Efficacy of Nanoparticle-based Localised Immunomodulation to Reduce Graft-versus-host Disease in Murine Model of Bone Marrow Transplantation: A Systematic Review
DOI:
https://doi.org/10.63501/xyvdbe23Keywords:
Bone Marrow Transplantation, Hematopoietic Stem Cell Transplantation , Graft vs Host Disease , NanoparticlesAbstract
Background and Aim
Bone marrow transplantation (BMT), 73.8% of all transplants, is a cornerstone therapy for various haematological disorders. It follows a life-threatening complication; acute graft vs host disease (aGVHD) with 30-60% of incidence. Despite being standard, conventional immunosuppressive therapies are frequently associated with toxicity, infections, and 70% of non-responding patient. A novel, highly targeted nanoparticle-based strategy, while being explored in solid organ transplantation, remains under-investigated in BMT. This systematic review aims to evaluate the efficacy of NP-based strategies to mitigate aGVHD following BMT.
Methods
A systematic search was conducted using PubMed, Cochrane Library, and Science Direct from April 23, 2001, to August 13, 2024 for propensity-matched studies evaluating efficacy of NP-based therapies in murine models to mitigate GVHD severity. Data were extracted independently by two reviewers. Study quality was assessed using SYRCLE tool. Descriptive analysis was performed as meta-analysis was not possible due to heterogeneity in intervention types.
Results
Of the 66 studies retrieved, 15 pre-clinical animal studies were selected sample size 2-30/group). Overall, risk of bias was moderate. 12/15 studies reported lower clinical GVHD scores (p< 0.001), 14/15 prevented weight loss (p<0.05), 14/15 prolonged survival with (HR 0.2055, p=0.0112). Histopathological assessments showed decreased tissue damage in the liver (10/11), the intestine (12/12), and the skin (7/7) with p<0.05. 14/15 reported lower levels of inflammatory cytokines (p<0.001).
Conclusion
NPs therapy has a promising efficacy in mitigating GVHD after BMT. Nevertheless, the heterogeneity of interventions makes generalizability still difficult. It underscores the need for future in-depth translational studies.
References
1. Mohty M, Apperley JF. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology [Internet]. 2010;2010(1):229–36. Available from: http://dx.doi.org/10.1182/asheducation-2010.1.229
2. Ali N, Iftikhar R, Mir MA, Bokhari SW, Rehman JU, Zaidi U, et al. Haematopoietic Stem Cell Transplant Trends in Pakistan: Activity Survey from Pakistan Bone Marrow Transplant Group. J Transplant [Internet]. 2023 Jan 1 [cited 2025 Jul 29];2023(1):8865364. Available from: /doi/pdf/10.1155/2023/8865364
3. Ranghar S, Sirohi P, Verma P, Agarwal V. BRAZILIAN ARCHIVES OF BIOLOGY AND TECHNOLOGY Nanoparticle-based Drug Delivery Systems: Promising Approaches Against Infections. Arch Biol Technol v. 57(2):209–22.
4. Holtan SG, Marcelo P, Weisdorf DJ. Acute graft-versus-host disease: A bench-to-bedside update. Blood [Internet]. 2014 Jul 17 [cited 2025 Jul 29];124(3):363–73. Available from: https://pubmed.ncbi.nlm.nih.gov/24914140/
5. Garnett C, Apperley JF, Pavlu J. Treatment and management of graft-versus-host disease: Improving response and survival. Ther Adv Hematol [Internet]. 2013 [cited 2025 Jul 29];4(6):366–78. Available from: https://pubmed.ncbi.nlm.nih.gov/24319572/
6. Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood [Internet]. 2012 Jan 5 [cited 2025 Jul 29];119(1):296–307. Available from: https://pubmed.ncbi.nlm.nih.gov/22010102/
7. Al Malki MM, Gendzekhadze K, Yang D, Mokhtari S, Parker P, Karanes C, et al. Long-Term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch. Transplantation [Internet]. 2020 May 1 [cited 2025 Jul 29];104(5):1070–80. Available from: https://pubmed.ncbi.nlm.nih.gov/31449184/
8. Ballen K, Logan BR, Chitphakdithai P, Kuxhausen M, Spellman SR, Adams A, et al. Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients. Biology of Blood and Marrow Transplantation [Internet]. 2020 Apr 1 [cited 2025 Jul 29];26(4):745–57. Available from: https://www.astctjournal.org/action/showFullText?pii=S1083879119307839
9. Greco R, Lorentino F, Nitti R, Lupo Stanghellini MT, Giglio F, Clerici D, et al. Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide. Front Immunol [Internet]. 2019 Oct 1 [cited 2025 Jul 29];10. Available from: https://pubmed.ncbi.nlm.nih.gov/31632401/
10. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: A comprehensive review. Anticancer Res [Internet]. 2017;37(4):1547–55. Available from: http://dx.doi.org/10.21873/anticanres.11483
11. Jamil MO, Mineishi S. State-of-the-art acute and chronic GVHD treatment. Int J Hematol [Internet]. 2015;101(5):452–66. Available from: http://dx.doi.org/10.1007/s12185-015-1785-1
12. Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood [Internet]. 2017;129(1):22–9. Available from: http://dx.doi.org/10.1182/blood-2016-08-686659
13. Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood [Internet]. 2012 Jan 5 [cited 2025 Jul 29];119(1):296–307. Available from: https://pubmed.ncbi.nlm.nih.gov/22010102/
14. Zeiser R, Blazar BR. Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy. New England Journal of Medicine [Internet]. 2017 Nov 30 [cited 2025 Jul 29];377(22):2167–79. Available from: https://pubmed.ncbi.nlm.nih.gov/29171820/
15. Mielcarek M, Furlong T, Storer BE, Green ML, McDonald GB, Carpenter PA, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: A randomized controlled trial. Haematologica [Internet]. 2015 [cited 2025 Jul 29];100(6):842–8. Available from: https://pubmed.ncbi.nlm.nih.gov/25682602/
16. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and Second-Line Systemic Treatment of Acute Graft-versus-Host Disease: Recommendations of the American Society of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation [Internet]. 2012 Aug [cited 2025 Jul 29];18(8):1150–63. Available from: https://pubmed.ncbi.nlm.nih.gov/22510384/
17. Lee SE, Cho BS, Kim JH, Yoon JH, Shin SH, Yahng SA, et al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant [Internet]. 2013 Apr [cited 2025 Jul 29];48(4):587–92. Available from: https://pubmed.ncbi.nlm.nih.gov/23000645/
18. Ragelle H, Danhier F, Préat V, Langer R, Anderson DG. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures. Expert Opin Drug Deliv [Internet]. 2017;14(7):851–64. Available from: http://dx.doi.org/10.1080/17425247.2016.1244187
19. Singh R, Lillard Jr JW. Nanoparticle-based targeted drug delivery. Exp Mol Pathol [Internet]. 2009;86(3):215–23. Available from: http://dx.doi.org/10.1016/j.yexmp.2008.12.004
20. Afshari AR, Sanati M, Mollazadeh H, Kesharwani P, Johnston TP, Sahebkar A. Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways. Semin Cancer Biol [Internet]. 2022 Nov 1 [cited 2025 Jun 21];86:860–72. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1044579X22000189?via%3Dihub
21. Wang H, Zhou Y, Sun Q, Zhou C, Hu S, Lenahan C, et al. Update on nanoparticle-based drug delivery system for anti-inflammatory treatment. Front Bioeng Biotechnol [Internet]. 2021;9:630352. Available from: http://dx.doi.org/10.3389/fbioe.2021.630352
22. Fang RH, Zhang L. Nanoparticle-based modulation of the immune system. Annu Rev Chem Biomol Eng [Internet]. 2016;7(1):305–26. Available from: http://dx.doi.org/10.1146/annurev-chembioeng-080615-034446
23. Fujii S, Miura Y. Immunomodulatory and Regenerative Effects of MSC-Derived Extracellular Vesicles to Treat Acute GVHD. Stem Cells [Internet]. 2022 Nov 29 [cited 2025 Jun 21];40(11):977–90. Available from: https://dx.doi.org/10.1093/stmcls/sxac057
24. Horwitz DA, Wang JH, Kim D, Kang C, Brion K, Bickerton S, et al. Nanoparticles loaded with IL-2 and TGF-β promote transplantation tolerance to alloantigen. Front Immunol. 2024;15.
25. Pareek S, Flegle AS, Boagni D, Kim JY, Yoo D, Trujillo-Ocampo A, et al. Post Transplantation Bilirubin Nanoparticles Ameliorate Murine Graft Versus Host Disease via a Reduction of Systemic and Local Inflammation. Front Immunol. 2022 Jun 1;13.
26. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016 Dec 5;5(1).
27. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Vol. 372, The BMJ. BMJ Publishing Group; 2021.
28. Hooijmans CR, Rovers MM, De Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014 Mar 26;14(1).
29. Przybylski S, Gasch M, Marschner A, Ebert M, Ewe A, Helmig G, et al. Influence of nanoparticle-mediated transfection on proliferation of primary immune cells in vitro and in vivo. PLoS One [Internet]. 2017 May 1 [cited 2025 Jul 29];12(5). Available from: https://pubmed.ncbi.nlm.nih.gov/28463994/
30. Kaiser TK, Li H, Roßmann L, Reichardt SD, Bohnenberger H, Feldmann C, et al. Glucocorticoids delivered by inorganic–organic hybrid nanoparticles mitigate acute graft-versus-host disease and sustain graft-versus-leukemia activity. Eur J Immunol [Internet]. 2020 Aug 1 [cited 2025 Jul 29];50(8):1220–33. Available from: https://pubmed.ncbi.nlm.nih.gov/32133644/
31. Li KL, Li JY, Xie GL, Ma XY. Exosomes Released From Human Bone Marrow–Derived Mesenchymal Stem Cell Attenuate Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Mice. Front Cell Dev Biol [Internet]. 2021 Apr 6 [cited 2025 Jul 29];9. Available from: https://pubmed.ncbi.nlm.nih.gov/33889570/
32. Mei D, Xue Z, Zhang T, Yang Y, Jin L, Yu Q, et al. Immune isolation-enabled nanoencapsulation of donor T cells: a promising strategy for mitigating GVHD and treating AML in preclinical models. J Immunother Cancer [Internet]. 2024 Sep 5 [cited 2025 Jul 29];12(9). Available from: https://pubmed.ncbi.nlm.nih.gov/39242117/
33. Wang L, Gu Z, Zhao X, Yang N, Wang F, Deng A, et al. Extracellular Vesicles Released from Human Umbilical Cord-Derived Mesenchymal Stromal Cells Prevent Life-Threatening Acute Graft-Versus-Host Disease in a Mouse Model of Allogeneic Hematopoietic Stem Cell Transplantation. Stem Cells Dev [Internet]. 2016 Dec 15 [cited 2025 Jul 29];25(24):1874–83. Available from: https://pubmed.ncbi.nlm.nih.gov/27649744/
34. Jiang Y, Zhao J, Wang M, Huang F, Li J, Liu R, et al. Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models. Front Immunol [Internet]. 2023 [cited 2025 Jul 29];14. Available from: https://pubmed.ncbi.nlm.nih.gov/38124750/
35. Liu W, Zhou N, Liu Y, Zhang W, Li X, Wang Y, et al. Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells. Stem Cell Res Ther [Internet]. 2021 Dec 1 [cited 2025 Jul 29];12(1):1–16. Available from: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02159-2
36. Kuroiwa T, Kakishita E, Hamano T, Kataoka Y, Seto Y, Iwata N, et al. Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function. Journal of Clinical Investigation [Internet]. 2001 [cited 2025 Jul 29];107(11):1365–73. Available from: https://pubmed.ncbi.nlm.nih.gov/11390418/
37. Fujii S, Miura Y, Fujishiro A, Shindo T, Shimazu Y, Hirai H, et al. Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations. Stem Cells [Internet]. 2018 Mar 1 [cited 2025 Jul 29];36(3):434–45. Available from: https://dx.doi.org/10.1002/stem.2759
38. Zhang Y, Shlomchik WD, Joe G, Louboutin JP, Zhu J, Rivera A, et al. APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease. The Journal of Immunology [Internet]. 2002 Dec 15 [cited 2025 Jul 29];169(12):7111–8. Available from: https://dx.doi.org/10.4049/jimmunol.169.12.7111
39. Bernardes PTT, Rezende BM, Resende CB, De Paula TP, Reis AC, Gonçalves WA, et al. Nanocomposite treatment reduces disease and lethality in a murine model of acute graft-versus-host disease and preserves anti-tumor effects. PLoS One [Internet]. 2015 Apr 13 [cited 2025 Jun 21];10(4). Available from: https://pubmed.ncbi.nlm.nih.gov/25875016/
40. Cheng J, Zhou Y, Chen B, Wang J, Xia G, Jin N, et al. Prevention of acute graft-versus-host disease by magnetic nanoparticles of Fe3O4 combined with cyclosporin A in murine models. Int J Nanomedicine [Internet]. 2011 [cited 2025 Jun 21];6:2183–9. Available from: https://pubmed.ncbi.nlm.nih.gov/22114482/
41. Zhao S, Zhang L, Han J, Chu J, Wang H, Chen X, et al. Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity. ACS Nano [Internet]. 2016 Jun 28 [cited 2025 Jun 21];10(6):6189–200. Available from: https://pubmed.ncbi.nlm.nih.gov/27224853/
42. Mia MB, Saxena RK. Poly dispersed acid-functionalized single walled carbon nanotubes target activated T and B cells to suppress acute and chronic GVHD in mouse model. Immunol Lett [Internet]. 2020 Aug 1 [cited 2025 Jun 21];224:30–7. Available from: https://pubmed.ncbi.nlm.nih.gov/32504776/
43. Pareek S, Flegle AS, Boagni D, Kim JY, Yoo D, Trujillo-Ocampo A, et al. Post Transplantation Bilirubin Nanoparticles Ameliorate Murine Graft Versus Host Disease via a Reduction of Systemic and Local Inflammation. Front Immunol [Internet]. 2022 Jun 1 [cited 2025 Jul 29];13:893659. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9199387/
44. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. The Lancet [Internet]. 2009 [cited 2025 Jul 29];373(9674):1550–61. Available from: https://pubmed.ncbi.nlm.nih.gov/19282026/
45. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation [Internet]. 2015 Mar 1 [cited 2025 Jul 29];21(3):389-401.e1. Available from: https://pubmed.ncbi.nlm.nih.gov/25529383/
46. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol [Internet]. 2015 Sep 8 [cited 2025 Jul 29];33(9):941–51. Available from: https://pubmed.ncbi.nlm.nih.gov/26348965/
47. Zou J, Peng H, Liu Y. The Roles of Exosomes in Immunoregulation and Autoimmune Thyroid Diseases. Front Immunol [Internet]. 2021 Nov 15 [cited 2025 Jul 29];12:757674. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8634671/
48. Wang J, Lu Z, Wientjes MG, Au JLS. Delivery of siRNA Therapeutics: Barriers and Carriers. AAPS J [Internet]. 2010 Dec [cited 2025 Jul 29];12(4):492. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2977003/
49. Bart van der Worp H, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med [Internet]. 2010 Mar [cited 2025 Jul 29];7(3):1–8. Available from: https://pubmed.ncbi.nlm.nih.gov/20361020/
50. Hooijmans CR, Ritskes-Hoitinga M. Progress in Using Systematic Reviews of Animal Studies to Improve Translational Research. PLoS Med [Internet]. 2013 Jul [cited 2025 Jul 29];10(7). Available from: https://pubmed.ncbi.nlm.nih.gov/23874162/
51. Hamilton BK. Current approaches to prevent and treat GVHD after allogeneic stem cell transplantation. Hematology: the American Society of Hematology Education Program [Internet]. 2018 Nov 30 [cited 2025 Jul 29];2018(1):228. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6246030/
52. Dobrovolskaia MA, McNeil SE. Immunological properties of engineered nanomaterials. Nat Nanotechnol [Internet]. 2007 [cited 2025 Jul 29];2(8):469–78. Available from: https://pubmed.ncbi.nlm.nih.gov/18654343/
53. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity [Internet]. 2016 Mar 15 [cited 2025 Jul 29];44(3):439–49. Available from: https://pubmed.ncbi.nlm.nih.gov/26982352/