CIN phenotype from stable cells, then it turns out that the emergence and growth of TSP(-/-) cells is never accelerated by CIN. Therefore, CIN does not arise because it accelerates the accumulation of adaptive mutations. Instead, it arises for other reasons, such as environmental factors, and is subsequently fine-tuned by selection to minimize the time to further cancer progression by means of the inactivation of TSP genes.

Animals↗
PubMed2004

Apparent competition and recovery from infection.

We use mathematical models to analyse how the recovery rate from infection influences the fitness of a host in a setting of interspecific competition. We show that sub-optimal immunity against pathogens can be advantageous for the host in the presence of cross-species infection. Weaker immunity allows the parasite to be used as a biological weapon, and this increases the fitness of the host relative to a competitor. A parameter region is observed in which the outcome of competition depends on the initial conditions. We extend this model and consider the dynamics in a spatial setting and find that the outcome depends on the migration rate of the host species. At low migration rates, coexistence of the host species is possible across space. For higher migration rates, the host species characterized by a lower recovery rate can invade the territory of its competitor. Finally, we study these dynamics in an evolutionary setting. Although a lower recovery rate from infection can increase the competitive ability of a species, we find that evolution maximizes the recovery rate and minimizes parasite burden. The models presented are related to the concept of apparent competition, and our results are discussed in relation to both theoretical and empirical studies.

Animals↗
PubMed2004

Perforin and IFN-gamma do not significantly regulate the virus-specific CD8+ T cell response in the absence of antiviral effector activity.

Using gene-targeted mice we have investigated whether perforin and/or interferon-gamma exert a direct regulatory effect on the expansion and contraction of antigen-specific CD8(+) T cells following infection with a virus (vesicular stomatitis virus) which is not controlled through these molecular effector systems. Unlike what has been observed when these molecules are essential for pathogen clearance, neither molecule was found to play an important role in regulating the kinetics of the virus-specific CD8(+) T cell response in the absence of antiviral effector activity.

Animals↗
PubMed2003

Evolutionary dynamics of mutator phenotypes in cancer: implications for chemotherapy.

Genetic instability is a central characteristic of cancers. However, the selective forces responsible for the emergence of genetic instability are not clear. We use mathematical models to determine the conditions under which selection favors instability, and when stable cells are advantageous. We take into account the processes of DNA damage, repair, cell cycle arrest, mutation, and death. We find that the rate of DNA damage can play a major role in this context. In particular, an increase in the rate of DNA damage can reverse the relative fitness of stable and unstable cells. In terms of cancer progression, we find the following results. If cells have intact apoptotic responses, stable cells prevail if the DNA hit rate is low. A high DNA hit rate can result in the selection of genetically unstable cells. This has implications for the induction of tumors by carcinogens. On the other hand, if cells are characterized by impaired apoptosis, we observe the opposite. Genetic instability is selected for if the DNA hit rate is low. A high DNA hit rate can select against instability and result in the persistence of stable cells. We propose that chemotherapy can be used to reverse the relative fitness of stable and unstable cells, such that unstable cells are the inferior competitors. This could result in the competitive exclusion of progressing cancer cells.

Animals↗
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↗