1932

Abstract

Despite significant advances in the field of transplantation in the past two decades, current clinically available therapeutic options for immunomodulation remain fairly limited. The advent of calcineurin inhibitor–based immunosuppression has led to significant success in improving short-term graft survival; however, improvements in long-term graft survival have stalled. Solid organ transplantation provides a unique opportunity for immunomodulation of both the donor organ prior to implantation and the recipient post transplantation. Furthermore, therapies beyond targeting the adaptive immune system have the potential to ameliorate ischemic injury to the allograft and halt its aging process, augment its repair, and promote recipient immune tolerance. Other recent advances include expanding the donor pool by reducing organ discard, and bioengineering and genetically modifying organs from other species to generate transplantable organs. Therapies discussed here will likely be most impactful if individualized on the basis of specific donor and recipient considerations.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-050522-034012
2024-01-29
2024-04-30
Loading full text...

Full text loading...

/deliver/fulltext/med/75/1/annurev-med-050522-034012.html?itemId=/content/journals/10.1146/annurev-med-050522-034012&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Matas A. 2011. Calcineurin inhibitors: short-term friend, long-term foe?. Clin. Pharmacol. Ther. 90:20911
    [Google Scholar]
  2. 2.
    Kinnear G, Jones ND, Wood KJ. 2013. Costimulation blockade: current perspectives and implications for therapy. Transplantation 95:52735
    [Google Scholar]
  3. 3.
    Sharpe AH, Freeman GJ. 2002. The B7-CD28 superfamily. Nat. Rev. Immunol. 2:11626
    [Google Scholar]
  4. 4.
    Kirk AD, Harlan DM, Armstrong NN et al. 1997. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. PNAS 94:878994
    [Google Scholar]
  5. 5.
    Pearson TC, Alexander DZ, Winn KJ et al. 1994. Transplantation tolerance induced by CTLA4-Ig. Transplantation 57:17016
    [Google Scholar]
  6. 6.
    Vincenti F, Rostaing L, Grinyo J et al. 2016. Belatacept and long-term outcomes in kidney transplantation. N. Engl. J. Med. 374:33343
    [Google Scholar]
  7. 7.
    Hancock WW, Sayegh MH, Zheng XG et al. 1996. Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection. PNAS 93:1396772
    [Google Scholar]
  8. 8.
    Pierson RN, Chang AC, Blum MG et al. 1999. Prolongation of primate cardiac allograft survival by treatment with ANTI-CD40 ligand (CD154) antibody. Transplantation 68:18005
    [Google Scholar]
  9. 9.
    Liu D, Ford ML. 2020. CD11b is a novel alternate receptor for CD154 during alloimmunity. Am. J. Transplant 20:221625
    [Google Scholar]
  10. 10.
    Higginbotham L, Mathews D, Breeden CA et al. 2015. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 22:22130
    [Google Scholar]
  11. 11.
    Pinelli DF, Ford ML. 2015. Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance. Immunotherapy 7:399410
    [Google Scholar]
  12. 12.
    Henn V, Slupsky JR, Gräfe M et al. 1998. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:59194
    [Google Scholar]
  13. 13.
    Kim SC, Wakwe W, Higginbotham LB et al. 2017. Fc-silent anti-CD154 domain antibody effectively prevents nonhuman primate renal allograft rejection. Am. J. Transplant 17:118292
    [Google Scholar]
  14. 14.
    Jordan SC, Tyan D, Stablein D et al. 2004. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J. Am. Soc. Nephrol. 15:325662
    [Google Scholar]
  15. 15.
    Stegall MD, Gloor J, Winters JL et al. 2006. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am. J. Transplant 6:34651
    [Google Scholar]
  16. 16.
    Vo AA, Peng A, Toyoda M et al. 2010. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation 89:1095102
    [Google Scholar]
  17. 17.
    Kwun J, Matignon M, Manook M et al. 2019. Daratumumab in sensitized kidney transplantation: potentials and limitations of experimental and clinical use. J. Am. Soc. Nephrol. 30:120619
    [Google Scholar]
  18. 18.
    Moreno Gonzales MA, Gandhi MJ, Schinstock CA et al. 2017. 32 Doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti-HLA antibody. Transplantation 101:122227
    [Google Scholar]
  19. 19.
    Ezekian B, Schroder PM, Mulvihill MS et al. 2019. Pretransplant desensitization with costimulation blockade and proteasome inhibitor reduces DSA and delays antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients. J. Am. Soc. Nephrol. 30:2399411
    [Google Scholar]
  20. 20.
    Jordan SC, Legendre C, Desai NM et al. 2021. Imlifidase desensitization in crossmatch-positive, highly sensitized kidney transplant recipients: results of an international phase 2 trial (Highdes). Transplantation 105:180817
    [Google Scholar]
  21. 21.
    Schinstock CA, Bentall AJ, Smith BH et al. 2019. Long-term outcomes of eculizumab-treated positive crossmatch recipients: allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am. J. Transplant 19:167183
    [Google Scholar]
  22. 22.
    Doberer K, Duerr M, Halloran PF et al. 2021. A randomized clinical trial of anti-IL-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection. J. Am. Soc. Nephrol. 32:70822
    [Google Scholar]
  23. 23.
    Koenig A, Mezaache S, Callemeyn J et al. 2021. Missing self-induced activation of NK cells combines with non-complement-fixing donor-specific antibodies to accelerate kidney transplant loss in chronic antibody-mediated rejection. J. Am. Soc. Nephrol. 32:47994
    [Google Scholar]
  24. 24.
    Sawitzki B, Harden PN, Reinke P et al. 2020. Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet 395:162739
    [Google Scholar]
  25. 25.
    Waldmann H. 2021. Regulatory T cells and transplantation tolerance: emerging from the darkness?. Eur. J. Immunol. 51:158091
    [Google Scholar]
  26. 26.
    Lee K, Nguyen V, Lee KM et al. 2014. Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy. Am. J. Transplant. 14:2738
    [Google Scholar]
  27. 27.
    Lee LM, Zhang H, Lee K et al. 2021. A comparison of ex vivo expanded human regulatory T cells using allogeneic stimulated B cells or monocyte-derived dendritic cells. Front. Immunol. 12:679675
    [Google Scholar]
  28. 28.
    Dawson NAJ, Rosado-Sanchez I, Novakovsky GE et al. 2020. Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells. Sci. Transl. Med. 12:eaaz3866
    [Google Scholar]
  29. 29.
    Luo X, Pothoven KL, McCarthy D et al. 2008. ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms. PNAS 105:1452732
    [Google Scholar]
  30. 30.
    Husain I, Luo X. 2021. Apoptotic donor cells in transplantation. Front. Immunol. 12:626840
    [Google Scholar]
  31. 31.
    Singh A, Ramachandran S, Graham ML et al. 2019. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nat. Commun. 10:3495
    [Google Scholar]
  32. 32.
    Issa F, Strober S, Leventhal JR et al. 2021. The Fourth International Workshop on Clinical Transplant Tolerance. Am. J. Transplant. 21:2131
    [Google Scholar]
  33. 33.
    Leventhal J, Abecassis M, Miller J et al. 2012. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl. Med. 4:124ra28
    [Google Scholar]
  34. 34.
    Fitch ZW, Kang L, Li J et al. 2022. Introducing thymus for promoting transplantation tolerance. J. Allergy Clin. Immunol. 150:54956
    [Google Scholar]
  35. 35.
    Zeleniak A, Wiegand C, Liu W et al. 2022. De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids. Nat. Methods 19:130619
    [Google Scholar]
  36. 36.
    Palevski D, Levin-Kotler LP, Kain D et al. 2017. Loss of macrophage Wnt secretion improves remodeling and function after myocardial infarction in mice. J. Am. Heart Assoc. 6:e004387
    [Google Scholar]
  37. 37.
    Morelli AE, Bracamonte-Baran W, Burlingham WJ. 2017. Donor-derived exosomes: the trick behind the semidirect pathway of allorecognition. Curr. Opin. Organ. Transplant. 22:4654
    [Google Scholar]
  38. 38.
    Kolonics F, Szeifert V, Timár CI et al. 2020. The functional heterogeneity of neutrophil-derived extracellular vesicles reflects the status of the parent cell. Cells 9:2718
    [Google Scholar]
  39. 39.
    Wang Y, Zhao M, Liu S et al. 2020. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 11:924
    [Google Scholar]
  40. 40.
    Kou M, Huang L, Yang J et al. 2022. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?. Cell Death Dis. 13:580
    [Google Scholar]
  41. 41.
    Eken C, Martin PJ, Sadallah S et al. 2010. Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages. J. Biol. Chem. 285:3991421
    [Google Scholar]
  42. 42.
    Gregorini M, Corradetti V, Pattonieri EF et al. 2017. Perfusion of isolated rat kidney with mesenchymal stromal cells/extracellular vesicles prevents ischaemic injury. J. Cell. Mol. Med. 21:338193
    [Google Scholar]
  43. 43.
    Gennai S, Monsel A, Hao Q et al. 2015. Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am. J. Transplant. 15:240412
    [Google Scholar]
  44. 44.
    Dooley K, McConnell RE, Xu K et al. 2021. A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties. Mol. Ther. 29:172943
    [Google Scholar]
  45. 45.
    Azzi J, Yin Q, Uehara M et al. 2016. Targeted delivery of immunomodulators to lymph nodes. Cell Rep. 15:120213
    [Google Scholar]
  46. 46.
    Zhao J, Jung S, Li X et al. 2022. Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice. J. Clin. Investig. 132:e159672
    [Google Scholar]
  47. 47.
    Thorp EB, Boada C, Jarbath C, Luo X. 2020. Nanoparticle platforms for antigen-specific immune tolerance. Front. Immunol. 11:945
    [Google Scholar]
  48. 48.
    Shah S, Daneshmandi S, Hughes KR et al. 2019. Optimizing PLG nanoparticle-peptide delivery platforms for transplantation tolerance using an allogeneic skin transplant model. Biomaterials 210:7082
    [Google Scholar]
  49. 49.
    Roberts RA, Eitas TK, Byrne JD et al. 2015. Towards programming immune tolerance through geometric manipulation of phosphatidylserine. Biomaterials 72:110
    [Google Scholar]
  50. 50.
    Kox J, Moers C, Monbaliu D et al. 2018. The benefits of hypothermic machine preservation and short cold ischemia times in deceased donor kidneys. Transplantation 102:134450
    [Google Scholar]
  51. 51.
    van Rijn R, Schurink IJ, de Vries Y et al. 2021. Hypothermic machine perfusion in liver transplantation—a randomized trial. N. Engl. J. Med. 384:1391401
    [Google Scholar]
  52. 52.
    Henry SD, Nachber E, Tulipan J et al. 2012. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation. Am. J. Transplant. 12:247786
    [Google Scholar]
  53. 53.
    Hosgood SA, Moore T, Kleverlaan T et al. 2017. Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model. J. Transl. Med. 15:216
    [Google Scholar]
  54. 54.
    Stone JP, Critchley WR, Major T et al. 2016. Altered immunogenicity of donor lungs via removal of passenger leukocytes using ex vivo lung perfusion. Am. J. Transplant. 16:3343
    [Google Scholar]
  55. 55.
    Coppé JP, Patil CK, Rodier F et al. 2008. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol. 6:285368
    [Google Scholar]
  56. 56.
    Lu RJ, Wang EK, Benayoun BA. 2022. Functional genomics of inflamm-aging and immunosenescence. Brief Funct. Genomics 25:4355
    [Google Scholar]
  57. 57.
    Gasek NS, Kuchel GA, Kirkland JL, Xu M. 2021. Strategies for targeting senescent cells in human disease. Nat. Aging 1:87079
    [Google Scholar]
  58. 58.
    Iske J, Seyda M, Heinbokel T et al. 2020. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat. Commun. 11:4289
    [Google Scholar]
  59. 59.
    Giraldo JA, Weaver JD, Stabler CL. 2010. Enhancing clinical islet transplantation through tissue engineering strategies. J. Diabetes Sci. Technol. 4:123847
    [Google Scholar]
  60. 60.
    Kawakami T, Lichtnekert J, Thompson LJ et al. 2013. Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions. J. Immunol. 191:335872
    [Google Scholar]
  61. 61.
    Mandrycky C, Phong K, Zheng Y. 2017. Tissue engineering toward organ-specific regeneration and disease modeling. MRS Commun. 7:33247
    [Google Scholar]
  62. 62.
    Mantha S, Pillai S, Khayambashi P et al. 2019. Smart hydrogels in tissue engineering and regenerative medicine. Materials 12:3323
    [Google Scholar]
  63. 63.
    Badylak SF, Taylor D, Uygun K. 2011. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu. Rev. Biomed. Eng. 13:2753
    [Google Scholar]
  64. 64.
    Guan Y, Liu S, Sun C et al. 2015. The effective bioengineering method of implantation decellularized renal extracellular matrix scaffolds. Oncotarget 6:3612638
    [Google Scholar]
  65. 65.
    Ott HC, Matthiesen TS, Goh SK et al. 2008. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat. Med. 14:21321
    [Google Scholar]
  66. 66.
    Stabler CT, Lecht S, Mondrinos MJ et al. 2015. Revascularization of decellularized lung scaffolds: principles and progress. Am. J. Physiol. Lung Cell Mol. Physiol. 309:L127385
    [Google Scholar]
  67. 67.
    Luo Y, Wen J, Luo C et al. 1999. Pig xenogeneic antigen modification with green coffee bean alpha-galactosidase. Xenotransplantation 6:23848
    [Google Scholar]
  68. 68.
    Sandrin MS, Fodor WL, Mouhtouris E et al. 1995. Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis. Nat. Med. 1:126167
    [Google Scholar]
  69. 69.
    Kwiatkowski P, Artrip JH, Edwards NM et al. 1999. High-level porcine endothelial cell expression of α(1,2)-fucosyltransferase reduces human monocyte adhesion and activation. Transplantation 67:21926
    [Google Scholar]
  70. 70.
    Jagdale A, Nguyen H, Li J et al. 2020. Does expression of a human complement-regulatory protein on xenograft cells protect them from systemic complement activation?. Int. J. Surg. 83:18488
    [Google Scholar]
  71. 71.
    Ménoret S, Plat M, Blancho G et al. 2004. Characterization of human CD55 and CD59 transgenic pigs and kidney xenotransplantation in the pig-to-baboon combination. Transplantation 77:146871
    [Google Scholar]
  72. 72.
    Salvaris E, Fisicaro N, Harrison S et al. 2012. Generation of transgenic pigs co-expressing human thrombomodulin and CD39. Transplantation 94:784 (Abstr.)
    [Google Scholar]
  73. 73.
    Wang W, He W, Ruan Y, Geng Q. 2022. First pig-to-human heart transplantation. Innovation 3:100223
    [Google Scholar]
  74. 74.
    Montgomery RA, Stern JM, Lonze BE et al. 2022. Results of two cases of pig-to-human kidney xenotransplantation. N. Engl. J. Med. 386:188998
    [Google Scholar]
/content/journals/10.1146/annurev-med-050522-034012
Loading
  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error