nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical University10.24884/1561-6274-2018-22-6-47-55nefr-1627Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИ. КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯORIGINAL ARTICLES. CLINICAL INVESTIGATIONSПРОГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ CD3+, CD68+, CD20+ КЛЕТОК В ИНТЕРСТИЦИИ У БОЛЬНЫХ С ГЛОМЕРУЛИТОМ АЛЛОГРАФТА ПОЧКИTHE PROGNOSTIC SIGNIFICANCE OF CD3+, CD68+, CD20+ INTERSTITIAL CELLS IN PATIENTS WITH KIDNEY ALLOGRAFT GLOMERULITISДобронравовВ. А.DobronravovV. A.

197022, Россия, Санкт-Петербург, ул. Л. Толстого, д. 17.

Проф. Добронравов Владимир Александрович, д-р мед. наук, заместитель директора.

197022, Russia, Lva Tostogo str. 17.

Prof. Vladimir A. Dobronravov, MD, PhD, DSci, vice director.

dobronravov@nephrolog.ruМухаметдиноваА. О.MukhametdinovaA. O.

197022, Россия, Санкт-Петербург, ул. Л. Толстого, д. 6/8.

Мухаметдинова Анастасия Олеговна.

197022, Russia, Saint-Petersburg, Str. Leo Tolstoy, 6/8.

Anastasiya O. Muhametdinova.

muhametdinovanastya@mail.ruХраброваМ. С.KhrabrovaM. S.

197022, Россия, Санкт-Петербург, ул. Л. Толстого, д. 17, корп. 54.

Храброва Мария Сергеевна, канд. мед. наук.

Тел.: (812) 338-01-65.

197022, Russia, Saint-Petersburg, Str. Leo Tolstoy, 17 build 54.

Maria S. Khrabrova, MD, PhD.

Phone: +78123380165.

hrabrovamc@gmail.comНабоковА. В.NabokowA.

34346, Германия, г. Ганн. Мюнден, Фогельзанг, д. 105.

Набоков Александр, заместитель директора.

34346, Germany, Hann.Muenden, Vogelsang, 105.

Dr. med. Alexander Nabokow.

a.nabokow@awogsd.deГренеХ. -Й.GröneH. -J.

69120, Германия, г. Гейдельберг, Им Нойенгеймер Фелд, д. 280.

Проф. Германн-Йозеф Грёне.

69120, Germany, Heidelberg, Im Neuenheimer Feld, 280.

Prof. Dr. med. Hermann-Josef Groene.

h.-j.groene@dkfz.deКлимФ.KliemV.

34346, Германия, г. Ганн. Мюнден, Фогельзанг, д. 105.

Проф. Клим Фолкер, директор.

 

34346, Germany, Hann.Muenden, Vogelsang, 105.

Prof. Dr. med. Volker Kliem.

v.kliem@awogsd.deНИИ нефрологии, Первый Санкт-Петербургский медицинский университет им. акад. И. П. Павлова.РоссияResearch Institute of Nephrology, First Pavlov Saint-Petersburg State Medical University.Russian FederationПервый Санкт-Петербургский медицинский университет им. акад. И. П. Павлова.РоссияFirst Pavlov Saint-Petersburg State Medical University.Russian FederationНИИ нефрологии, Первый Санкт-Петербургский медицинский университет им. акад. И. П. Павлова, кафедра пропедевтики внутренних болезней.РоссияResearch Institute of Nephrology, First Pavlov Saint-Petersburg State Medical University, Department of propaedeutics of internal diseases.Russian FederationНефрологический центр Нижней Саксонии.ГерманияNephrology center of Lower Saxony.GermanyЛаборатория клеточной и молекулярной патологии, Германский центр изучения рака.ГерманияDivision of cellular and molecular pathology, German center of cancer research.Germany2018231220182264755Copyright © Добронравов В.А., Мухаметдинова А.О., Храброва М.С., Набоков А.В., Грене Х.-., Клим Ф., 20182018Добронравов В.А., Мухаметдинова А.О., Храброва М.С., Набоков А.В., Грене Х.-., Клим Ф.Dobronravov V.A., Mukhametdinova A.O., Khrabrova M.S., Nabokow A., Gröne H.-., Kliem V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/1627ЦЕЛЬ ИССЛЕДОВАНИЯ

ЦЕЛЬ ИССЛЕДОВАНИЯ. Оценить связь выраженности инфильтрации интерстиция CD3+, CD68+ и CD20+ клетками при гломерулите с отдаленным прогнозом аллотрансплантации почки (АТП).

ПАЦИЕНТЫ И МЕТОДЫ

ПАЦИЕНТЫ И МЕТОДЫ. В ретроспективное исследование были включены 86 реципиентов аллографта почки (АП) с морфологически верифицированным в соответствии с критериями Banff гломерулитом. Случаи далее были разделены на подгруппы: 1) изолированный гломерулит без донор-специфических антител (ДСА) (n=53); 2) гломерулит с положительными ДСА (n=22); 3) гломерулит с неуточненными ДСА (n=11). Производили количественный анализ позитивных клеток в интерстиции после идентификации CD68+, CD3+, CD20+ лейкоцитов с помощью стандартного иммуногистохимического (ИГХ) окрашивания. Использовали метод Каплана–Мейера и мультивариантный регрессионный анализ Кокса для оценки связи выраженности инфильтрации интерстиция CD3+, CD68+, CD20+ клетками с риском потери АП.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. CD68+ и CD3+ клетки в интерстиции преобладали при гломерулите АП. CD20+ инфильтраты были выявлены в 60 % случаев. CD20+ клетки имели склонность к образованию инфильтратов, которые в 9 случаях достигали значительных размеров (≥ 50 CD20+ лимфоцитов) с формированием нодулярных структур. Подгруппы с/без ДСА не отличались по выраженности инфильтрации интерстиция CD3+, CD68+ клетками и наличию CD20+ инфильтратов. Уровни CD68+ клеток в интерстиции ≥ 5 клеток на поле зрения (х400), а CD3+ ≥ 8 были ассоциированы со снижением выживаемости АП, как и наличие значительных CD20+ инфильтратов (plog-rank < 0,05). В мультивариантных регрессионных моделях Кокса показатели уровней CD68+ (≥ 5 клеток/поле зрения), CD3+ (≥ 8 клеток/поле зрения) клеток и наличие значительных CD20+ инфильтратов в интерстиции являлись независимыми предикторами потери АП при коррекции моделей по наличию ДСА, времени холодовой и тепловой ишемии (p < 0,05). ВЫВОДЫ. Выраженность инфильтрации интерстиция CD3+, CD68+ и CD20+ клетками при гломерулите может быть предиктором выживаемости АП.

THE OBJECTIVE of the study was to assess the impact of the count of interstitial CD3+, CD68+ and CD20+ cells on long-term prognosis of renal allograft (RA).

PATIENTS AND METHODS

PATIENTS AND METHODS. 86 RA recipients with biopsy-proven according to the Banff 2013- 2017 criteria glomerulitis were enrolled in this retrospective study. The patients were subdivided into the following groups: 1) isolated glomerulitis with negative donor-specific antibodies (DSA) at the biopsy (n=53); 2) glomerulitis with positive DSA (n=22); 3) glomerulitis with undetermined DSA (n=11). Quantitative assay of interstitial positive cells was performed after immunohistochemical staining for CD68+, CD3+, CD20+. The Kaplan-Meier method and Cox proportional hazards regression model were used for the analysis of the relationship between interstitial CD3+, CD68+, CD20+ cells and risk of RA loss.

RESULTS

RESULTS. CD68+ and CD3+ cells prevailed in interstitium in RA glomerulitis. CD20+ infiltrates were found in 60% of cases. CD20+ cells tended to form infiltrates, in 9 cases these infiltrates reached large sizes (≥ 50 CD20+ lymphocytes) and formed nodular structures. There was no difference in the count of interstitial CD3+ and CD68+ cells and in the presence of CD20+ infiltrates between DSA subgroups. Interstitial CD68+ ≥ 5 cells per field of view (FOV) (x400) and CD3+ ≥ 8 cells per FOV (x400), as well as the presence of large CD20+ infiltrates were associated with a lower RA survival (plog-rank < 0,05). Interstitial CD68+ (≥ 5 cells/FOV), CD3 + (≥ 8 cells/FOV) and the presence of large CD20+ interstitial infiltrates were independently associated with the risk of RA loss in the multivariable Cox regression analysis adjusted for DSA, cold and warm ischemia time (p < 0.05). CONCLUSION. Grade of interstitial infiltration by CD68+, CD3+ and CD20+ cells in RA glomerulitis could be independent predictor of RA loss.

трансплантация почкигломерулитинтерстициальная инфильтрациядонор-специфические антителаCD20+CD68+CD3+ клеткиrenal transplantationglomerulitisinterstitial inflammationdonor-specific antibodiesCD20+CD68+CD3+ cellsReferencesSellares J, de Freitas DG, Mengel M et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12(2):388–399. doi: 10.1111/j.1600-6143.2011.03840.xSellares J, de Freitas DG, Mengel M et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12(2):388–399. doi: 10.1111/j.1600-6143.2011.03840.xLamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: A critical reappraisal. Am J Transplant 2011;11(3):450–462. doi: 10.1111/j.1600-6143.2010.03283.xLamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: A critical reappraisal. Am J Transplant 2011;11(3):450–462. doi: 10.1111/j.1600-6143.2010.03283.xGaston RS, Cecka JM, Kasiske BL et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation 2010;90(1):68–74. doi: 10.1097/TP.0b013e3181e065deGaston RS, Cecka JM, Kasiske BL et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation 2010;90(1):68–74. doi: 10.1097/TP.0b013e3181e065deLoupy A, Haas M, Solez K et al. The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant 2017;17(1):28–41. doi: 10.1111/ajt.14107Loupy A, Haas M, Solez K et al. The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant 2017;17(1):28–41. doi: 10.1111/ajt.14107Haas M, Sis B, Racusen LC, Solez K et al. Banff 2013 Meeting Report: Inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014;14: 272–283. doi: 10.1111/ajt.12590Haas M, Sis B, Racusen LC, Solez K et al. Banff 2013 Meeting Report: Inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014;14: 272–283. doi: 10.1111/ajt.12590Добронравов ВА, Храброва МС. Иммуноморфологические фенотипы повреждения аллографта почки. Нефрология 2017; 21(6): 9–19. https://doi.org/10.24884/1561-6274-2017-21-6-9-19Dobronravov VA, Khrabrova MS. Immune and morphological phenotypes of kidney allograft injury. Nephrology (Saint-Petersburg) 2017; 21(6): 9–19. (In Russ.) https://doi.org/10.24884/1561-6274-2017-21-6-9-19Nabokow A, Dobronravov VA, Khrabrova M et al. Longterm kidney allograft survival in patients with transplant glomerulitis. Transplantation 2015; 99(2): 331–339. doi: 10.1097/TP.0000000000000606Nabokow A, Dobronravov VA, Khrabrova M et al. Longterm kidney allograft survival in patients with transplant glomerulitis. Transplantation 2015; 99(2): 331–339. doi: 10.1097/TP.0000000000000606Mengel M, Reeve J, Bunnag S, et al. Scoring total inflammation is superior to the current Banff inflammation score in predicting outcome and the degree of molecular disturbance in renal allografts. Am J Transplant 2009;9(8):1859–1867. doi: 10.1111/j.1600-6143.2009.02727.xMengel M, Reeve J, Bunnag S, et al. Scoring total inflammation is superior to the current Banff inflammation score in predicting outcome and the degree of molecular disturbance in renal allografts. Am J Transplant 2009;9(8):1859–1867. doi: 10.1111/j.1600-6143.2009.02727.xХраброва МС, Мухаметдинова АО, Набоков АВ, Грене Х, Клим Ф, Добронравов ВА. Cубпопуляции иммунных клеток при гломерулите аллографта почки: состав и прогностическое значение. Нефрология 2017; 21(6): 29–38. https://doi.org/10.24884/1561-6274-2017-21-6-29-38Khrabrova MS, Mukhametdinova AO, Nabokow AV, Gröne H, Kliem V, Dobronravov VA. Immune cell subpopulations in kidney allograft glomerulitis: composition and prognostic significance. Nephrology (Saint-Petersburg) 2017;21(6):29–38. (In Russ.) https://doi.org/10.24884/1561-6274-2017-21-6-29-38Moreso F, Seron D, O'Valle F et al. Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis. Am J Transplant 2007;7:2739–2747. doi:10.1111/j.1600-6143.2007.02013.xMoreso F, Seron D, O'Valle F et al. Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis. Am J Transplant 2007;7:2739–2747. doi:10.1111/j.1600-6143.2007.02013.xSicard A, Meas-Yedid V, Rabeyrin M et al. Computerassisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection. Kidney Int 2017;92(1):214–226. doi: 10.1016/j.kint.2017.01.011Sicard A, Meas-Yedid V, Rabeyrin M et al. Computerassisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection. Kidney Int 2017;92(1):214–226. doi: 10.1016/j.kint.2017.01.011Sellarés J, de Freitas DG, Mengel M et al. Inflammation lesions in kidney transplant biopsies: association with survival is due to the underlying diseases. Am J Transplant 2011;11(3):489–499. doi: 10.1111/j.1600-6143.2010.03415.xSellarés J, de Freitas DG, Mengel M et al. Inflammation lesions in kidney transplant biopsies: association with survival is due to the underlying diseases. Am J Transplant 2011;11(3):489–499. doi: 10.1111/j.1600-6143.2010.03415.xMengel M, Reeve J, Bunnag S et al. Scoring total inflammation is superior to the current Banff inflammation score in predicting outcome and the degree of molecular disturbance in renal allografts. Am J Transplant 2009;9(8):1859–1867Mengel M, Reeve J, Bunnag S et al. Scoring total inflammation is superior to the current Banff inflammation score in predicting outcome and the degree of molecular disturbance in renal allografts. Am J Transplant 2009;9(8):1859–1867Bräsen JH, Khalifa A, Schmitz J et al. Macrophage density in early surveillance biopsies predicts future renal transplant function. Kidney Int 2017;92(2):479–489. doi: 10.1016/j.kint.2017.01.029.Bräsen JH, Khalifa A, Schmitz J et al. Macrophage density in early surveillance biopsies predicts future renal transplant function. Kidney Int 2017;92(2):479–489. doi: 10.1016/j.kint.2017.01.029.Piotti G, Palmisano A, Maggiore U et al. Vascular endothelium as a target of immune response in renal transplant rejection. Front Immunol 2014;5:505. doi: 10.3389/fimmu.2014.00505Piotti G, Palmisano A, Maggiore U et al. Vascular endothelium as a target of immune response in renal transplant rejection. Front Immunol 2014;5:505. doi: 10.3389/fimmu.2014.00505Kilgore KS, Schmid E, Shanley TP et al. Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation. Am J Pathol 1997;150(6):2019–2031Kilgore KS, Schmid E, Shanley TP et al. Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation. Am J Pathol 1997;150(6):2019–2031Valenzuela NM, Trinh KR, Mulder A et al. Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and FcγRIIa polymorphisms. Am J Transplant 2015;15(6):1502–1518. doi: 10.1111/ajt.13174.Valenzuela NM, Trinh KR, Mulder A et al. Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and FcγRIIa polymorphisms. Am J Transplant 2015;15(6):1502–1518. doi: 10.1111/ajt.13174.Valenzuela NM, Mulder A, Reed EF. HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging FcγRs. J Immunol 2013;190(12):6635–6650. doi: 10.4049/jimmunol.1201434Valenzuela NM, Mulder A, Reed EF. HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging FcγRs. J Immunol 2013;190(12):6635–6650. doi: 10.4049/jimmunol.1201434Wyburn KR, Jose MD, Wu H et al. The role of macrophages in allograft rejection. Transplantation 2005;80(12):1641–1647. doi: 10.1097/01.tp.0000173903.26886.20Wyburn KR, Jose MD, Wu H et al. The role of macrophages in allograft rejection. Transplantation 2005;80(12):1641–1647. doi: 10.1097/01.tp.0000173903.26886.20Zecher D, van Rooijen N, Rothstein DM et al. An innate response to allogeneic nonself mediated by monocytes. J Immunol 2009;183(12):7810–7816. doi: 10.4049/jimmunol.0902194Zecher D, van Rooijen N, Rothstein DM et al. An innate response to allogeneic nonself mediated by monocytes. J Immunol 2009;183(12):7810–7816. doi: 10.4049/jimmunol.0902194Oberbarnscheidt MH, Zeng Q, Li Q et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 2014;124(8):3579–3589. doi: 10.1172/JCI74370Oberbarnscheidt MH, Zeng Q, Li Q et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 2014;124(8):3579–3589. doi: 10.1172/JCI74370Hirohashi T, Chase CM, Della Pelle P et al. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 2012;12(2):313–321. doi: 10.1111/j.1600-6143.2011.03836.xHirohashi T, Chase CM, Della Pelle P et al. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 2012;12(2):313–321. doi: 10.1111/j.1600-6143.2011.03836.xKreisel D, Krupnick AS, Gelman AE et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med 2002; 8(3):233–239. doi:10.1038/nm0302-233Kreisel D, Krupnick AS, Gelman AE et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med 2002; 8(3):233–239. doi:10.1038/nm0302-233Ishii D, Rosenblum JM, Nozaki T et al. Novel CD8 T cell alloreactivities in CCR5-deficient recipients of class II MHC disparate kidney grafts. J Immunol 2014;193(7):3816–3824. doi: 10.4049/jimmunol.1303256Ishii D, Rosenblum JM, Nozaki T et al. Novel CD8 T cell alloreactivities in CCR5-deficient recipients of class II MHC disparate kidney grafts. J Immunol 2014;193(7):3816–3824. doi: 10.4049/jimmunol.1303256Jackson AM, Sigdel TK, Delville M et al. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol 2015;26(5):1161–1171. doi: 10.1681/ASN.2013121277Jackson AM, Sigdel TK, Delville M et al. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol 2015;26(5):1161–1171. doi: 10.1681/ASN.2013121277Cardinal H, Dieudé M, Brassard N et al. Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury. Am J Transplant 2013;13(4):861–874. doi: 10.1111/ajt.12168Cardinal H, Dieudé M, Brassard N et al. Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury. Am J Transplant 2013;13(4):861–874. doi: 10.1111/ajt.12168Dieude M, Bell C, Turgeon J et al. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med 2015;16;7(318):318ra200. doi: 10.1126/scitranslmed.aac9816.Dieude M, Bell C, Turgeon J et al. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med 2015;16;7(318):318ra200. doi: 10.1126/scitranslmed.aac9816.Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol 2015;6:602. doi:10.3389/fimmu.2015.00602Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol 2015;6:602. doi:10.3389/fimmu.2015.00602Toki D, Zhang W, Hor KL et al. The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. Am J Transplant 2014;14(9):2126–2136. doi: 10.1111/ajt.12803Toki D, Zhang W, Hor KL et al. The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. Am J Transplant 2014;14(9):2126–2136. doi: 10.1111/ajt.12803Nankivell BJ, Shingde M, Keung KL et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion. Am J Transplant 2018;18(2):364–376. doi: 10.1111/ajt.14609Nankivell BJ, Shingde M, Keung KL et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion. Am J Transplant 2018;18(2):364–376. doi: 10.1111/ajt.14609Scheepstra C, Bemelman FJ, Van Der Loos C et al. B clinical outcome of renal allograft rejection. Transplantation 2008;86(6):772–778. doi: 10.1097/TP.0b013e3181860a74Scheepstra C, Bemelman FJ, Van Der Loos C et al. B clinical outcome of renal allograft rejection. Transplantation 2008;86(6):772–778. doi: 10.1097/TP.0b013e3181860a74Kayler LK, Lakkis FG, Morgan C et al. Acute cellular rejection with CD20-positive lymphoid clusters in kidney transplant patients following lymphocyte depletion. Am J Transplant 2007;7(4):949–954. doi: 10.1111/j.1600-6143.2007.01737.xKayler LK, Lakkis FG, Morgan C et al. Acute cellular rejection with CD20-positive lymphoid clusters in kidney transplant patients following lymphocyte depletion. Am J Transplant 2007;7(4):949–954. doi: 10.1111/j.1600-6143.2007.01737.xHippen BE, DeMattos A, Cook WJ et al. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant 2005;5(9):2248–2252. doi: 10.1111/j.1600-6143.2005.01009.xHippen BE, DeMattos A, Cook WJ et al. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant 2005;5(9):2248–2252. doi: 10.1111/j.1600-6143.2005.01009.xMoreso F, Seron D, O'Valle F et al. Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis. Am J Transplant 2007;7(12):2739–2747. doi: 10.1111/j.1600-6143.2007.02013.xMoreso F, Seron D, O'Valle F et al. Immunephenotype of glomerular and interstitial infiltrating cells in protocol renal allograft biopsies and histological diagnosis. Am J Transplant 2007;7(12):2739–2747. doi: 10.1111/j.1600-6143.2007.02013.xJiang Y, Wang R, Wang H et al. The Effect of Histological CD20-Positive B Cell Infiltration in Acute Cellular Rejection on Kidney Transplant Allograft Survival. J Immunol Res 2016;16:7473239. doi: 10.1155/2016/7473239Jiang Y, Wang R, Wang H et al. The Effect of Histological CD20-Positive B Cell Infiltration in Acute Cellular Rejection on Kidney Transplant Allograft Survival. J Immunol Res 2016;16:7473239. doi: 10.1155/2016/7473239Lee KM, Stott RT, Zhao G et al. TGF-beta-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur J Immunol 2014;44(6):1728–1736. doi: 10.1002/eji.201344062Lee KM, Stott RT, Zhao G et al. TGF-beta-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur J Immunol 2014;44(6):1728–1736. doi: 10.1002/eji.201344062Ding Q, Yeung M, Camirand G et al. Regulatory B cells are identified by expression of Tim-1 and can be induced through Tim-1 ligation to promote tolerance in mice. J Clin Invest 2011;121(9):3645–3656. doi: 10.1172/JCI46274.Ding Q, Yeung M, Camirand G et al. Regulatory B cells are identified by expression of Tim-1 and can be induced through Tim-1 ligation to promote tolerance in mice. J Clin Invest 2011;121(9):3645–3656. doi: 10.1172/JCI46274.Lal G, Nakayama Y, Sethi A et al. Interleukin-10 from marginal zone precursor B-cell subset is required for costimulatory blockade-induced transplantation tolerance. Transplantation 2015;99(9):1817–1828. doi: 10.1097/TP.0000000000000718Lal G, Nakayama Y, Sethi A et al. Interleukin-10 from marginal zone precursor B-cell subset is required for costimulatory blockade-induced transplantation tolerance. Transplantation 2015;99(9):1817–1828. doi: 10.1097/TP.0000000000000718Zeng Q, Ng YH, Singh T et al. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest 2014;124(3):1052–1056. doi: 10.1172/JCI70084Zeng Q, Ng YH, Singh T et al. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest 2014;124(3):1052–1056. doi: 10.1172/JCI70084Nutt SL, Hodgkin PD, Tarlinton DM et al. The generation of antibody-secreting plasma cells. Nat Rev Immunol 2015;15(3):160–171. doi: 10.1038/nri3795Nutt SL, Hodgkin PD, Tarlinton DM et al. The generation of antibody-secreting plasma cells. Nat Rev Immunol 2015;15(3):160–171. doi: 10.1038/nri3795Thaunat O, Graff-Dubois S, Brouard S et al. Immune responses elicited in tertiary lymphoid tissues display distinctive features. PLoS One 2010;5(6):e11398. doi: 10.1371/journal.pone.0011398Thaunat O, Graff-Dubois S, Brouard S et al. Immune responses elicited in tertiary lymphoid tissues display distinctive features. PLoS One 2010;5(6):e11398. doi: 10.1371/journal.pone.0011398Thaunat 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(1):717–728. doi: 10.4049/jimmunol.0903589Thaunat 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(1):717–728. doi: 10.4049/jimmunol.0903589Adeyi OA, Girnita AL, Howe J et al. Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches. Transpl Immunol 2005;14(1): 53–62. doi: 10.1016/j.trim.2005.01.001Adeyi OA, Girnita AL, Howe J et al. Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches. Transpl Immunol 2005;14(1): 53–62. doi: 10.1016/j.trim.2005.01.001Del Bello A, Congy-Jovilet N, Sallusto F et al. Donorspecific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy. Clin J Am Soc Nephrol 2012;7(8): 1310–1319. doi: 10.2215/CJN.00260112Del Bello A, Congy-Jovilet N, Sallusto F et al. Donorspecific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy. Clin J Am Soc Nephrol 2012;7(8): 1310–1319. doi: 10.2215/CJN.00260112Marrari M, Duquesnoy RJ. Detection of donor-specific HLA antibodies before and after removal of a rejected kidney transplant. Transpl Immunol 2010;22(3-4):105–109. doi: 10.1016/j.trim.2009.12.005Marrari M, Duquesnoy RJ. Detection of donor-specific HLA antibodies before and after removal of a rejected kidney transplant. Transpl Immunol 2010;22(3-4):105–109. doi: 10.1016/j.trim.2009.12.005Pipi E, Nayar S, Gardner DH et al. Tertiary Lymphoid Structures: Autoimmunity Goes Local. Front Immunol 2018;9: 1952. doi: 10.3389/fimmu.2018.01952Pipi E, Nayar S, Gardner DH et al. Tertiary Lymphoid Structures: Autoimmunity Goes Local. Front Immunol 2018;9: 1952. doi: 10.3389/fimmu.2018.01952

The authors declare that there are no conflicts of interest present.