特集・総説（４４行）／Ｐ４３８～４４４＿特集　中村（４Ｃ）

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1 438 Vol. 51, No. 6 HLA Donor-specific anti-hla antibodies in renal transplantation 1 Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, 2 Department of Blood Transfusion and Cell Therapy, Kyoto Prefectural University of Medicine Tsukasa NAKAMURA 1, Shumpei HARADA 1, Kiyoko WATABE 2, Yui IMANISHI 2, Hidetaka USHIGOME 1,NorioYOSHIMURA 1 Summary Advances in immunosuppressants, such as rituximab, basiliximab, and others, enable organ transplantation for sensitized patients. In fact, an adequate desensitization protocol would lead to acceptable outcomes in the acute phase. However, it is true that the management of acute or, in particular, chronic antibodymediated rejection resulting from donor-specific antihuman leukocyte antigens HLA antibodies, is still an important issue to improve better long-term graft survival. Thus DSAs seem to be a central research topic in the field of organ transplantation. In the 1960s, the introduction of azathioprine brought the beginning of contemporary renal transplantation. Following this, the barrier of anti-ab antigens and anti- HLA antibodies was recognized: incompatibilities were considered as a high risk factor for renal transplantation. In the next half-century, the main attention was paid to T cell-mediated rejection. This led to the development of calcineurin inhibitors and several antibody drugs: a depletion of lymphocytes that enabled the control of T cell-mediated rejection. DSAs have finally received much attention in the 21 st century because controlling them brings better outcomes in renal transplantations. This manuscript refers to examination, diagnoses, management, treatment, and outcomes in DSA-positive renal transplantation. antibody mediated rejection AMR, donor specific anti-hla antibody DSA, renal transplantation antibody-mediated rejection AMR HLA donor specific anti-hla antibodies DSA AMR acute antibody-mediated rejection AAMR AMR chronic active antibody-mediated rejection CAAMR DSA 1960 azathioprine HLA DSA T

2 HLA 439 DSA AMR 2000 DSA lymphocyte cytotoxic test LCT flow cytometry FCM immunocomplex capture fluorescence analysis ICFA 3 HLA flow PRA DSA HLA complement dependent cytotoxicity CDC 1 FCM FCXM LCT CD3 CD19 T B FCM HLA 2 Luminex 100 Luminex beadshla class I A B C class II DR DQ DP Lysis HLA HLA HLA class I class II PE PE goat anti human IgG PE PE Luminex HLA 3 HLA DSA FCM HLA HLA FITC HLA HLA FCM HLA %PRA class I class II 30 HLA 4 single antigen

3 440 Vol. 51, No HLA HLA Luminex HLA DSA 5 virtual crossmatch VXM HLA HLA VXM 6, 7 peritubular capillary PTC C4 d DSA 8 CAAMR PTC interstitial fibrosis/tubular atrophy IFTA C4d 9 DSA mean fluorescence intensity MFI AMR 10, 11 1 MFI AMR 12 Banff classification 2013 AAMR 1 1 g 0 ptc 0 v DSA 1 1 PTC C4d C4d2 or 3 C4d 0 2 g ptc 2 3 DSA CAAMR 1 1 cg 0 2 PTC 3 DSA 1 1 PTC C4d C4d2 or 3 C4d 0 2 g ptc 2 3 DSA 13

4 HLA 441 DSA ABO B B rituximab Rit CD20 DSA mg/body CD19/20 B Ishida 14 DSA Rit DSA Rit DSA Rit DSA Rit DSA Rit % 19% 15% 0% CAAMR 50% 22% 18% 0% 5 84% 95% 98% 91% DSA Rit DSA Rit double filtration plasmapheresis DFPP plasma exchange PE MFI 2,000 DFPP DFPP MFI Bachelet DSA sdsa DSA gdsa sdsa gdsa sdsa gdsa sdsa MFI 7,369 4,932 vs. 2,158 3,694 p MFI 2,000 DSA Malheiro DSA DSA MFI 15,000 C1q C1q DSA AMR odds ratio OR p C1q DSA C1q AMR DSA DSA class I II Lefaucheur 11 DSA class I II Fidler 17 class II hazard ratio HR 2.9 class I II HR 3.7 class I DSA HLA Cw DP DR anti HLA Cw DP AMR 18 MFI DSA intravenous immune globulin IVIG Vo HLA IVIG 2 g/ kg day1 day30 Rit 1 g day15 T FCXM 37% 2 95% 84% Rit B AMR B AAMR CAAMR DFPP PE IVIG Rit AMR 20 AAMR bortezomib CAAMR Billing 25 15

5 442 移植 Vol. 51, No. 6 平均 egfr 43.0 ml/min/1.73m2 程度の小児腎移植後 2 い結果と考えられる CAAMR 患者を対象に Rit 375 mg/m 2 IVIG 1 g/kg/ 当院での生体腎移植患者 243 例を対象とした DSA wk 4 wks による加療を実施したところ sdsa およ陽性症例での腎移植の成績を示す28 DSA 陽性患者びグラフト内の補体活性の低下とともに移植腎機能低 n 11 に対し術前減感作療法として平均 Rit 下率の改善を認めたと報告したしかし Bachelet ら ±165.8 mg を術前 1 2 週間目に投与し PE 2.7±1.1 は平均年齢 40 歳平均 egfr 30.6 ml/min/1.73m2 の回実施した結果病理学的に確認された AAMR 発症 CAAMR 患者に Rit 375 mg/m2 2 IVIG 1 g/kg/wk 4 率は抗体陰性コントロール群と比較し多く確認され wks 療法を実施したところ sdsa MFI は低下傾向にた減感作が成功した例においては図 1 に示すようあったが 2 年後のグラフト生着率は治療群で 47% に残存する DSA の影響を受けて一過性に微小血管非治療群で 40% と治療効果を認めなかったと報告し障害 g 0 ptc 0 を発症し病理学的に AMR とているこれらは慢性期の変化を来した症例に対する診断されることが多いがその後 DSA 追加産生がな治療の難しさを物語っているしたがって慢性期にい場合はグラフトへの抗体吸着の結果 sdsa は消失入る前の段階での予防早期治療が重要であることはし病理所見は自然に改善するその結果術後 1 カ月言うまでもないこれらの制御が今後腎移植後の長期 1 年の Cr 値 1 5 年グラフト生着率に有意差を認め生着率の向上に寄与すると考えられるなかったしたがって十分な術前減感作療法により DSA 陽性腎移植も比較的安全に施行可能であるが DSA 陽性腎移植の成績 CAAMR の発症を含め遠隔期の成績等不明点も多く今後の検討課題である術前 DSA 陽性症例に対する腎移植では術後の遷延した sdsa 陽性症例で AMR の発症率が高く多変結語量解析性別年齢マージナルドナー生体/死体腎移植前感作歴 DSA 遷延では DSA 遷延が HR いずれの臓器移植においても一般的には現状での半 5.71 とグラフト生着率の悪化を認めまたレシピエン定量 sdsa MFI 値を参考に術前減感作治療方針が決ト年齢 50 歳以下再移植術前 DSA MFI 3,500 以上定されることが多いが遠い過去の感作症例における等が sdsa 陽性遷延の危険因子として報告されてい memory B 細胞の存在による移植後 1 週間程度での急る27 逆に術前減感作成功例で術後の sdsa 遷延がな激な AMR やグラフトへの吸着によるみかけ上のい症例においては術前 DSA 陰性症例に比較し遜色な MFI の低下等一概に sdsa MFI のみで議論すること図 1 減感作成功術前 DSA 陽性症例での病理学的変化の推移白矢印糸球体炎黒矢印傍尿細管毛細血管炎 scale bar 50 μm

6 HLA 443 DSA n=11 DSA n=232 p value SD Cr mg/dl SD NS 12 Cr mg/dl SD NS n % NS n % n % NS 1 C4d n % NS C4d n % N/A NS NS 16 sdsa MFI 1 Peña JR, Fitzpatrick D, Saidman SL. Complementdependent cytotoxicity crossmatch. Methods Mol Biol 2013; 1034: Maguire O, Tario JD Jr, Shanahan TC, et al.flow cytometry and solid organ transplantation: a perfect match. Immunol Invest 2014; 43: Nishimura K, Hashimoto M, Kinoshita T, et al.excellent results of immunocomplex capture fluorescence analysis-i for cross-match test in renal transplantation. Transplant Proc 2014; 46: Pei R, Wang G, Tarsitani C, et al. Simultaneous HLA Class I and Class II antibodies screening with flow cytometry. Hum Immunol 1998; 59: Billen EV, Voorter CE, Christiaans MH, et al. Luminex donor-specific crossmatches. Tissue Antigens 2008; 71: Zangwill S, Ellis T, Stendahl G, et al. Practical application of the virtual crossmatch. Pediatr Transplant 2007; 11: Veale J, Hil G. The National Kidney Registry: 175 transplants in one year. Clin Transpl 2011: Papadimitriou JC, Drachenberg CB, Klassen DK, et al. Histological grading of chronic pancreas allograft rejection/graft sclerosis. Am J Transplant 2003; 3: Solez K, Colvin RB, Racusen LC, et al.banff 05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy CAN. Am J Transplant 2007; 7: Eskandary F, Bond G, Kozakowski N, et al.diagnostic contribution of donor-specific antibody characteristics to uncover late silent antibody-mediated rejection-results of a cross-sectional screening study. Transplantation 2016; DOI: /TP Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 2010; 21:

7 444 Vol. 51, No Wiebe C, Gibson IW, Blydt-Hansen TD, et al.evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 2012; 12: Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of c4d-negative antibodymediated rejection and antibody-associated arterial lesions. Am J Transplant 2014; 14: Ishida H, Furusawa M, Shimizu T, et al. Influence of preoperative anti-hla antibodies on short- and longterm graft survival in recipients with or without rituximab treatment. Transpl Int 2014; 27: 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: Malheiro J, Tafulo S, Dias L, et al. Determining donor-specific antibodies C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation. Transpl Int 2016; DOI: / tri Fidler SJ, Irish AB, Lim W, et al. Pre-transplant donor specific anti-hla antibody is associated with antibody-mediated rejection, progressive graft dysfunction and patient death. Transpl Immunol 2013; 28: Bachelet T, Martinez C, Del Bello A, et al. Deleterious impact of donor-specific anti-hla antibodies toward HLA-Cw and HLA-DP in kidney transplantation. Transplantation 2016; 100: Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation 2010; 89: Sautenet B, Blancho G, Büchler M, et al. One-year results of the effects of rituximab on acute antibodymediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation 2016; 100: Stegall MD, Diwan T, Raghavaiah S, et al.terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 2011; 11: Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am J Transplant 2016; DOI: /ajt Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- and cellmediated acute rejection. Transplantation 2008; 86: Locke JE, Zachary AA, Haas M, et al. The utility of splenectomy as rescue treatment for severe acute antibody mediated rejection. Am J Transplant 2007; 7: Billing H, Rieger S, Süsal C, et al. IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up. Transpl Int 2012; 25: Bachelet T, Nodimar C, Taupin JL, et al. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibodymediated rejection: a pilot study. Clin Transplant 2015; 29: Caillard S, Becmeur C, Gautier-Vargas G, et al.preexisting donor-specific antibodies are detrimental to kidney allograft only when persistent after transplantation. Transpl Int 2016; DOI: /tri Ushigome H, Harada S, Nakao M, et al. Livingdonor kidney transplantation with existing anti-donor specific antibodies at a Japanese single center. Transplant Proc 2015; 47:

Major Histocompatibility Complex 2018; 25 (2): 抄録集 2 HLA A 3 128

Major Histocompatibility Complex 2018; 25 (: 128 138 抄録集 2018 4 14 A 3 128 MHC 2018; 25 ( HLA 2013 10.5 10 8 12 10 8 2016 CD34 + HLA NC 10 8 CD34 + CD34 + 10 6 NC10.5 2013.Apr 2014.Mar NC11 2014.Apr 2016.Jun

特集・総説（４４行）／Ｐ４３８～４４４＿特集 中村（４Ｃ）

特集・総説（４４行）／Ｐ４３８～４４４＿特集　中村（４Ｃ）