Quick Links

Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.

Authors: Z Solhjou|||M Uehara|||B Bahmani|||O H Maarouf|||T Ichimura|||C R Brooks|||W Xu|||M Yilmaz|||A Elkhal|||S G Tullius|||I Guleria|||M M McGrath|||R Abdi

Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Tr

Publication Type: Journal Article

Date: 2017

DOI: NIHMS858790

ID: 28296000

Affiliations:

Affiliations

    Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Abstract

Ischemia-reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti-IL-6 nanoparticles with capacity for controlled release of anti-IL-6 over time. Compared with systemic delivery of anti-IL-6, localized delivery of anti-IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.


Chemical List

    Antibodies, Monoclonal|||Atg5 protein, mouse|||Autophagy-Related Protein 5|||Interleukin-6

Reference List

    Fischbein MP, et al. CD40 signaling replaces CD4+ lymphocytes and its blocking prevents chronic rejection of heart transplants. J Immunol. 2000 Dec 15;165(12):7316–22. Epub 2000/12/20. eng.|||Heuer M, et al. Use of marginal organs in kidney transplantation for marginal recipients: too close to the margins of safety? European journal of medical research. Jan 29;15(1):31–4.|||Huang E, Segev DL, Rabb H. Kidney transplantation in the elderly. Seminars in nephrology. 2009 Nov;29(6):621–35.|||Hirth RA, Pan Q, Schaubel DE, Merion RM. Efficient utilization of the expanded criteria donor (ECD) deceased donor kidney pool: an analysis of the effect of labeling. Am J Transplant. Feb;10(2):304–9.|||Baldwin WM, 3rd, et al. Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes. Transplantation. 1999 Sep 27;68(6):894–900. Epub 1999/10/09. eng.|||Wilhelm MJ, et al. Activation of the heart by donor brain death accelerates acute rejection after transplantation. Circulation. 2000;102(19):2426–33.|||Solhjou Z, Athar H, Xu Q, Abdi R. Emerging therapies targeting intra-organ inflammation in transplantation. Am J Transplant. 2015 Feb;15(2):305–11.|||Methe H, Zimmer E, Grimm C, Nabauer M, Koglin J. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation. Transplantation. 2004 Nov 15;78(9):1324–31. Epub 2004/11/19. eng.|||Morris S, et al. Autophagy-mediated dendritic cell activation is essential for innate cytokine production and APC function with respiratory syncytial virus responses. J Immunol. 2011 Oct 15;187(8):3953–61. Epub 2011/09/14. eng.|||Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011 Jan 20;469(7330):323–35. Epub 2011/01/21. eng.|||Corry RJ, Winn HJ, Russell PS. Primarily vascularized allografts of hearts in mice. The role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation. 1973 Oct;16(4):343–50.|||Azzi J, et al. Serine protease inhibitor 6 plays a critical role in protecting murine granzyme B-producing regulatory T cells. Journal of immunology. 2013 Sep 01;191(5):2319–27.|||Batal I, et al. The mechanisms of up-regulation of dendritic cell activity by oxidative stress. Journal of leukocyte biology. 2014 Aug;96(2):283–93.|||Wang CH, Wu SB, Wu YT, Wei YH. Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Experimental biology and medicine. 2013 May;238(5):450–60.|||Cui H, Kong Y, Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. Journal of signal transduction. 2012;2012:646354.|||Fiorina P, et al. Characterization of Donor Dendritic Cells and Enhancement of Dendritic Cell Efflux With cc-Chemokine Ligand 21: A Novel Strategy to Prolong Islet Allograft Survival. Diabetes. 2007 Apr;56(4):912–20.|||Jurewicz M, et al. Ischemic injury enhances dendritic cell immunogenicity via TLR4 and NF-kappa B activation. J Immunol. 2010 Mar 15;184(6):2939–48.|||Colussi C, Albertini MC, Coppola S, Rovidati S, Galli F, Ghibelli L. H2O2-induced block of glycolysis as an active ADP-ribosylation reaction protecting cells from apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2000 Nov;14(14):2266–76.|||Los M, Droge W, Stricker K, Baeuerle PA, Schulze-Osthoff K. Hydrogen peroxide as a potent activator of T lymphocyte functions. European journal of immunology. 1995 Jan;25(1):159–65.|||Takahashi A, et al. Preferential cell death of CD8+ effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress. J Immunol. 2005 May 15;174(10):6080–7.|||Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation. 2008 Apr 22;117(16):2131–41. Epub 2008/04/23. eng.|||Schenk S, et al. Alloreactive T cell responses and acute rejection of single class II MHC-disparate heart allografts are under strict regulation by CD4+ CD25+ T cells. J Immunol. 2005 Mar 15;174(6):3741–8.|||Yang J, et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol. 2011 Aug 1;187(3):1113–9. Epub 2011/06/24. eng.|||Okuda Y. Review of tocilizumab in the treatment of rheumatoid arthritis. Biologics. 2008 Mar;2(1):75–82. Epub 2008/03/01. eng.|||Murphy SP, Porrett PM, Turka LA. Innate immunity in transplant tolerance and rejection. Immunol Rev. 2011 May;241(1):39–48. Epub 2011/04/15. eng.|||Kupiec-Weglinski JW. Tolerance induction. Current opinion in organ transplantation. 2008 Aug;13(4):331–2.|||Land W. Innate alloimmunity: history and current knowledge. Exp Clin Transplant. 2007 Jun;5(1):575–84.|||Land W, et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation. 1994 Jan;57(2):211–7.|||Booth AJ, Grabauskiene S, Wood SC, Lu G, Burrell BE, Bishop DK. IL-6 promotes cardiac graft rejection mediated by CD4+ cells. Journal of immunology. 2011 Dec 1;187(11):5764–71.|||Liang Y, Christopher K, Finn PW, Colson YL, Perkins DL. Graft produced interleukin-6 functions as a danger signal and promotes rejection after transplantation. Transplantation. 2007 Sep 27;84(6):771–7.|||Shen H, Goldstein DR. IL-6 and TNF-alpha synergistically inhibit allograft acceptance. Journal of the American Society of Nephrology : JASN. 2009 May;20(5):1032–40.|||Zhao X, et al. Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012 Jan;12(1):90–101.|||Ireland JM, Unanue ER. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med. 2011 Dec 19;208(13):2625–32. Epub 2011/12/14. eng.|||Cooney R, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010 Jan;16(1):90–7. Epub 2009/12/08. eng.|||Lee HK, et al. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity. 2010 Feb 26;32(2):227–39.|||Reed M, Morris SH, Jang S, Mukherjee S, Yue Z, Lukacs NW. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection. J Immunol. 2013 Sep 1;191(5):2526–37. Epub 2013/07/31. eng.|||Hill BG, et al. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biological chemistry. 2012 Dec;393(12):1485–512.|||Zhang H, et al. Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci. 2009 Aug;110(2):376–88. Epub 2009/05/20. eng.|||She C, Zhu LQ, Zhen YF, Wang XD, Dong QR. Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPH maintenance: new implications for osteonecrosis treatment? Cell Signal. 2014 Jan;26(1):1–8. Epub 2013/10/02. eng.|||Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2008 Jan;15(1):171–82. Epub 2007/10/06. eng.|||Li L, Chen Y, Gibson SB. Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal. 2013 Jan;25(1):50–65.|||Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol. 2010 Dec 15;185(12):7349–57.|||Verghese DA, Yadav A, Bizargity P, Murphy B, Heeger PS, Schroppel B. Costimulatory blockade-induced allograft survival requires Beclin1. Am J Transplant. 2014 Mar;14(3):545–53.|||Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. The EMBO journal. 2007 Apr 4;26(7):1749–60.|||Chen Y, Azad MB, Gibson SB. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ. 2009 Jul;16(7):1040–52.|||Booth AJ, Bishop DK. TGF-beta, IL-6, IL-17 and CTGF direct multiple pathologies of chronic cardiac allograft rejection. Immunotherapy. 2010 Jul;2(4):511–20. Epub 2010/07/20. eng.|||Diaz JA, Booth AJ, Lu G, Wood SC, Pinsky DJ, Bishop DK. Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Aug;9(8):1773–83.|||Fogal B, et al. Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells. Journal of immunology. 2011 Dec 15;187(12):6268–80.|||Iida S, et al. Interleukin-6 receptor signaling disruption prevents cardiac allograft deterioration in mice. Exp Clin Transplant. 2012 Aug;10(4):375–85. Epub 2012/07/05. eng.|||Kimura N, et al. Interleukin-16 deficiency suppresses the development of chronic rejection in murine cardiac transplantation model. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011 Dec;30(12):1409–17.|||Kielar ML, et al. Maladaptive role of IL-6 in ischemic acute renal failure. Journal of the American Society of Nephrology : JASN. 2005 Nov;16(11):3315–25.|||Jong WM, et al. Reduced acute myocardial ischemia-reperfusion injury in IL-6-deficient mice employing a closed-chest model. Inflammation research : official journal of the European Histamine Research Society [et al] 2016 Jun;65(6):489–99.|||Patel NS, et al. Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion. The Journal of pharmacology and experimental therapeutics. 2005 Mar;312(3):1170–8.|||Nechemia-Arbely Y, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. Journal of the American Society of Nephrology : JASN. 2008 Jun;19(6):1106–15.|||de Vries DK, et al. Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Jul;9(7):1574–84.|||Camargo CA, Jr, Madden JF, Gao W, Selvan RS, Clavien PA. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology. 1997 Dec;26(6):1513–20.|||Denton MD, et al. The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection. Pediatr Transplant. 2000 Nov;4(4):252–60.|||Baratin M, Bonin K, Daniel C. Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition. European journal of immunology. 2004 Dec;34(12):3305–14. Epub 2004/10/16. eng.|||Marelli-Berg FM, Scott D, Bartok I, Peek E, Dyson J, Lechler RI. Activated murine endothelial cells have reduced immunogenicity for CD8+ T cells: a mechanism of immunoregulation? Journal of immunology. 2000 Oct 15;165(8):4182–9.|||Marelli-Berg FM, et al. Cognate recognition of the endothelium induces HY-specific CD8+ T-lymphocyte transendothelial migration (diapedesis) in vivo. Blood. 2004 Apr 15;103(8):3111–6. Epub 2004/04/09. eng.|||Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015 Sep;33(9):941–51. Epub 2015/09/09. eng.|||Azzi J, et al. Polylactide-cyclosporin A nanoparticles for targeted immunosuppression. FASEB Journal. 2010 Oct;24(10):3927–38.|||Fisher JD, Acharya AP, Little SR. Micro and nanoparticle drug delivery systems for preventing allotransplant rejection. Clin Immunol. 2015 Sep;160(1):24–35. Epub 2015/05/06. eng.|||Shirali AC, et al. Nanoparticle delivery of mycophenolic acid upregulates PD-L1 on dendritic cells to prolong murine allograft survival. Am J Transplant. 2011 Dec;11(12):2582–92. Epub 2011/09/03. eng.