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大学・研究所にある論文を検索できる 「Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts

Miyamoto, Ei 京都大学 DOI:10.14989/doctor.k23100

2021.03.23

概要

肺移植後の抗体関連拒絶は不可逆的な移植肺機能不全につながるものとして解決すべき重要な臨床課題である。特に血清学的に抗ドナー抗体が消失した、または未検出の状態で進行する抗体関連拒絶がしばしば問題となる。本論文では、肺移植片に対する液性免疫応答は循環血液を介したものに限らず肺移植片局所においても生じるという仮説に基づき、肺移植後の拒絶肺の組織培養液中に抗ドナー抗体が産生されるかを検証した。

ラットを用い、ドナーより心肺ブロックを採取し同所性左肺移植を行った。レシピエントに Lewis ラットを用い、同系移植では Lewis、主要組織適合遺伝子複合体(Major Histocompatibility Complex: MHC)ミスマッチである異系移植では Brown-Norway ラットをそれぞれドナーに用いた。異系移植レシピエントには Cyclosporine A (25mg/kg)を投与し、移植後 14 日または 35 日目まで継続したものをそれぞれ short IS 群、long IS 群とした。移植後 28 日, 63 日または 98 日後にレシピエントより肺移植片および血清を採取した。生理食塩水でフラッシュした肺移植片 100mg を細断し XVIVO15 組織培養液で 4 日間培養した。Brown-Norway ラット MHC class I 分子(RT-A1n)に対するラット IgG 抗体力価を定量化するため、マウス線維芽細胞株(L cell)に対し、RT-A1n を導入した細胞(L cell + A1n)を作成した。20 万個の L cell + A1n を(コントロールとして L cell)組織培養液上清またはレシピエント血清 100μL と混ぜたのち flow cytometry を用いて抗ラット IgG 抗体の平均蛍光強度(MFI)を求めた。摘出された肺移植片について急性肺障害、急性及び慢性肺移植片拒絶を組織学的にスコア化し、検討した。肺移植片内のリンパ球免疫染色を行った。

Short IS 群の異系移植片では同系移植片に比べ移植後 28 日目に急性肺移植片拒絶と血管障害の増強が認められ、98 日目には肺実質繊維化および細気管支閉塞の増強が認められた。移植後 98 日において、異系移植 long IS 群や同系移植に比べて、異系移植 short IS 群では肺移植片培養液上清と混合したのち洗浄した L cell + A1n では抗ラット IgG 抗体の MFI は有意に高く、また培養期間とともに増大した。一方で、レシピエント血清と混合した L cell + A1n では異系移植 short IS 群であっても抗ラット IgG 抗体の MFI の有意な上昇を認めなかった。移植後 98 日目の short IS 群の肺移植片内では T および B 細胞の密な増生を認め、ラット IgG および Ki-67 陽性 B 細胞及びレシピエント型 MHC class II(RT1-B)陽性抗原提示細胞が含まれていた。

本論文の結果は、抗ドナーMHC 抗体が慢性拒絶に至った肺移植後の移植片局所において産生される可能性を示唆した。本研究によって導かれる今後の方向性は移植片局所で産生される抗ドナー抗体が肺移植片慢性拒絶を引き起こす原因となるかの検討である。

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参考文献

1. Witt CA, Gaut JP, Yusen RD, et al. Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant. 2013;32:1034–1040.

2. Lobo LJ, Aris RM, Schmitz J, et al. Donor-specific antibodies are associ- ated with antibody-mediated rejection, acute cellular rejection, bronchiol- itis obliterans syndrome, and cystic fibrosis after lung transplantation. J Heart Lung Transplant. 2013;32:70–77.

3. Daoud AH, Betensley AD. Diagnosis and treatment of antibody mediated rejection in lung transplantation: a retrospective case series. Transpl Immunol. 2013;28:1–5.

4. Levine DJ, Glanville AR, Aboyoun C, et al. Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2016;35:397–406.

5. Kannabhiran D, Lee J, Schwartz JE, et al. Characteristics of circulating donor human leukocyte antigen-specific immunoglobulin G antibodies predictive of acute antibody-mediated rejection and kidney allograft failure. Transplantation. 2015;99:1156–1164.

6. Heilman RL, Nijim A, Desmarteau YM, et al. De novo donor-specific human leukocyte antigen antibodies early after kidney transplantation. Transplantation. 2014;98:1310–1315.

7. Tikkanen JM, Singer LG, Kim SJ, et al. De novo DQ donor-specific an- tibodies are associated with chronic lung allograft dysfunction after lung transplantation. Am J Respir Crit Care Med. 2016;194:596–606.

8. Monchaud C, Marin B, Estenne M, et al. Consensus conference on a composite endpoint for clinical trials on immunosuppressive drugs in lung transplantation. Transplantation. 2014;98:1331–1338.

9. Bachelet T, Couzi L, Lepreux S, et al. Kidney intragraft donor-specific antibodies as determinant of antibody-mediated lesions and poor graft outcome. Am J Transplant. 2013;13:2855–2864.

10. Huibers MM, Gareau AJ, Beerthuijzen JM, et al. Donor-specific antibodies are produced locally in ectopic lymphoid structures in cardiac allografts. Am J Transplant. 2017;17:246–254.

11. Visentin J, Chartier A, Massara L, et al. Lung intragraft donor-specific an- tibodies as a risk factor for graft loss. J Heart Lung Transplant. 2016;35: 1412–1413.

12. Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic “ignorance” of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6:686–688.

13. Nasr IW, Reel M, Oberbarnscheidt MH, et al. Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transplant. 2007;7:1071–1079.

14. Thaunat O, Field AC, Dai J, et al. Lymphoid neogenesis in chronic rejec- tion: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A. 2005;102:14723–14728.

15. Sato M, Hirayama S, Hwang DM, et al. The role of intrapulmonary de novo lymphoid tissue in obliterative bronchiolitis after lung transplantation. J Immunol. 2009;182:7307–7316.

16. Wagnetz D, Sato M, Hirayama S, et al. Rejection of tracheal allograft by intrapulmonary lymphoid neogenesis in the absence of secondary lym- phoid organs. Transplantation. 2012;93:1212–1220.

17. Plissonnier D, Henaff M, Poncet P, et al. Involvement of antibody- dependent apoptosis in graft rejection. Transplantation. 2000;69: 2601–2608.

18. Zhai W, Ge J, Inci I, et al. Simplified rat lung transplantation by using a modified cuff technique. J Invest Surg. 2008;21:33–37.

19. Tanaka S, Chen-Yoshikawa TF, Miyamoto E, et al. Vascular endothelial- cadherin expression after reperfusion correlates with lung injury in rat lung transplantation. Ann Thorac Surg. 2016;101:2161–2167.

20. Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working for- mulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26:1229–1242.

21. Wallace WD, Li N, Andersen CB, et al. Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies. J Heart Lung Transplant. 2016;35:40–48.

22. Saggar R, Ross DJ, Saggar R, et al. Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft. Am J Transplant. 2008;8:1921–1930.

23. Huibers MM, Gareau AJ, Vink A, et al. The composition of ectopic lym- phoid structures suggests involvement of a local immune response in car- diac allograft vasculopathy. J Heart Lung Transplant. 2015;34:734–745.

24. Zinkernagel RM, Ehl S, Aichele P, et al. Antigen localisation regulates im- mune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol Rev. 1997;156:199–209.

25. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10:927–934.

26. Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med. 2003;349:125–138.

27. Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230–242.

28. Colvin RB, Smith RN. Antibody-mediated organ-allograft rejection. Nat Rev Immunol. 2005;5:807–817.

29. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, et al. Persistence and re- sponsiveness of immunologic memory in the absence of secondary lym- phoid organs. Immunity. 2006;25:643–654.

30. GeurtsvanKessel CH, Willart MA, Bergen IM, et al. Dendritic cells are cru- cial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med. 2009;206:2339–2349.

31. Cassese G, Lindenau S, de Boer B, et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur J Immunol. 2001; 31:2726–2732.

32. Thaunat O, Patey N, Caligiuri G, et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol. 2010;185: 717–728.

33. Thaunat O, Graff-Dubois S, Brouard S, et al. Immune responses elicited in tertiary lymphoid tissues display distinctive features. PLoS One. 2010;5: e11398.

34. Charreau B. Signaling of endothelial cytoprotection in transplantation. Hum Immunol. 2012;73:1245–1252.

35. Halle S, Dujardin HC, Bakocevic N, et al. Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is main- tained by dendritic cells. J Exp Med. 2009;206:2593–2601.

36. Foo SY, Phipps S. Regulation of inducible BALT formation and contribu- tion to immunity and pathology. Mucosal Immunol. 2010;3:537–544.

37. Berry G, Burke M, Andersen C, et al. Pathology of pulmonary antibody- mediated rejection: 2012 update from the Pathology Council of the ISHLT. J Heart Lung Transplant. 2013;32:14–21.

38. Hidalgo LG, Campbell PM, Sis B, et al. De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathol- ogy and late graft failure. Am J Transplant. 2009;9:2532–2541.

39. Russell PS, Chase CM, Winn HJ, et al. Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol. 1994;152:5135–5141.

40. Safavi S, Robinson DR, Soresi S, et al. De novo donor HLA-specific anti- bodies predict development of bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2014;33:1273–1281.

41. Zeevi A, Lunz J, Feingold B, et al. Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant. 2013;32:98–105.

42. Tiriveedhi V, Takenaka M, Ramachandran S, et al. T regulatory cells play a significant role in modulating MHC class I antibody-induced obliterative air- way disease. Am J Transplant. 2012;12:2663–2674.

43. Jaramillo A, Smith CR, Maruyama T, et al. Anti-HLA class I antibody bind- ing to airway epithelial cells induces production of fibrogenic growth fac- tors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003;64:521–529.

44. Bian H, Reed EF. Alloantibody-mediated class I signal transduction in en- dothelial cells and smooth muscle cells: enhancement by IFN-gamma and TNF-alpha. J Immunol. 1999;163:1010–1018.

45. Lee RS, Yamada K, Houser SL, et al. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc Natl Acad Sci U S A. 2001;98:3276–3281.

46. Sato M, Keshavjee S, Liu M. Translational research: animal models of oblit- erative bronchiolitis after lung transplantation. Am J Transplant. 2009;9: 1981–1987.

47. Kwun J, Farris AB, Song H, et al. Impact of leukocyte function-associated antigen-1 blockade on endogenous allospecific T cells to multiple minor histocompatibility antigen mismatched cardiac allograft. Transplantation. 2015;99:2485–2493.

48. Hodge G, Hodge S, Yeo A, et al. BOS is associated with increased cyto- toxic pro-inflammatory CD8 T, NKT-like and NK cells in the small airways. Transplantation. 2016.

49. Ius F, Sommer W, Kieneke D, et al. IgM-enriched human intravenous immunoglobulin-based treatment of patients with early donor specific Anti-HLA antibodies after lung transplantation. Transplantation. 2016; 100:2682–2692.

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