Immunoengineering for autoimmune-kidney disease

Nephrology Dialysis Transplantation, vol. 39, pp. 1934–1937

Abstract

Despite recent advances in the field of immune-mediated kidney diseases, a significant proportion of patients continue to fail to achieve long-term remission and suffer from adverse events mainly arising from the use of non-targeted immunosuppressive agents. These agents, including high doses of glucocorticoids, constitute an important cause of morbidity [1]. Unmet treatment needs have paved the way for new sophisticated molecular technologies that have been seen as a means to the next generation of tailored, disease-modifying agents. Notably, studies involving proteomics, transcriptomics, and single-cell genomics have demonstrated promising results that may be the target of new tailored therapeutics [2]. Very recently, McBride et al. [3] suggested that immunoengineering might be of use for precision medicine in patients with systemic autoimmune diseases. Chemically engineered biomaterials with immune cell-instructive capabilities are considered as potential agents that can induce immunomodulation. These biomaterials come in a range of sizes: nanoparticles, microparticles, and macroscale materials. Nanoparticles can be modified in terms of composition, size, and geometry, and coating or conjugating with ligands may be used for tailored applications. Notably, nanoparticles between 5 and 200 nm can be distributed within the circulation and lymphatics leading to immune cell activation and recognition by various antigen-presenting cells. Albumin can facilitate the transport to the nearest lymph nodes and engineering products including a cargo linked to an albumin-binding tail might result in the accumulation of desired antigens in the lymphatic system. Using microparticles that encapsulate immunomodulatory compounds as biodegradable tissue-resident depots may lead to the sustained release of these agents. Of note, adjustment of the composition and geometry of microparticles is also possible, and particles with the sizes of tens of micrometers may resist phagocytosis and nest in the desired localizations for a long period of time. These features make microparticles an appealing option for the delivery of various agents to target tissues in the context of immunization, which has been realized in oncology [4]. However, delivery into the kidneys would be a significant challenge considering the complexity of the structure and whether it could be achieved is currently unknown [5]. Macroscale materials are different with respect to their sizes but mechanical properties of these molecules can also be adjusted. They may be biological or synthetic, and be used for creating microenvironments that mimic tissues, ranging from organoids to organs-on-chips [6], which might lead to testing new hypotheses. Engineered biomaterials, potential applications, and plausible targets for the delivery into the kidney are summarized in Figure 1. Biomaterial-based immunoengineering for precision medicine. Immunoengineering of biomaterial is a rapid evolving field of nanotechnology that has been implicated in broad range of diseases including cancer, infectious diseases, and autoimmune diseases, and may hold promise for kidney-related autoimmune diseases and beyond. Engineered biomaterials, such as nanoparticles, vesicles, liposomes, and lipid- or polymer-based micelles, have a spherical and well-defined morphology (e.g. size, shape) and composition (e.g. surface charge), and are ideal for cellular recognition, targeting, modulation, and uptake by immune and non-immune cells. Additionally, microparticle-based delivery of immunoregulatory agents and macroscale materials can also be used to enhance stability, delivery, and efficacy of therapeutic agents. Owing to their tunability, biomaterials also present a promising approach for tissue-specific immunomodulation in acute kidney injury and chronic kidney disease to tackle challenges in delivery of payloads, such as proteins, nucleic acids, peptides, and antibodies, and to achieve a balanced and controlled activation or suppression of the immune response and promote tissue repair. Potential targets for biomaterials in the kidney are endothelial cells, mesangial cells, tubular epithelial cells, and immune cells [5]. Immunoengineered compounds may be of use in the context of immunoregulation and tolerization. Distribution of nanoparticles in the lymphatic system, especially with the help of albumin, can result in the delivery of several agents that have been shown to have limited efficacy when applied systemically. Interleukin-10 (IL-10) is a well-known anti-inflammatory cytokine, but its biological form does not have enough stability to go through systemic administration, leading to degradation. Albumin-bound IL-10 was shown to persist within the lymphatic system and demonstrates anti-inflammatory effects [7]. Similar concepts can be considered for other anti-inflammatory cytokines. For example, the immune response in patients with systemic lupus erythematosus and lupus nephritis (LN) is multifaceted, and anti-inflammatory cytokines such as IL-4, whose receptor signaling has been considered to have a role in disease pathogenesis, may aid in therapeutic processes [8]. Considering the regulator role of calcitriol in dendritic cell biology, nanoparticles including calcitriol and antigenic peptide can target dendritic cells in an experimental model of anti-glomerular basement membrane (anti-GBM) disease. Treatment of mice with liposomes encapsulating calcitriol and autoreactive HLA-DR15-restricted collagen IV α3135–145 peptides reduced the development of glomerulonephritis and albuminuria in an antigen-specific manner [9]. In addition, reduced injury was associated with fewer intrarenal α3135–145-specific CD4+Foxp3− effector T cells while the proportion of α3135–145-specific regulatory T cells increased in the spleen. Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy might be another avenue for nanoparticle-driven antigen-specific tolerization. PLA2R is a 180-kDa membrane protein involving 10 globular domains: a cysteine-rich domain that includes the immunodominant epitope, a fibronectin type II domain, and 8 C-type lectin domains [10]. The immunodominant epitope and key residues within the epitope have been recently shown in a study demonstrating the high-resolution structure of PLA2R, which may lead to in silico selection of various compounds and development of immunoengineered products to induce tolerance [11]. Another aspect of tolerization with nanoparticles is gut-targeted immunoengineering. The particles can be designed as polymeric micelles assembling into a bilayer structure that includes butyrate, which may induce immunoregulation through epigenetic modification. Neutral-charged nanoparticles deliver butyrate mainly in the ileum; when particles are encapsulated with a negative charge, the location of delivery is the caecum, leading to the spatial control of the delivery. IgA nephropathy (IgAN) has been associated with gut dysbiosis that could stimulate the overproduction of galactose-deficient IgA1, and Escherichia, Shigella, and Clostridium have been shown to be more enriched in these patients [12]. Notably, it has been recently demonstrated that Akkermansia muciniphila, a mucin-degrading bacterium, could deglycosylate human IgA1, and after incubation with A. muciniphila, human IgA1 was recognized by autoantibodies in the sera of patients with IgAN [13]. To this end, a conjugated nanoparticle called HABN modulates gut microbiota increasing A. muciniphila; thus, a nanoparticle suppressing its activity might be of use in these patients in the future. Chimeric antigen receptor (CAR) T-cell therapies are expanding and are now being used as a potential treatment option in (refractory) autoimmune diseases, especially LN [14]. Macroscale extracellular matrix scaffolds might induce and improve the quality of CAR T cells. Viscoelastic mechanical property of the scaffold can be tuned to regulate T-cell activation by using the activator-protein-1 signaling pathway. In addition to the limited treatment options for refractory disease, a lack of biomarkers of disease activity is an ongoing unmet need in LN. Conventional biomarkers such as proteinuria, urinary sediment, glomerular filtration rate, anti-dsDNA antibody, and serum complement levels do not meet the definition of ideal biomarkers, and numerous molecules have been investigated over two decades without solid results. Nanoparticles can be engineered with the use of protease-sensitive linkers that create a fluorescent signal after cleavage. On meeting with disease-specific signals in the microenvironment, the linkers get activated and the fluorescent signal can be taken up by a colorimetric test assay. Collection of nanoparticles for readout could be easily done with non-invasive methods such as urinalysis. C3dg is a late product of the complement system and a key linkage between innate and adaptive immunity capable of stimulating both humoral and cell-mediated immune responses [15]. In patients with C3 glomerulopathy, C3dg has been shown as the most abundant protein in C3 deposits after cleavage [16]. There is a growing interest in C3dg as a molecular adjuvant, and a strategy to assemble C3dg into supramolecular nanofibers has been recently reported [15]. Notably, a murine model of imiquimod-induced psoriasis demonstrated that immunization with nanofibers was equivalent to standard treatment options in efficacy. In addition, no significant susceptibility to bacterial infections was observed. Engineering nanofibers for complement-mediated kidney diseases might also be pursued. Immunoengineering might be a promising avenue for immune-mediated kidney diseases in the context of precision medicine. Nevertheless, this developing field will go through significant challenges [3]. Suggested compounds should undergo thorough evaluation in preclinical models that have inherent limitations. Selection of materials will be limited to the current armamentarium, and novel compounds will be needed. Well-designed clinical trials will be challenging to conduct in rare kidney diseases, and cost-effectiveness of the process will also be challenged. Additionally, practical issues—such as how to achieve delivery of not only these engineered compounds but also RNA therapeutics, which have started to gain momentum in nephrology [17], into both kidneys—need to be established. Whether severe hypoalbuminemia in patients with nephrotic syndrome could affect the transport of albumin-bound agents is also unknown. Nonetheless, this field offers great potential to more specifically manage autoimmune disorders and thus reduce the inherent side-effect profile of systemic and often non-specific immunosuppression. The Immunonephrology Working Group is an official body of the ERA. No specific funding for this report. S.M., A.K., and S.S. drafted the first version of the article. All authors significantly contributed to the content and reviewed the manuscript. Outside the submitted work, S.M. received support for meeting registration and travel from Amgen and Sanofi Genzyme. A.B. received consultancy fees from Boehringer-Ingelheim and CSL Vifor, and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Chemocentryx, CSL Vifor, Fresenius, GSK, and Otsuka. F.C.F. received consultancy fees from Novartis, SOBI, and Apellis, payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, and participated on a data safety monitoring board or advisory board for Novartis and SOBI. J.F. received consultancy fees from AstraZeneca, Bayer, Boehringer, Calliditas, CSL Vifor, HiBio, Novartis, Omeros, Roche, Travere, and Vera Tx, payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Boehringer, Calliditas, CSL Vifor, HiBio, Novartis, Omeros, Roche, Stadapharm, Travere, and Vera Tx, and participated on a data safety monitoring board or advisory board for NovoNordisk. E.F. received grants or contracts and support for meeting registration and travel from State Health Services Organization of Cyprus. K.I.S. received consultancy fees from CSL Vifor, Boehringer-Ingelheim, and Bayer. A.K. received support for meeting registration and travel from AstraZeneca and Otsuka, an unrestricted research grant from CSL Vifor, and consultancy fees or speaking fees from AstraZeneca, Catalyst Biosciences, CSL Vifor, Delta4, GlaxoSmithKline, Miltenyi Biotech, Novartis, Roche, and Walden Biosciences. S.M., E.F., A.K., and S.S. are editorial board members of the Nephrology Dialysis Transplantation journal. The remaining authors have no disclosures.

Authors 14

1. Şafak Mirioğlu corresponding

   Istanbul University

   Affiliation as printed

   Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University , Istanbul ,

2. Annette N. Bruchfeld

   Linköping University · Karolinska University Hospital · Karolinska Institutet

   Affiliation as printed

   Department of Health, Medicine and Caring Sciences, Linköping University , Linköping ,

   Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet , Stockholm ,

3. Fernando Caravaca‐Fontán

   Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre

   Affiliation as printed

   Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12) , Madrid ,

4. Gema Maria Fernandez Juarez

   Hospital Universitario Fundación Alcorcón

   Affiliation as printed

   Department of Nephrology, Hospital Unversitatio Fundacion Alcorcon , Alcorcon ,

5. Jürgen Floege Aachen Division of Nephrology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Division of Nephrology, RWTH Aachen University Hospital , Aachen ,

6. Eleni A. Frangou

   University of Nicosia · National and Kapodistrian University of Athens · Limassol General Hospital

   Affiliation as printed

   Department of Nephrology, Limassol General Hospital , State Health Services Organization, Limassol ,

   Medical School, National and Kapodistrian University of Athens , Athens ,

   University of Nicosia Medical School , Nicosia ,

7. Dimitrios S. Goumenos

   General University Hospital of Patras

   Affiliation as printed

   Department of Nephrology and Renal Transplantation, Patras University Hospital , Patras ,

8. Megan E. Griffith

   Imperial College Healthcare NHS Trust · Hammersmith Hospital

   Affiliation as printed

   Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital , London ,

9. Sarah Margaret Moran

   University College Cork · Cork University Hospital

   Affiliation as printed

   Cork University Hospital, University College Cork , Cork ,

10. Kate Stevens

    Queen Elizabeth University Hospital

    Affiliation as printed

    Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital , Glasgow ,

11. Y K Onno Teng Aachen Center of Expertise for Lupus-, Vasculitis- and Complement-mediated systemic diseases Department of Internal Medicine-Nephrology Section

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Diseases (LuVaCs), Department of Internal Medicine—Nephrology Section, Leiden University Medical Center , Leiden ,

12. Kültiğin Türkmen

    Necmettin Erbakan University

    Affiliation as printed

    Division of Nephrology, Necmettin Erbakan University Faculty of Medicine , Konya ,

13. Andreas Kronbichler

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck , Innsbruck ,

14. Stefanie Steiger

    Ludwig-Maximilians-Universität München

    Affiliation as printed

    Division of Nephrology, Department of Internal Medicine IV, Hospital of the Ludwig-Maximilians-University , Munich ,