Clin Transplant Res.  2024 Dec;38(4):341-353. 10.4285/ctr.24.0047.

Contribution of long-lived plasma cells to antibody-mediated allograft rejection

• Jang E
• Youn J

• KMID: 2563955
• DOI: http://doi.org/10.4285/ctr.24.0047

Abstract

Persistent alloantigens derived from allograft tissues can be recognized by the host’s alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.

Keyword

Allografts; Graft rejection; Antibody-producing cells; Plasma cells

Figure

• 

  Fig. 1 Humoral alloimmune responses in the context of solid organ transplantation. Adaptive immune responses to alloantigens are initiated by the activation of alloreactive dendritic cells. Within secondary lymphoid organs, B cells that have engaged with alloantigens interact with cognate CD4+ T cells at the interface of the T cell zone and the follicle. This interaction prompts the B cells to proliferate and differentiate into either extrafollicular PCs or GC B cells. The latter undergo a mutation-prone proliferation process and eventually give rise to memory B cells and affinity-matured PCs. Whether generated by the extrafollicular or GC responses, most PCs are short-lived. However, a subset migrates to the bone marrow, which provides survival niches. In the bone marrow, they further differentiate into LLPCs. LLPCs can also be found in intragraft tissues, where they may develop in situ within tertiary lymphoid clusters that form in the graft, or they may migrate from secondary lymphoid organs. DC, dendritic cell; SLPC, short-lived plasma cell; eTFH, extrafollicular helper T cell; TFH, follicular helper T cell; GC, germinal center; FDC, follicular dendritic cell; SHM, somatic hypermutation; PC, plasma cell; TLC, tertiary lymphoid cluster; LLPC, long-lived PC.

• 

  Fig. 2 Characteristics of LLPCs. LLPCs exhibit numerous characteristics that distinguish them from SLPCs. Molecules associated with plasma cell survival and function are upregulated in LLPCs, whereas B cell markers are downregulated. These molecular changes not only contribute to the resistance of LLPCs to traditional cytostatic treatments and B cell depletion therapies but also inform the mechanisms of action for ongoing therapeutic trials. SLPC, short-lived plasma cell; LLPC, long-lived plasma cell; ATG, autophagy gene; BCMA, B cell maturation antigen.

Reference

1. Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniego-Picota MD, et al. 2017; The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant. 17:1574–84. DOI: 10.1111/ajt.14161. PMID: 27977905. PMCID: PMC5445019.

2. Everly MJ, Rebellato LM, Haisch CE, Ozawa M, Parker K, Briley KP, et al. 2013; Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation. 95:410–7. DOI: 10.1097/TP.0b013e31827d62e3. PMID: 23380861.

3. Viglietti D, Loupy A, Vernerey D, Bentlejewski C, Gosset C, Aubert O, et al. 2017; Value of donor-specific anti-HLA antibody monitoring and characterization for risk stratification of kidney allograft loss. J Am Soc Nephrol. 28:702–15. DOI: 10.1681/ASN.2016030368. PMID: 27493255. PMCID: PMC5280026.

4. Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, et al. 2015; Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant. 15:2921–30. DOI: 10.1111/ajt.13347. PMID: 26096305.

5. Smith JD, Banner NR, Hamour IM, Ozawa M, Goh A, Robinson D, et al. 2011; De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant. 11:312–9. DOI: 10.1111/j.1600-6143.2010.03383.x. PMID: 21219570.

6. Morrell MR, Pilewski JM, Gries CJ, Pipeling MR, Crespo MM, Ensor CR, et al. 2014; De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation. J Heart Lung Transplant. 33:1288–94. DOI: 10.1016/j.healun.2014.07.018. PMID: 25443870.

7. Kaneku H, O'Leary JG, Banuelos N, Jennings LW, Susskind BM, Klintmalm GB, et al. 2013; De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant. 13:1541–8. DOI: 10.1111/ajt.12212. PMID: 23721554. PMCID: PMC4408873.

8. Cheng EY, Everly MJ, Kaneku H, Banuelos N, Wozniak LJ, Venick RS, et al. 2017; Prevalence and clinical impact of donor-specific alloantibody among intestinal transplant recipients. Transplantation. 101:873–82. DOI: 10.1097/TP.0000000000001391. PMID: 27490417. PMCID: PMC7228620.

9. Lentine KL, Smith JM, Lyden GR, Miller JM, Dolan TG, Bradbrook K, et al. 2024; OPTN/SRTR 2022 annual data report: kidney. Am J Transplant. 24(2 Suppl 1):S19–118. DOI: 10.1016/j.ajt.2024.01.012. PMID: 38431360.

10. Kwong AJ, Kim WR, Lake JR, Schladt DP, Schnellinger EM, Gauntt K, et al. 2024; OPTN/SRTR 2022 annual data report: liver. Am J Transplant. 24(2 Suppl 1):S176–265. DOI: 10.1016/j.ajt.2024.01.014. PMID: 38431359.

11. Valapour M, Lehr CJ, Schladt DP, Smith JM, Swanner K, Weibel CJ, et al. 2024; OPTN/SRTR 2022 annual data report: lung. Am J Transplant. 24(2 Suppl 1):S394–456. DOI: 10.1016/j.ajt.2024.01.017. PMID: 38431363.

12. Butler CL, Valenzuela NM, Thomas KA, Reed EF. 2017; Not all antibodies are created equal: factors that influence antibody mediated rejection. J Immunol Res. 2017:7903471. DOI: 10.1155/2017/7903471. PMID: 28373996. PMCID: PMC5360970.

13. Zorn E, See SB. 2017; Polyreactive natural antibodies in transplantation. Curr Opin Organ Transplant. 22:8–13. DOI: 10.1097/MOT.0000000000000376. PMID: 28005572. PMCID: PMC8667280.

14. Notkins AL. 2004; Polyreactivity of antibody molecules. Trends Immunol. 25:174–9. DOI: 10.1016/j.it.2004.02.004. PMID: 15039043.

15. Alba AC, Tinckam K, Foroutan F, Nelson LM, Gustafsson F, Sander K, et al. 2015; Factors associated with anti-human leukocyte antigen antibodies in patients supported with continuous-flow devices and effect on probability of transplant and post-transplant outcomes. J Heart Lung Transplant. 34:685–92. DOI: 10.1016/j.healun.2014.11.024. PMID: 25638296.

16. Bielmann D, Hönger G, Lutz D, Mihatsch MJ, Steiger J, Schaub S. 2007; Pretransplant risk assessment in renal allograft recipients using virtual crossmatching. Am J Transplant. 7:626–32. DOI: 10.1111/j.1600-6143.2007.01667.x. PMID: 17352712.

17. Irving CA, Carter V, Gennery AR, Parry G, Griselli M, Hasan A, et al. 2015; Effect of persistent versus transient donor-specific HLA antibodies on graft outcomes in pediatric cardiac transplantation. J Heart Lung Transplant. 34:1310–7. DOI: 10.1016/j.healun.2015.05.001. PMID: 26123951.

18. Roux A, Bendib Le Lan I, Holifanjaniaina S, Thomas KA, Hamid AM, Picard C, et al. 2016; Antibody-mediated rejection in lung transplantation: clinical outcomes and donor-specific antibody characteristics. Am J Transplant. 16:1216–28. DOI: 10.1111/ajt.13589. PMID: 26845386.

19. Tran A, Fixler D, Huang R, Meza T, Lacelle C, Das BB. 2016; Donor-specific HLA alloantibodies: impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation. J Heart Lung Transplant. 35:87–91. DOI: 10.1016/j.healun.2015.08.008. PMID: 26422083.

20. de Kort H, Munivenkatappa RB, Berger SP, Eikmans M, van der Wal A, de Koning EJ, et al. 2010; Pancreas allograft biopsies with positive c4d staining and anti-donor antibodies related to worse outcome for patients. Am J Transplant. 10:1660–7. DOI: 10.1111/j.1600-6143.2010.03079.x. PMID: 20455878.

21. Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, et al. 2009; Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 9:2520–31. DOI: 10.1111/j.1600-6143.2009.02799.x. PMID: 19843030.

22. Loupy A, Toquet C, Rouvier P, Beuscart T, Bories MC, Varnous S, et al. 2016; Late failing heart allografts: pathology of cardiac allograft vasculopathy and association with antibody-mediated rejection. Am J Transplant. 16:111–20. DOI: 10.1111/ajt.13529. PMID: 26588356.

23. Wozniak LJ, Hickey MJ, Venick RS, Vargas JH, Farmer DG, Busuttil RW, et al. 2015; Donor-specific HLA antibodies are associated with late allograft dysfunction after pediatric liver transplantation. Transplantation. 99:1416–22. DOI: 10.1097/TP.0000000000000796. PMID: 26038872. PMCID: PMC5283576.

24. Iacob S, Cicinnati VR, Lindemann M, Heinemann FM, Radtke A, Kaiser GM, et al. 2015; Donor-specific anti-HLA antibodies and endothelial C4d deposition-association with chronic liver allograft failure. Transplantation. 99:1869–75. DOI: 10.1097/TP.0000000000000613. PMID: 25706274.

25. Smith RN, Brousaides N, Grazette L, Saidman S, Semigran M, Disalvo T, et al. 2005; C4d deposition in cardiac allografts correlates with alloantibody. J Heart Lung Transplant. 24:1202–10. DOI: 10.1016/j.healun.2004.07.021. PMID: 16143234.

26. Coxon A, Cullere X, Knight S, Sethi S, Wakelin MW, Stavrakis G, et al. 2001; Fc gamma RIII mediates neutrophil recruitment to immune complexes: a mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity. 14:693–704. DOI: 10.1016/S1074-7613(01)00150-9. PMID: 11420040.

27. Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G, et al. 2010; NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant. 10:1812–22. DOI: 10.1111/j.1600-6143.2010.03201.x. PMID: 20659089.

28. Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee SR. 1995; Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant. 14:632–9.

29. Miyagawa-Hayashino A, Yoshizawa A, Uchida Y, Egawa H, Yurugi K, Masuda S, et al. 2012; Progressive graft fibrosis and donor-specific human leukocyte antigen antibodies in pediatric late liver allografts. Liver Transpl. 18:1333–42. DOI: 10.1002/lt.23534. PMID: 22888064.

30. Ioannou A, Dalle Lucca J, Tsokos GC. 2011; Immunopathogenesis of ischemia/reperfusion-associated tissue damage. Clin Immunol. 141:3–14. DOI: 10.1016/j.clim.2011.07.001. PMID: 21839685.

31. Jin H, Yang K, Zhang H, Chen Y, Qi H, Fan Z, et al. 2019; Expansion of circulating extrafollicular helper T-like cells in patients with chronic graft-versus-host disease. J Autoimmun. 100:95–104. DOI: 10.1016/j.jaut.2019.03.006. PMID: 30878167.

32. Deng R, Hurtz C, Song Q, Yue C, Xiao G, Yu H, et al. 2017; Extrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease. Nat Commun. 8:978. DOI: 10.1038/s41467-017-00880-2. PMID: 29042531. PMCID: PMC5645449.

33. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zúñiga E, et al. 2003; Extrafollicular antibody responses. Immunol Rev. 194:8–18. DOI: 10.1034/j.1600-065X.2003.00058.x. PMID: 12846803.

34. Allen CD, Okada T, Cyster JG. 2007; Germinal-center organization and cellular dynamics. Immunity. 27:190–202. DOI: 10.1016/j.immuni.2007.07.009. PMID: 17723214. PMCID: PMC2242846.

35. Batista FD, Harwood NE. 2009; The who, how and where of antigen presentation to B cells. Nat Rev Immunol. 9:15–27. DOI: 10.1038/nri2454. PMID: 19079135.

36. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, et al. 2012; Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 119:1570–80. DOI: 10.1182/blood-2011-07-364414. PMID: 22072556. PMCID: PMC3286218.

37. Basso K, Dalla-Favera R. 2010; BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol. 105:193–210. DOI: 10.1016/S0065-2776(10)05007-8. PMID: 20510734.

38. Pridans C, Holmes ML, Polli M, Wettenhall JM, Dakic A, Corcoran LM, et al. 2008; Identification of Pax5 target genes in early B cell differentiation. J Immunol. 180:1719–28. DOI: 10.4049/jimmunol.180.3.1719. PMID: 18209069.

39. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, et al. 2004; XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 21:81–93. DOI: 10.1016/j.immuni.2004.06.010. PMID: 15345222.

40. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH. 2003; Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol. 4:321–9. DOI: 10.1038/ni907. PMID: 12612580.

41. Ochiai K, Katoh Y, Ikura T, Hoshikawa Y, Noda T, Karasuyama H, et al. 2006; Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. J Biol Chem. 281:38226–34. DOI: 10.1074/jbc.M607592200. PMID: 17046816.

42. Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, et al. 2013; Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity. 38:918–29. DOI: 10.1016/j.immuni.2013.04.009. PMID: 23684984. PMCID: PMC3690549.

43. Brynjolfsson SF, Persson Berg L, Olsen Ekerhult T, Rimkute I, Wick MJ, Mårtensson IL, et al. 2018; Long-lived plasma cells in mice and men. Front Immunol. 9:2673. DOI: 10.3389/fimmu.2018.02673. PMID: 30505309. PMCID: PMC6250827.

44. Lightman SM, Utley A, Lee KP. 2019; Survival of long-lived plasma cells (LLPC): piecing together the puzzle. Front Immunol. 10:965. DOI: 10.3389/fimmu.2019.00965. PMID: 31130955. PMCID: PMC6510054.

45. Tellier J, Tarasova I, Nie J, Smillie CS, Fedele PL, Cao WH, et al. 2024; Unraveling the diversity and functions of tissue-resident plasma cells. Nat Immunol. 25:330–42. DOI: 10.1038/s41590-023-01712-w. PMID: 38172260.

46. Robinson MJ, Ding Z, Dowling MR, Hill DL, Webster RH, McKenzie C, et al. 2023; Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan. Immunity. 56:1596–12. DOI: 10.1016/j.immuni.2023.04.015. PMID: 37164016.

47. Liu X, Yao J, Zhao Y, Wang J, Qi H. 2022; Heterogeneous plasma cells and long-lived subsets in response to immunization, autoantigen and microbiota. Nat Immunol. 23:1564–76. DOI: 10.1038/s41590-022-01345-5. PMID: 36316480.

48. Halliley JL, Tipton CM, Liesveld J, Rosenberg AF, Darce J, Gregoretti IV, et al. 2015; Long-lived plasma cells are contained within the CD19(-)CD38(hi)CD138(+) subset in human bone marrow. Immunity. 43:132–45. DOI: 10.1016/j.immuni.2015.06.016. PMID: 26187412. PMCID: PMC4680845.

49. Koike T, Fujii K, Kometani K, Butler NS, Funakoshi K, Yari S, et al. 2023; Progressive differentiation toward the long-lived plasma cell compartment in the bone marrow. J Exp Med. 220:e20221717. DOI: 10.1084/jem.20221717. PMID: 36515679. PMCID: PMC9754767.

50. Manz RA, Thiel A, Radbruch A. 1997; Lifetime of plasma cells in the bone marrow. Nature. 388:133–4. DOI: 10.1038/40540. PMID: 9217150.

51. Fooksman DR, Jing Z, Park R. 2024; New insights into the ontogeny, diversity, maturation and survival of long-lived plasma cells. Nat Rev Immunol. 24:461–70. DOI: 10.1038/s41577-024-00991-0. PMID: 38332373.

52. Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. 2004; Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 200:967–77. DOI: 10.1084/jem.20040973. PMID: 15492122. PMCID: PMC2211847.

53. Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. 2005; Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med. 202:1471–6. DOI: 10.1084/jem.20051611. PMID: 16314438. PMCID: PMC2213334.

54. McCarron MJ, Park PW, Fooksman DR. 2017; CD138 mediates selection of mature plasma cells by regulating their survival. Blood. 129:2749–59. DOI: 10.1182/blood-2017-01-761643. PMID: 28381397. PMCID: PMC5437827.

55. Rozanski CH, Arens R, Carlson LM, Nair J, Boise LH, Chanan-Khan AA, et al. 2011; Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med. 208:1435–46. DOI: 10.1084/jem.20110040. PMID: 21690252. PMCID: PMC3135367.

56. O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. 2004; BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 199:91–8. DOI: 10.1084/jem.20031330. PMID: 14707116. PMCID: PMC1887725.

57. Peperzak V, Vikström I, Walker J, Glaser SP, LePage M, Coquery CM, et al. 2013; Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 14:290–7. DOI: 10.1038/ni.2527. PMID: 23377201. PMCID: PMC4041127.

58. Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T. 2004; Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity. 20:707–18. DOI: 10.1016/j.immuni.2004.05.001. PMID: 15189736.

59. Chu VT, Fröhlich A, Steinhauser G, Scheel T, Roch T, Fillatreau S, et al. 2011; Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol. 12:151–9. DOI: 10.1038/ni.1981. PMID: 21217761.

60. Winter O, Moser K, Mohr E, Zotos D, Kaminski H, Szyska M, et al. 2010; Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood. 116:1867–75. DOI: 10.1182/blood-2009-12-259457. PMID: 20538807.

61. Geffroy-Luseau A, Jégo G, Bataille R, Campion L, Pellat-Deceunynck C. 2008; Osteoclasts support the survival of human plasma cells in vitro. Int Immunol. 20:775–82. DOI: 10.1093/intimm/dxn035. PMID: 18397910.

62. Cassese G, Lindenau S, de Boer B, Arce S, Hauser A, Riemekasten G, et al. 2001; Inflamed kidneys of NZB /W mice are a major site for the homeostasis of plasma cells. Eur J Immunol. 31:2726–32. DOI: 10.1002/1521-4141(200109)31:9<2726::AID-IMMU2726>3.0.CO;2-H. PMID: 11536171.

63. Tsubaki T, Takegawa S, Hanamoto H, Arita N, Kamogawa J, Yamamoto H, et al. 2005; Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of early rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. Clin Exp Immunol. 141:363–71. DOI: 10.1111/j.1365-2249.2005.02850.x. PMID: 15996201. PMCID: PMC1809426.

64. van Laar JM, Melchers M, Teng YK, van der Zouwen B, Mohammadi R, Fischer R, et al. 2007; Sustained secretion of immunoglobulin by long-lived human tonsil plasma cells. Am J Pathol. 171:917–27. DOI: 10.2353/ajpath.2007.070005. PMID: 17690187. PMCID: PMC1959503.

65. Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, et al. 2004; Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med. 199:1577–84. DOI: 10.1084/jem.20040168. PMID: 15173206. PMCID: PMC2211779.

66. Erickson LD, Lin LL, Duan B, Morel L, Noelle RJ. 2003; A genetic lesion that arrests plasma cell homing to the bone marrow. Proc Natl Acad Sci U S A. 100:12905–10. DOI: 10.1073/pnas.2131686100. PMID: 14555759. PMCID: PMC240717.

67. Jang E, Cho WS, Cho ML, Park HJ, Oh HJ, Kang SM, et al. 2011; Foxp3+ regulatory T cells control humoral autoimmunity by suppressing the development of long-lived plasma cells. J Immunol. 186:1546–53. DOI: 10.4049/jimmunol.1002942. PMID: 21209284.

68. Mahévas M, Patin P, Huetz F, Descatoire M, Cagnard N, Bole-Feysot C, et al. 2013; B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest. 123:432–42. DOI: 10.1172/JCI65689. PMID: 23241960. PMCID: PMC3533302.

69. Mahévas M, Michel M, Vingert B, Moroch J, Boutboul D, Audia S, et al. 2015; Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab. J Autoimmun. 62:22–30. DOI: 10.1016/j.jaut.2015.05.006. PMID: 26112660.

70. Jang E, Cho S, Pyo S, Nam JW, Youn J. 2021; An inflammatory loop between spleen-derived myeloid cells and CD4+ t cells leads to accumulation of long-lived plasma cells that exacerbates lupus autoimmunity. Front Immunol. 12:631472. DOI: 10.3389/fimmu.2021.631472. PMID: 33643317. PMCID: PMC7904883.

71. Jang E, Cho WS, Oh YK, Cho ML, Kim JM, Paik DJ, et al. 2016; Splenic long-lived plasma cells promote the development of follicular helper T cells during autoimmune responses. J Immunol. 196:1026–35. DOI: 10.4049/jimmunol.1401059. PMID: 26729802.

72. Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac M, et al. 2003; Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol. 171:1684–90. DOI: 10.4049/jimmunol.171.4.1684. PMID: 12902466.

73. Underhill GH, Minges Wols HA, Fornek JL, Witte PL, Kansas GS. 2002; IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood. 99:2905–12. DOI: 10.1182/blood.V99.8.2905. PMID: 11929781.

74. Turner CA Jr, Mack DH, Davis MM. 1994; Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 77:297–306. DOI: 10.1016/0092-8674(94)90321-2. PMID: 8168136.

75. Messika EJ, Lu PS, Sung YJ, Yao T, Chi JT, Chien YH, et al. 1998; Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J Exp Med. 188:515–25. DOI: 10.1084/jem.188.3.515. PMID: 9687529. PMCID: PMC2212483.

76. Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K. 2003; Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity. 19:607–20. DOI: 10.1016/S1074-7613(03)00267-X. PMID: 14563324.

77. Iwakoshi NN, Lee AH, Glimcher LH. 2003; The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev. 194:29–38. DOI: 10.1034/j.1600-065X.2003.00057.x. PMID: 12846805.

78. Jeong M, Jang E, Choi SS, Ji C, Lee K, Youn J. 2017; The function of FK506-binding protein 13 in protein quality control protects plasma cells from endoplasmic reticulum stress-associated apoptosis. Front Immunol. 8:222. DOI: 10.3389/fimmu.2017.00222. PMID: 28303141. PMCID: PMC5332356.

79. Deretic V, Saitoh T, Akira S. 2013; Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 13:722–37. DOI: 10.1038/nri3532. PMID: 24064518. PMCID: PMC5340150.

80. Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, et al. 2013; Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol. 14:298–305. DOI: 10.1038/ni.2524. PMID: 23354484.

81. Aronov M, Tirosh B. 2016; Metabolic control of plasma cell differentiation: what we know and what we don't know. J Clin Immunol. 36(Suppl 1):12–7. DOI: 10.1007/s10875-016-0246-9. PMID: 26910101.

82. Lam WY, Becker AM, Kennerly KM, Wong R, Curtis JD, Llufrio EM, et al. 2016; Mitochondrial pyruvate import promotes long-term survival of antibody-secreting plasma cells. Immunity. 45:60–73. DOI: 10.1016/j.immuni.2016.06.011. PMID: 27396958. PMCID: PMC4956536.

83. Bortnick A, Chernova I, Quinn WJ 3rd, Mugnier M, Cancro MP, Allman D. 2012; Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens. J Immunol. 188:5389–96. DOI: 10.4049/jimmunol.1102808. PMID: 22529295. PMCID: PMC4341991.

84. Taillardet M, Haffar G, Mondière P, Asensio MJ, Gheit H, Burdin N, et al. 2009; The thymus-independent immunity conferred by a pneumococcal polysaccharide is mediated by long-lived plasma cells. Blood. 114:4432–40. DOI: 10.1182/blood-2009-01-200014. PMID: 19767510.

85. Reynolds AE, Kuraoka M, Kelsoe G. 2015; Natural IgM is produced by CD5- plasma cells that occupy a distinct survival niche in bone marrow. J Immunol. 194:231–42. DOI: 10.4049/jimmunol.1401203. PMID: 25429072. PMCID: PMC4272881.

86. Miller JJ 3rd, Cole LJ. 1967; Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine, and actinomycin D. J Exp Med. 126:109–25. DOI: 10.1084/jem.126.1.109. PMID: 6027642. PMCID: PMC2138307.

87. Slifka MK, Antia R, Whitmire JK, Ahmed R. 1998; Humoral immunity due to long-lived plasma cells. Immunity. 8:363–72. DOI: 10.1016/S1074-7613(00)80541-5. PMID: 9529153.

88. Silverman GJ, Weisman S. 2003; Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum. 48:1484–92. DOI: 10.1002/art.10947. PMID: 12794814.

89. Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, Mekki Y, et al. 2010; Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol. 185:717–28. DOI: 10.4049/jimmunol.0903589. PMID: 20525884.

90. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, et al. 2004; Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol. 15:603–12. DOI: 10.1097/01.ASN.0000113316.52371.2E. PMID: 14978162.

91. Baddoura FK, Nasr IW, Wrobel B, Li Q, Ruddle NH, Lakkis FG. 2005; Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection. Am J Transplant. 5:510–6. DOI: 10.1111/j.1600-6143.2004.00714.x. PMID: 15707405.

92. Thaunat O, Field AC, Dai J, Louedec L, Patey N, Bloch MF, et al. 2005; Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A. 102:14723–8. DOI: 10.1073/pnas.0507223102. PMID: 16192350. PMCID: PMC1253595.

93. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. 2017; Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 139(3 Suppl):S1–46. DOI: 10.1016/j.jaci.2016.09.023. PMID: 28041678.

94. Bonomini V, Vangelista A, Frascà GM, Di Felice A, Liviano D'Arcangelo G. 1985; Effects of plasmapheresis in renal transplant rejection: a controlled study. Trans Am Soc Artif Intern Organs. 31:698–703.

95. Allen NH, Dyer P, Geoghegan T, Harris K, Lee HA, Slapak M. 1983; Plasma exchange in acute renal allograft rejection: a controlled trial. Transplantation. 35:425–8. DOI: 10.1097/00007890-198305000-00006. PMID: 6342220.

96. Kirubakaran MG, Disney AP, Norman J, Pugsley DJ, Mathew TH. 1981; A controlled trial of plasmapheresis in the treatment of renal allograft rejection. Transplantation. 32:164–5. DOI: 10.1097/00007890-198108000-00019. PMID: 7027553.

97. Lefaucheur C, Viglietti D, Hidalgo LG, Ratner LE, Bagnasco SM, Batal I, et al. 2018; Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment. J Am Soc Nephrol. 29:620–35. DOI: 10.1681/ASN.2017050589. PMID: 29042454. PMCID: PMC5791056.

98. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. 2008; Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 359:242–51. DOI: 10.1056/NEJMoa0707894. PMID: 18635429.

99. Sautenet B, Blancho G, Büchler M, Morelon E, Toupance O, Barrou B, et al. 2016; One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation. 100:391–9. DOI: 10.1097/TP.0000000000000958. PMID: 26555944.

100. Bailly E, Ville S, Blancho G, Morelon E, Bamoulid J, Caillard S, et al. 2020; An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation. Transpl Int. 33:786–95. DOI: 10.1111/tri.13613. PMID: 32279367.

101. Huang H, Benoist C, Mathis D. 2010; Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A. 107:4658–63. DOI: 10.1073/pnas.1001074107. PMID: 20176942. PMCID: PMC2842072.

102. Kamburova EG, Koenen HJ, Borgman KJ, ten Berge IJ, Joosten I, Hilbrands LB. 2013; A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function. Am J Transplant. 13:1503–11. DOI: 10.1111/ajt.12220. PMID: 23570303.

103. Looney CM, Schroeder A, Tavares E, Garg J, Schindler T, Vincenti F, et al. 2023; Obinutuzumab effectively depletes key B-cell subsets in blood and tissue in end-stage renal disease patients. Transplant Direct. 9:e1436. DOI: 10.1097/TXD.0000000000001436. PMID: 36700064. PMCID: PMC9851678.

104. Arnold J, Dass S, Twigg S, Jones CH, Rhodes B, Hewins P, et al. 2022; Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. Rheumatology (Oxford). 61:4905–9. DOI: 10.1093/rheumatology/keac150. PMID: 35266512.

105. Kwun J, Burghuber C, Manook M, Iwakoshi N, Gibby A, Hong JJ, et al. 2017; Humoral compensation after bortezomib treatment of allosensitized recipients. J Am Soc Nephrol. 28:1991–6. DOI: 10.1681/ASN.2016070727. PMID: 28232617. PMCID: PMC5491279.

106. Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, et al. 2018; A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol. 29:591–605. DOI: 10.1681/ASN.2017070818. PMID: 29242250. PMCID: PMC5791086.

107. Woodle ES, Shields AR, Ejaz NS, Sadaka B, Girnita A, Walsh RC, et al. 2015; Prospective iterative trial of proteasome inhibitor-based desensitization. Am J Transplant. 15:101–18. DOI: 10.1111/ajt.13050. PMID: 25534446.

108. Ensor CR, Yousem SA, Marrari M, Morrell MR, Mangiola M, Pilewski JM, et al. 2017; Proteasome inhibitor carfilzomib-based therapy for antibody-mediated rejection of the pulmonary allograft: use and short-term findings. Am J Transplant. 17:1380–8. DOI: 10.1111/ajt.14222. PMID: 28173620.

109. van de Donk NW, Zweegman S. 2023; T-cell-engaging bispecific antibodies in cancer. Lancet. 402:142–58. DOI: 10.1016/S0140-6736(23)00521-4. PMID: 37271153.

110. Study for desensitization of chronic kidney disease in adult patients in need of a kidney transplant who are highly sensitized to human leukocyte antigen. ClinicalTrials.gov identifier: NCT05092347. Updated 2024 Jul 31. Accessed 2024 Dec 6. https://clinicaltrials.gov/study/NCT05092347.

111. Tacchetti P, Barbato S, Mancuso K, Zamagni E, Cavo M. 2024; Bispecific antibodies for the management of relapsed/refractory multiple myeloma. Cancers (Basel). 16:2337. DOI: 10.3390/cancers16132337. PMID: 39001399. PMCID: PMC11240369.

112. Du Z, Zhu S, Zhang X, Gong Z, Wang S. 2023; Non-conventional allogeneic anti-BCMA chimeric antigen receptor-based immune cell therapies for multiple myeloma treatment. Cancers (Basel). 15:567. DOI: 10.3390/cancers15030567. PMID: 36765526. PMCID: PMC9913487.

113. Hill JA, Kiem ES, Bhatti A, Liu W, Keane-Candib J, Fitzpatrick KS, et al. 2023; Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy. Am J Transplant. 23:416–22. DOI: 10.1016/j.ajt.2022.11.001. PMID: 36748802. PMCID: PMC10266802.

114. Zhang Z, Markmann C, Yu M, Agarwal D, Rostami S, Wang W, et al. 2023; Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies. Cell Rep Med. 4:101336. DOI: 10.1016/j.xcrm.2023.101336. PMID: 38118406. PMCID: PMC10772570.