Nanotechnology-based Strategies to Modulate Immune Responses

Nanotechnology has shown an important potential in the immunotherapeutic field, as the modulation of a variety of immune processes can be achieved both in vitro and in vivo. Nanotechnology can be used to promote the immune activation or to induce tolerance depending on the nanocarrier composition and its physicochemical properties. The use of ligands for specific cell receptors could substantially increase the targeting to a particular subset of immune cells, and the combination of nanoparticles with other immunomodulators may constitute a useful strategy to effectively polarize the immune response.

Treatments based on the modulation of the immune system is a field in expansion where the contribution of nanotechnology is growing exponentially [1], as it represents a new way of communication with the immune system. Nanocarrier characteristics such as the composition, physicochemical properties, size and the presence of molecules involved in immune processes [2] can influence the immune system behavior by reinforcing either its activation in order to generate a response against a specific pathogen, or the induction of immunotolerance against antigens and immunoactive drugs. The first mechanism improves the control of infectious diseases and cancer, whereas the second refers to the development of vaccines against autoimmune diseases as well as the targeted administration of immunomodulatory drugs [3]. In this context, nanotechnology means versatility.

Different routes for nanoparticle delivery to different immune system subsets. Dacoba, T. G., et al. Modulating the immune system through nanotechnology. Seminars in immunology, 2017, 34, 78–102. https://doi.org/10.1016/j.smim.2017.09.007

Nanoparticles (NPs) should be specifically engineered to go preferentially to the target tissue from the site of administration. As the key cells involved in immunity are concentrated in the lymphoid tissues, targeting nanoparticles to them will facilitate the access to immune cells and increase the efficacy of administered NPs. There are two main administration ways for NPs: mucosal or parenteral. Following mucosal administration, NPs can either induce mucosal responses due to the activation of mucosal resident T [4] and B [5] cells or generate a tolerance reaction [6]. NPs first overcome the mucus layer that cover the mucosal surfaces and then are either transported by M cells or epithelial cells, internalized by paracellular transport, or taken up by dendritic cells (DCs) that extent their dendrites into the lumen. Designing a proper NP composition that allows its interaction with cells within the mucosal surface has been a hot topic in recent years. In contrast, by parenteral administration NPs can drain directly to the closest lymph node (LN) or stay in the injection site to attract migratory DCs or macrophages. NPs up to 100 nm are able to self-drain to the nearest LN, being the drainage inversely proportional to the particle size [7], and particles smaller than 10 nm can directly drain to blood capillaries, showing no retention when reaching the LNs [8]. All the experimentation with NPs points that their final outcome is determined by the simultaneous influence of the particle size, surface charge, shape, hydrophobicity and stiffness, among others.

Immune system responses against self- and non-self-antigens. Dacoba, T. G., et al. Modulating the immune system through nanotechnology. Seminars in immunology, 2017, 34, 78–102. https://doi.org/10.1016/j.smim.2017.09.007

Two different approaches can be used to generate a biased immune response: a) NP features can be changed to facilitate their passive access to immune cells, although a good discrimination between cells can only be achieved through the use of active targeting ligands, and b) immunomodulatory molecules that modify the response given for a specific immune cell subset can be introduced into the NPs, activating different receptors that will lead to cellular or humoral immune responses. Alternatively, some cytokines can be loaded into NPs to induce tolerogenic responses. 

Immunomodulation is a desirable strategy to avoid exacerbated immune responses against self proteins, as it happens during the autoimmune diseases when autologous proteins are recognized as non-self-antigens by the immune system, leading to the generation of autoreactive T and B cell clones. During autoimmune diseases, the generation of tolerance is needed to control the immune response developed against self-antigens. Tolerance is achieved when antigen presenting cells process and present antigens within a tolerogenic environment. At present the treatment of autoimmune disorders is symptomatic and relies on the use of classical anti-inflammatory drugs and immunosuppressive therapies which are unspecific and lead to significant side effects. Nanotechnology can be used for the co-deliver of a drug/antigen and the adequate immunomodulatory molecule to the desired cell population. Delivery of nucleic acids coding for modulatory cytokines with the goal of inducing tolerogenic profiles in immune cells has also been explored [9, 10]. In this regard, NPs offers the possibility to protect the drugs from degradation, thus increasing its half time life, and decorating the NPs with antibodies against specific cell populations can assure the specific delivery of the payload. 

During the central tolerance process, T cells that recognize self-antigens are eliminated to prevent self-reactivity; furthermore, there are peripheral mechanisms that regulate these self reactive T cells if they reach the bloodstream. Most of the mechanisms for maintenance of peripheral self-tolerance include DCs and regulatory T (Treg) cells as the main modulators of self reactive T cell responses. Phenotypical changes in DCs can promote T cell anergy, depletion and Treg cell proliferation after immune synapsis formation and antigen recognition, and Treg cells later promotes the suppression of specific self-reactive T cell clones [11]. NPs treatments offer the ability of specific cell targeting, being capable of delivery antigens that will induce tolerance before epitope spreading happens. Most strategies are focused on the delivery of self antigens to DCs, taking advantage of the natural peripheral tolerance mechanism that they mediate. 

Strategies for nanotechnology-based anti-inflammatory treatment of autoimmune diseases. pDNA:  Plasmid DNA. siRNA: small interference RNA. AONs: antisense oligonucleotides. Dacoba, T. G., et al. Modulating the immune system through nanotechnology. Seminars in immunology, 2017, 34, 78–102.https://doi.org/10.1016/j.smim.2017.09.007

Inflammation is triggered by extracellular signaling factors that attract plasma proteins, immune cells and phagocytes, and that could be either acute or chronic. Chronic inflammation lasts longer, leads to complications due to tissue degeneration and can be divided into autoimmune (such as inflammatory bowel disease, rheumatoid arthritis, type I diabetes, lupus or multiple sclerosis) diseases in which T cells are though to play the major role, and auto-inflammatory diseases (such as sepsis, gout or type II diabetes) which are mainly mediated by innate immune system effectors such as macrophages, the complement cascade and cytokines. Targeted treatment of inflammatory conditions could be considered as an immunomodulatory approach, slowing down the disease progression and ameliorating the symptoms by changing the immune response, both directly by using immunosuppressant drugs or indirectly using anti-inflammatory drugs. Nanoencapsulation of these molecules has been shown to increase their therapeutic effect based on the principle of passive or active targeting, leading to the reduction of their side effects and improving their action on the inflammatory signaling routes mediated by immune cells.  

Since the introduction of recombinant insulin as a treatment for type 1 diabetes, the use of biomolecules as a therapeutic agents (biodrugs) has been growing steadily. Nevertheless, one of the major concerns is the induction of undesired immunogenicity. Antidrug antibodies (ADAs) recognize epitopes in a recombinant molecule and bind to them, causing different outcomes in the pharmacological activity of the drug depending on their neutralizing potential. Despite that the use of humanized or fully-human biodrugs has contributed to reduce the risk, immunogenicity associated to the aggregation of biodrugs is a major concern for the optimum use of these medicaments [12]. Although contradictory, biodrug association upon injection has been though to be a natural way to enhance antigen processing and presentation in the cells, and together with the administration route and patient-related issues could impact immunogenicity.

At present the only treatment to avoid ADAs effects consist of using drugs to achieve tolerance to the biodrug, maintaining its safety and efficacy without systemic immunosuppression. In this regard, nanotechnology is emerging as a new approach where a biodrug can be specifically delivered together with an immunosuppressive drug, thus avoiding immunogenic effects and increasing the treatment efficacy. 

As we build a deeper knowledge of how the immune system works, the design and engineer of new nanosystems will be faster and better, contributing to finding a cure for the most relevant pathologies of our time. 

References:

1. Smith, D.M., J.K. Simon, and J.R. Baker, Jr., Applications of nanotechnology for immunology. Nat Rev Immunol, 2013. 13(8): p. 592-605.

2. Gause, K.T., et al., Immunological Principles Guiding the Rational Design of Particles for Vaccine Delivery. ACS Nano, 2017. 11(1): p. 54-68.

3. Serra, P. and P. Santamaria, Nanoparticle-based autoimmune disease therapy. Clin Immunol, 2015. 160(1): p. 3-13.

4. Brandtzaeg, P., Induction of secretory immunity and memory at mucosal surfaces. Vaccine, 2007. 25(30): p. 5467-84.

5. Cerutti, A., K. Chen, and A. Chorny, Immunoglobulin responses at the mucosal interface. Annu Rev Immunol, 2011. 29: p. 273-93.

6. Kim, W.U., et al., Suppression of collagen-induced arthritis by single administration of poly(lactic-co-glycolic acid) nanoparticles entrapping type II collagen: a novel treatment strategy for induction of oral tolerance. Arthritis Rheum, 2002. 46(4): p. 1109-20.

7. Abellan-Pose, R., N. Csaba, and M.J. Alonso, Lymphatic Targeting of Nanosystems for Anticancer Drug Therapy. Curr Pharm Des, 2016. 22(9): p. 1194-209.

8. Kourtis, I.C., et al., Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice. PLoS One, 2013. 8(4): p. e61646.

9. Phillips, B., et al., A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. Diabetes, 2008. 57(6): p. 1544-55.

10. Basarkar, A. and J. Singh, Poly (lactide-co-glycolide)-polymethacrylate nanoparticles for intramuscular delivery of plasmid encoding interleukin-10 to prevent autoimmune diabetes in mice. Pharm Res, 2009. 26(1): p. 72-81.

11. Vignali, D.A., L.W. Collison, and C.J. Workman, How regulatory T cells work. Nat Rev Immunol, 2008. 8(7): p. 523-32.

12. Moussa, E.M., et al., Immunogenicity of Therapeutic Protein Aggregates. J Pharm Sci, 2016. 105(2): p. 417-430.

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