Biomaterial strategies for generating therapeutic immune responses

Abstract

Biomaterials employed to raise therapeutic immune responses have become a complex and active field. Historically, vaccines have been developed primarily to fight infectious diseases, but recent years have seen the development of immunologically active biomaterials towards an expanding list of non-infectious diseases and conditions including inflammation, autoimmunity, wounds, cancer, and others. This review structures its discussion of these approaches around a progression from single-target strategies to those that engage increasingly complex and multifactorial immune responses. First, the targeting of specific individual cytokines is discussed, both in terms of delivering the cytokines or blocking agents, and in terms of active immunotherapies that raise neutralizing immune responses against such single cytokine targets. Next, non-biological complex drugs such as randomized polyamino acid copolymers are discussed in terms of their ability to raise multiple different therapeutic immune responses, particularly in the context of autoimmunity. Last, biologically derived matrices and materials are discussed in terms of their ability to raise complex immune responses in the context of tissue repair. Collectively, these examples reflect the tremendous diversity of existing approaches and the breadth of opportunities that remain for generating therapeutic immune responses using biomaterials.

Keywords: Autoimmunity; Immunoengineering; Inflammation; Vaccine; Wound healing.

Figure 1

Biomaterials raising therapeutic immune responses have been developed across a spectrum of complexity, from those targeting single cytokines (A) to those with increasingly complex and multifactorial mechanisms of action (B–D). Strategies targeting single cytokines have used monoclonal neutralizing antibodies, nanoparticles that competitively inhibit cytokine activation, and nanoparticles containing siRNA for the targeted cytokine (A). Although directed at a single target, such therapies can have off-target or pleiotropic effects, as a particular cytokine has multiple downstream effects (A, bottom). As a step up in complexity, active immunotherapies can raise polyclonal antibody responses in T-independent or T-dependent processes (B). More complexly, randomized polyamino acid copolymers used to treat autoimmune diseases engage a variety of immune processes including MHC blocking, T-cell biasing, and the induction of therapeutic antibodies (C). Even further, decellularized extracellular matrices can engage in multiple processes including T cell polarization and macrophage polarization (D). Paradoxically, single-target interventions can have off-target or pleiotropic effects (A, bottom), and more complex materials can elicit a reproducible overall phenotype (right). Current research in biomaterials immunology is beginning to elucidate strategies and mechanisms by which biomaterials can reproducibly engage these complex processes.

Figure 2

The development of a nanoparticle system for delivery IL1Ra to the rat knee joint. Particles of 500 nm diameter were assembled and chemically conjugated with IL1Ra (A) before being tagged with a near-infrared dye and injected into the rat knee joint. Fluorescent intensity was then measured over 14 days and compared to a similarly tagged soluble IL1Ra to determine residence time in the joint (B). In a subsequent study 900 nm particles were developed (C) which maintained bioactivity while increasing total signal retention in the knee as measured by near-infrared fluorescent signal intensity (D). Reproduced with permission from references [24] (A–B), [26] (C), and [25] (D).

Figure 3

Active Immunotherapy used in mice to treat inflammatory conditions by targeting the cytokine IL17 with a Qβ bacteriophage VLP. VLPs conjugated with IL17 elicited high anti-IL17 titers of IgG antibodies (A). In the context of myocarditis, mice receiving IL17-targeted active immunotherapy had (B) reduced clinical scores for inflammation, and (C) decreased immune cell infiltration and fibrosis as demonstrated by Hematoxylin and Eosin staining. Furthermore, in both models of anti-collagen antibody-induced arthritis (D) and Experimental Autoimmune Encephalitis (E) severity and progression of disease was limited in the IL17-targeted treatment group. Reproduced with permission from references [60] (A-C) and [59] (D-E).

Figure 4

Glatiramer acetate treatment applied to a variety of diseases. (A) Illustration of the mechanism of action of GA, emphasizing MHC blocking, Th2 polarization, and antibody responses. (B) GA in a preclinical R6/2 mouse model of Huntington’s Disease (left, naïve mouse, right GA-treated). Arrows indicate brain-derived neurotrophic factor (BDNF)-positive astrocytes, stars indicate brain-derived neurotrophic factor (BDNF)-positive non-astroglial cells. (C) GA in a transgenic (Tg) mouse model of Alzheimer's Disease: CD11b (activated microglia) and Aβ are more pronounced in the brains of untreated Tg mice (center) versus those treated with GA (right). (D) GA for macular degeneration: fundus photographs before and 12 weeks after weekly GA injections; circles indicate areas of drusen (stained yellow), which were reduced following treatment. (E) GA for inflammatory bowel disease in a dextran sulfate sodium (DSS) colitis mouse model: untreated mice died by day 12, whereas GA-treated mice survived and exhibited repair. Images show histology 10 days after DSS administration in an untreated mouse (top) and 30 days after DSS administration in a GA-treated mouse (bottom), with restored tissue. Reproduced with permission from references [74] (A), [166] (B), [167] (C), [168] (D), and [97] (E).

Figure 5

Early clinical results of acellular ECM scaffolds for the treatment of volumetric muscle loss. Data from a single patient treated with the porcine dermal matrix XenMatrix (Bard) for a sports-related hamstring injury, is compiled. After pre-operative physical therapy, the patient underwent surgical debridement of scar tissue, followed by implantation of the scaffold in the injury site. Shown is an example of an ECM scaffold sheet similar to that used for this patient (A). The included data show pre- and post-operational images of the patient’s hamstring area (B); functional assessments of muscular performance (C); and CT imaging of the treated area (D). Reproduced with permission from references [105] (A) and [109] (B–D).

Figure 6

ECM scaffolds induce Th2-dependent constructive myeloid polarization. Cardiac muscle-derived ECM was implanted into hamstring volumetric muscle loss injuries in wild type (WT), Rag1−/−, and Il4ra−/− mice; and in Rag1−/− mice reconstituted with CD4 T cells from either WT mice (T-WT) or Th2-deficient Rictr−/− mice (T−Rictr−/−). Expression of the M2 macrophage marker CD206 at 3 weeks post-injury indicated that Th2 cells supported M2 polarization of macrophages (A). In particular, CD206 expression was not rescued after repopulation with T cells from a Th2-deficient mouse. Functional treadmill assays at 2 weeks post-injury similarly indicated the importance of Th2 cells (B, distance is normalized to an uninjured control). Function was not restored after repopulation with T cells from a Th2-deficient mouse. Reproduced with permission from reference [125].