The Role of Computational Models of the Immune System in Designing Vaccination Strategies

Mathematical and computational models are designed to improve our understanding of biological phenomena, to confirm/reject hypotheses, and to find points of intervention by altering the behavior of the studied systems. Here we describe the role of mathematical/computational models of the immune system. In particular, we analyze some examples of how mathematical modeling can contribute to finding optimal vaccination strategies. Indeed, computational modeling offers an intriguing opportunity from the theoretical point of view, and it will be of interest for clinically oriented investigators who wish to find optimal therapeutic strategies and for pharmaceutical industries that want to produce effective and successful drugs.     

New insights into mathematical modeling of the immune system

In order to understand the integrated behavior of the immune system, there is no alternative to mathematical modeling. In addition, the advent of experimental tools such as gene arrays and proteomics poses new challenges to immunologists who are now faced with more information than can be readily incorporated into existing paradigms of immunity. We review here our ongoing efforts to develop mathematical models of immune responses to infectious disease, highlight a new modeling approach that is more accessible to immunologists, and describe new ways to analyze microarray data. These are collaborative studies between experimental immunologists, mathematicians, and computer scientists.     

Analysis of the step response of the saccadic feedback: computational models

 We present results of theoretical analysis and computational simulations of two models of the saccadic burst generator: the Scudder model and the Jurgens model. We used the experimental paradigm of prolonged stimulation in monkey superior colliculus (SC) to compare the performance of the two models. We excluded the Scudder model since it was not capable of reproducing the experimentally observed staircase movements. We modified the Jurgens model by replacing the originally proposed feedback integrator with an active reset mechanism by a leaky integrator. With this modification we have shown that the staircase movement elicited by prolonged stimulation in the SC can be modeled as a damped oscillatory step response of this model. Furthermore, to replicate the changes in the kinetic profiles of the staircase movements with increased stimulation we modified the functionality of the model. Our results suggest that prolonged stimulation of the SC dynamically changes the gains and time constant of the saccadic feedback. Received: 6 September 1996 / Accepted: 19 February 1997     

On compensatory strategies and computational models: The case of pure alexia

The article is concerned with inferences from the behaviour of neurological patients to models of normal function. It takes the letter-by-letter reading strategy common in pure alexic patients as an example of the methodological problems involved in making such inferences that compensatory strategies produce. The evidence is discussed on the possible use of three ways the letter-by-letter reading process might operate: “reversed spelling”; the use of the phonological input buffer as a temporary holding store during word building; and the use of serial input to the visual word-form system entirely within the visual–orthographic domain such as in the model of Plaut [1999. A connectionist approach to word reading and acquired dyslexia: Extension to sequential processing. Cognitive Science, 23, 543–568]. The compensatory strategy used by, at least, one pure alexic patient does not fit with the third of these possibilities. On the more general question, it is argued that even if compensatory strategies are being used, the behaviour of neurological patients can be useful for the development and assessment of first-generation information-processing models of normal function, but they are not likely to be useful for the development and assessment of second-generation computational models.     

The role of the immune system in kidney disease

The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune‐mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti‐glomerular basement membrane disease. Indirect immune‐mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune‐mediated disease or non‐immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re‐established may reveal new treatment possibilities.     

On stent-graft models in thoracic aortic endovascular repair: a computational investigation of the hemodynamic factors

In treating thoracic aortic diseases, endovascular repair involves the placement of a self-expanding stent-graft system across the diseased thoracic aorta. Computational fluid dynamic techniques are applied to model the blood flow by numerically solving the three-dimensional continuity equation and the time-dependent Navier-Stokes equations for an incompressible fluid. From our results, high blood pressure level and high systolic slope of the pressure waveform will significantly increase the drag force on a stent-graft whereas high blood viscosity causes only a mild increase. It indicates that hemodynamic factors might have an important impact on the drag force and thus play a significant role in the risk of stent-graft failure.     

泛素-蛋白酶体系统与免疫系统的关系

泛素-蛋白酶体系统是一种广泛存在于真核细胞内的依赖atp的高选择性的蛋白质降解体系,具有清除衰老、损伤以及错误折叠蛋白的功能,其在细胞周期调控、细胞凋亡、受体信号传导等过程中都有重要的作用。泛素-蛋白酶体系统与免疫系统之间联系密切,因而研究其在感染免疫、自身免疫和肿瘤免疫中的调控很有必要。     

The role of the immune system in the pathophysiology of osteoporosis

Summary: The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses on our current understanding of how the components of this complex‐interlinked system are regulated and how these fit with previous models of senile and postmenopausal osteoporosis. There is certainly substantial evidence that bone remodeling is a tightly regulated, finely balanced process influenced by subtle changes in proinflammatory and inhibitory cytokines as well as hormones and cellular components that act primarily but not exclusively through the receptor activator of nuclear factor‐κB (RANK)/RANK ligand/osteoprotegerin system. In addition, an acute or chronic imbalance in the system due to infection or inflammation could contribute to systemic (or local) bone loss and increase the risk of fracture. Although significant progress has been made, there remains much to be done in unraveling this complex interaction between the immune system and bone.     

The role of the cellular prion protein in the immune system

Prion protein (PrP) plays a key role in the pathogenesis of prion diseases. However, the normal function of the protein remains unclear. The cellular isoform (PrP(C)) is expressed widely in the immune system, in haematopoietic stem cells and mature lymphoid and myeloid compartments in addition to cells of the central nervous system. It is up-regulated in T cell activation and may be expressed at higher levels by specialized classes of lymphocyte. Furthermore, antibody cross-linking of surface PrP modulates T cell activation and leads to rearrangements of lipid raft constituents and increased phosphorylation of signalling proteins. These findings appear to indicate an important but, as yet, ill-defined role in T cell function. Although PrP(-/-) mice have been reported to have only minor alterations in immune function, recent work has suggested that PrP is required for self-renewal of haematopoietic stem cells. Here, we consider the evidence for a distinctive role for PrP(C) in the immune system and what the effects of anti-prion therapeutics may be on immune function.     

Recognition strategies in the innate immune system of ancestral chordates

Many components of the innate immune system in vertebrates can be reliably traced to urochordates and successful strategies for the detection and elimination of pathogens are present at that level of animal evolution, but the issue of where and how the adaptive immune system emerged is still obscure. There is a paucity of evidence for a gradual transition from the innate immune system of invertebrates to the recombinatorial immune system of higher vertebrates. None of the classical elements of MHC based transplantation immunity (MHC, TCR) or humoral immunity (Ig) have been found in urochordates or Agnathans. Nevertheless there is abundant evidence for adaptive immune responses in the agnathans. This remarkable paradox raises a number of questions. How do these ancestral chordates discriminate between the constituents of the external world and the constituents of "self"? Are these strategies universal within the animal kingdom and among chordates, or are different strategies used by representatives of the different taxonomic groups? The current state of our knowledge indicates that the immune system of lower chordates is very different from that of cartilaginous fishes. Pure homology hunting for vertebrate-specific immuno-relevant molecules in invertebrates is therefore of limited value. A more promising approach may involve unbiased functional screening methods. To understand better the evolution of adaptive immune systems, more comparative data from jawless vertebrates (lamprey or hagfish) and a representative of Acrania (e.g. Amphioxus) are clearly needed.     

The role of the adaptive immune system in regulation of gut microbiota

The gut nourishes rich bacterial communities that affect profoundly the functions of the immune system. The relationship between gut microbiota and the immune system is one of reciprocity. The microbiota contributes to nutrient processing and the development, maturation, and function of the immune system. Conversely, the immune system, particularly the adaptive immune system, plays a key role in shaping the repertoire of gut microbiota. The fitness of host immune system is reflected in the gut microbiota, and deficiencies in either innate or adaptive immunity impact on diversity and structures of bacterial communities in the gut. Here, we discuss the mechanisms that underlie this reciprocity and emphasize how the adaptive immune system via immunoglobulins (i.e. IgA) contributes to diversification and balance of gut microbiota required for immune homeostasis.     

The common mucosal immune system and current strategies for induction of immune responses in external secretions

The selective induction of antibodies in external secretions is desirable for the prevention of various systemic as well as predominantly mucosa-restricted infections. An enormous surface area of mucosal membranes is protected primarily by antibodies that belong, in many species, to the IgA isotype. Such antibodies are produced locally by large numbers of IgA-containing plasma cells distributed in subepithelial spaces of mucosal membranes and in the stroma of secretory glands. In humans and in some animal species, plasma-derived IgA antibodies do not enter external secretions in significant quantities and systemically administered preformed IgA antibodies would be of little use for passive immunization. Systemic administration of microbial antigens may boost an effective S-IgA immune response only in a situation whereby an immunized individual had previously encountered the same antigen by the mucosal route. Local injection of antigen in the vicinity of secretory glands is usually accompanied by an undesirable concomitant systemic response and frequently requires the addition of adjuvants that are unacceptable for administration in humans. Immunization routes that involve ingestion or possibly inhalation of antigens lead to the induction of not only local but also generalized immune responses manifested by the parallel appearance of S-Iga antibodies to ingested or inhaled antigens in secretions of glands distant from the site of immunization. Based on extensive studies in animal models as well as in humans, convincing evidence is available that antigen-sensitized and IgA-committed precursors of plasma cells from GALT are disseminated to the gut, other mucosa-associated tissues, and exocrine glands. However, due to the limited absorption of desired antigens from the gut lumen of orally immunized individuals, repeated large doses of antigens are required for an effective S-IgA response. Novel antigen delivery systems for the stimulation of such responses are currently being examined in several laboratories. Live attenuated or genetically manipulated bacteria expressing other microbial antigens have also been used for selective colonization of gut-associated lymphoid tissues. Unique antigen packaging and the use of adjuvants suitable for oral administration hold promise for an efficient antigen delivery to critical tissues in the intestine and deserve extensive exploration. The oral immunization route appears to have many advantages over systemic immunization.(ABSTRACT TRUNCATED AT 400 WORDS)     

The role of HIV gp120 in the disruption of the immune system

The existence of HIV positive individuals who do not appear to progress to disease, or do so only very slowly (LTNPs), strongly suggest that factors other than virus pathogenicity determine disease. The occurence of HIV infected chimpanzees that remain disease free and other African SIV infected primates where disease is apparently species specific underscores the importance of host factors [1,2]. We have examined the immune response of LTNP patients using a variety of techniques including intracellular cytokine FACscan, anchor PCR analysis of the T cell receptor and HLA typing of class II genes by DNA sequencing. Our results to date confirm that the development of disease is consistent with activation of a susceptible immune system, and that this could be due to the fact that HLA-like sequences of HIV may 'allo' activate the host immune response. In order to test this hypothesis further we have examined whether gp120 itself can bind and present specific peptides which may be capable of eliciting 'allo' activation responses in particular hosts.     

The role of the kinin system in various inflammatory models in the rat

The plasma of a peculiar strain of Brown Norway rats (BN/May Pfd f) is devoid of high molecular weight kininogen and poor in kallikrein. This strain could be used to estimate the involvement of the kinin system in inflammatory processes. In these rats, the oedema induced by kaolin, carrageenans, uric acid and urate crystals exhibited a small development, while the oedemas induced by 48/80, dextran, zymosan, trypsin, nystatin, concanavalin A and heating were not reduced. The exudates withdrawn from Brown Norway rats contained no kinin and a low level of PGE2. The involvement of the kinin system in these inflammatory models is discussed.     

Aging of the immune system: Focus on inflammation and vaccination

Major advances in preventing, delaying, or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching eight to nine decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T‐cell or B‐cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.     

The role of the immune system in central nervous system regeneration (theoretical considerations)

The nervous and immune systems are shown to be interrelated. Steroids inhibit both regeneration and the immune response. Crushing injuries enhance regeneration. A synthesis of these apparently unrelated phenomena is formulated into an immune hypothesis of regeneration. Steroids, in suppressing the immune response, decrease lymphokine production and the subsequent stimulation of nerve cell regeneration. Crushing injuries to nerve fibers cause nerve protein to become antigenic, thereby eliciting the production of "non-toxic" antibodies, which paradoxically protect the nerve fibers from immune attack and cause an augmented lymphokine production and subsequent nerve cell regeneration.     

Using computational modeling to assess the impact of clinical decision support on cancer screening improvement strategies within the community health centers

Our conceptual model demonstrates our goal to investigate the impact of clinical decision support (CDS) utilization on cancer screening improvement strategies in the community health care (CHC) setting. We employed a dual modeling technique using both statistical and computational modeling to evaluate impact. Our statistical model used the Spearman’s Rho test to evaluate the strength of relationship between our proximal outcome measures (CDS utilization) against our distal outcome measure (provider self-reported cancer screening improvement). Our computational model relied on network evolution theory and made use of a tool called Construct-TM to model the use of CDS measured by the rate of organizational learning. We employed the use of previously collected survey data from community health centers Cancer Health Disparities Collaborative (HDCC). Our intent is to demonstrate the added valued gained by using a computational modeling tool in conjunction with a statistical analysis when evaluating the impact a health information technology, in the form of CDS, on health care quality process outcomes such as facility-level screening improvement. Significant simulated disparities in organizational learning over time were observed between community health centers beginning the simulation with high and low clinical decision support capability.     

The role of the immune system in clearance of Abeta from the brain.

In Alzheimer's disease (AD), there is abnormal accumulation of Abeta and tau proteins in the brain. There is an associated immunological response, but it is still unclear whether this is beneficial or harmful. Inflammation in AD, specifically in the form of microglial activation, has, for many years, been considered to contribute to disease progression. However, two types of evidence suggest that it may be appropriate to revise this view: first, the disappointing results of prospective clinical trials of anti-inflammatory agents and, second, the observation that microglia can clear plaques in AD following Abeta immunization. Although Abeta immunization alters AD pathology, there is limited evidence so far of benefit to cognitive function. Immunization against microorganisms is almost always used as a method of disease prevention rather than to treat a disease process that has already started. In animal models, immunotherapy at an early age can protect against Abeta accumulation and it will be interesting to see if this can usefully be applied to humans to prevent AD.