Original Research ArticleHematopoietic stem cell based therapy of immunosuppressive viral infection—Numerical simulations
Introduction
The immune system of higher organisms utilizes innate and adaptive (acquired) immune responses to fight viral infections [1], [2]. Innate immunity is not virus-specific and consists of many diverse mechanisms (e.g. stomach acid, inflammation, and macrophages). Adaptive immune mechanisms are virus-specific, i.e. they react specifically to given virus strain (lymphocytes can recognize the physical structure of virus particles). Moreover, adaptive mechanisms can establish immunological memory for better responses in following encounters with the same antigen.
There are two branches of adaptive immunity [3]. Humoral immune responses are carried out by B lymphocytes and antibodies. They are directed against free virus particles in the system. Cell-mediated (cellular) immunity is, on the other hand, directed against infected cells that produce new virus particles. It is carried out by cytotoxic T lymphocytes (CTL, CD8+) and T helper lymphocytes (Th cells, CD4+) [4]. In response to antigen stimulation, the population of precursor CTL proliferates and differentiates into effector CTL that recognize and kill infected cells [5]. Th cells play a regulatory role in both humoral and cellular responses.
Some of viral infections are immunosuppressive, i.e. they can impair immune responses (e.g. HIV and LCMV [6]). One way to achieve this is to infect Th lymphocytes. Since functional Th cells are needed for expansion of memory cells [7], successful infection will reduce adaptive immunity to weak helper-independent responses only.
There are many approaches to develop a successful treatment of immunosuppressive infection. Among others, we can distinguish gene based therapies. Until now, they have focused on redirecting mature CTL towards selected antigen (see e.g. [8]). However, recent advantages in stem cell research (e.g. blood cells can now be reversed to stem cell state [9]) make it possible to develop new strategies. One such strategy is to genetically modify human hematopoietic stem cells (HSC) to create functional virus-specific CTL, capable of suppression of virus spread.
Hematopoietic stem cells are present in the bone marrow. These cells give rise to T cell precursors that are translocated to the thymus. Within the thymus, they mature into CD8+ lymphocytes specific for a vast repertoire of antigenic epitopes. After the selection process, these cells translocate to lymph nodes, where they may be activated to CTL.
The idea underlying the HSC-based therapy (see e.g. [10], [11]) is to obtain HSCs of the patient and genetically modify them to bear a concrete T cell receptor. These modified cells are then introduced into thymus. This should result in production of CTL specific to given virus strain. The main advantage of this approach is the fact that these newly produced cells have to pass the selection process in the thymus (autoimmunity is avoided). Moreover, this production of CTL is independent of antigen stimulation, so the effects of immune impairment are limited.
Recent experiments related to HSC based therapy have shown that CTL derived from genetically modified HSCs were capable of ex vivo and in vivo suppression of virus population [12], [13]. In the latter experiment, the following results were reported: multilineage human hematopoiesis, creation of effector CTL, reduced Th cell depletion, suppression of HIV replication and plasma viremia.
Interestingly, antigenic escape was not observed in the mentioned in vivo experiment. This gives us a clear view on virus-immune system dynamics, but it makes it hard to evaluate the obtained results. For more details on limitations of this approach see Section 4.
Section snippets
Mathematical model
In order to best address the results of experiment described in [13], we propose a modified version of the basic model for virus-induced impairment of help presented in [4]. We introduce two alterations of the basic model: (i) an additional equation is used to describe the virus dynamics (as in the model of virus dynamics in [14]) and (ii) an additional term γ is introduced to describe the effects of therapy.
The model consists of five ordinary differential equations. Initial conditions, as well
Changing precursor CTL production
Our simulations show that increase in parameter γ effectively changes the relation between viral replication and immune response, leading to overall good results. Moreover, our numerical results are similar to those obtained from the in vivo experiment [13]. In the studied scenario, the equilibrium numbers of populations were not influenced by the time of treatment initiation.
Increasing the precursor CTL production (parameter γ) results in suppression of Th cell depletion. With the increase of γ
Discussion
Hematopoietic stem cell based therapy of immunosuppressive viral infection gives promising results, both theoretical and practical [12], [13], [16]. It leads to antigen-independent creation of functional virus-specific CTL that have successfully went through selection process in the thymus. These CTL are able to differentiate into effector cells that can suppress viral replication in vivo. This, in turn, leads to reversed Th cell depletion and reduced immunosuppression.
However, there are many
Acknowledgements
The author would like to express his gratitude to Mikhail Kolev and anonymous reviewers for their useful comments that led to improvement of this paper.
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2016, BioSystemsCitation Excerpt :Mathematical and numerical approaches have also been applied to predict the dynamics of HSC based therapy of viral infections, see e.g. (Murray et al., 2009). In our previous work (Korpusik, 2014; Korpusik and Kolev, 2013), we have studied the influence of a constant influx of new CTLs on the virus – immune system interactions, using a modification of the basic mathematical model of virus induced impairment of help (Wodarz, 2007). Our results were qualitatively the same as those obtained in the in vivo experiment (Kitchen et al., 2012): restored cellular response, limited Th cell depletion, suppression of plasma virus and lower numbers of infected Th cells.
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