대한수혈학회지 : 제 30 권제 1 호, 2019 The Korean Journal of Blood Transfusion Vol. 30, No. 1, 1-14, April 2019 https://doi.org/10.17945/kjbt.2019.30.1.1 pissn 1226-9336 eissn 2383-6881 Review Article HLA 불일치장기이식의탈감작치료 박금보래 고려대학교구로병원진단검사의학과 Desensitization in HLA Incompatible Transplantation Borae G. Park Department of Laboratory Medicine, Korea University Guro Hospital, Seoul, Korea In terminally ill patients, organ transplantation could be recommended as the treatment of choice. In Korea, living donor liver or kidney transplantation is much more frequent than deceased donor transplantation due to organ shortages from deceased donors. ABO or HLA incompatibility in transplantation can be a major barrier in living donor transplantation. Currently, the rate of ABO incompatible organ transplantation accompanied by desensitization is 20 25% of living donor transplantation, and the blood bank laboratory plays an active role by plasmapheresis. The desensitization of HLA incompatible transplantation in highly sensitized patients is more difficult than that of ABO incompatible transplantation. The HLA antibody is not easy to remove and it is difficult to prevent sensitization. In addition, setting the target treatment goals and predicting the treatment outcomes based on the HLA antibody results are problematic. Therefore, a range of desensitization protocols have been attempted and various therapeutic goals have been introduced. This article reviews the various desensitization methods for antibody removal focusing on HLA incompatible kidney transplantation, and discusses the prognosis of desensitization methods for antibody removal based on the literature. (Korean J Blood Transfus 2019;30:1-14) Key words: HLA, Plasmapheresis, Desensitization, Transplantation 서론뇌사장기이식을위해서는기증자와이식을받는사람의 ABO 혈액형이적혈구수혈이가능한관계에있어야하며, 신장이식에서는조직적합성항원 (human leukocyte antigen, HLA) 의불일치 (mismatch) 정도는작을수록이식후좋은예후를나 타낸다 [1]. 이러한근거에따라뇌사기증자의신장및췌장이식에서는 HLA가모두일치할때, 대기자중에서우선장기이식을받을수있는조건이된다. 2017년 IRODaT (International registry in organ donation and transplantation) 에따르면우리나라는뇌사장기기증자수가인구백만명당 9.95명수준인반면, 생존기증자는백만명당 44.28 Received on February 28, 2019. Revised on March 25, 2019. Accepted on March 26, 2019 Correspondence to: Borae G. Park Department of Laboratory Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea Tel: 82-2-2626-1454, Fax: 82-2-2626-1465, E-mail: borae.park@gmail.com, ORCID: http://orcid.org/0000-0001-9710-9253 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright C 2019 The Korean Society of Blood Transfusion - 1 -
Korean J Blood Transfus Vol. 30, No. 1, 1-14, Apr. 2019 명으로뇌사자보다는생존기증자로부터장기를이식받는경우가많은실정이다. 생존장기기증은많은경우가족관계에서이루어지고있으며, 뇌사장기이식과달리 HLA 불일치정도에따른장기배분의원칙은적용되지않아, 이식받는사람이기증자의 ABO 혈액형이나, HLA에대한항체를가지고있지않은경우, 이식이가능하다. 최근에는기증자의 ABO 혈액형항원에대한항체를가지고있는혈액형불일치장기이식에서도다양한탈감작 (desensitization) 방법으로항체를제거하고성공적으로이식을시행하고있어, 신장과간이식에서는 ABO 혈액형불일치장기이식의비율이지속적으로증가하는추세이다 [2,3]. 2017년도 KONOS (Korean Network for Organ Sharing) 통계에따르면국내에서는전체생존장기이식 2,293건중 548건이 ABO 혈액형불일치이식으로시행되었다 (Fig. 1). 탈감작은원래알레르기나천식의치료법중하나로, 항원을주입하여 IgG 항체를유도하고, 이를통해비만세포 (mast cell) 의 IgE 활성을막아효과를나타내는치료법을일컫는용어이지만, 장기이식에서는 ABO 혈액형항원이나 HLA에대한항체를제거하고, 항체생성을억제하는치료방법을말한다. HLA 탈감작치료는이식받는사람의체내에있는 HLA 항체를제거하여수술직후초급성거부반응 (hyperacute rejection) 이일어나지않도록하는것이주목적이다. 심장이식등응급으로이식을받아야하는상황에서뇌사장기이식전에제한적으로 HLA 탈감작치료가시도되기도하지만, 일반적으로는뇌사가아닌생존신장이식에서탈감작을시행하게된다. 최근에는수술후발생한항체매개거부반응 (antibody mediated rejection, ABMR) 을치료하기위해탈감작치료를시행하기도한다. 국내에서는 2002년처음으로생존신장기증자에대해 HLA 교차시험양성을보인환자에서혈장성분채집술 (plasmapheresis, PP) 로항체를제거하고, 교차시험음성반응으로전환시킨후성공적으로신장이식을시행한증례가보고되었으며, 이후 HLA 불일치장기이식은꾸준히시도되어왔다 [4]. 본종설에서는이식전 HLA 항체를가지고있는환자에서성공적인이식을시행하기위해시도되고있는 HLA 탈감작치료방법의종류, 치료목표및예후에대한현황을기술하고자한다. 본론 1. 탈감작치료의종류 Fig. 1. KONOS (Korean Network for Organ Sharing) statistical data for living and deceased donor transplant in 2017. 탈감작은항체의생성을억제하고, 생성된항체를제거하는방법을병행할수있다. 항체의생성을억제하기위한약물치료는 B세포의생성을 - 2 -
박금보래 : HLA 불일치장기이식의탈감작치료 억제하는리툭시맙 (rituximab, anti-cd20) 이나, 형질세포 (plasma cell) 의자살 (apoptosis) 을유도하는보르테조밉 (bortezomib, proteasome inhibitor) 등이사용된다. 항체의제거를위해서는 PP, 선택적흡착 (immunoadsorption, IA), 고농도정맥내면역글로불린 (intravenous immunoglobulin, IVIG) 투여, 또는 PP와저농도 IVIG를병행하는방법등을사용할수있다 (Table 1). PP는혈장에존재하는 HLA 항체의제거를위해시행하는데, 항체외에도항원-항체반응에의해부수적으로생성되는산물인면역복합체, 보체, 시토카인등의제거효과가있다는장점이있다. 그러나, 혈관내에존재하는항체를제거하기때문에, IgM 항체의제거효과는뛰어나지만, IgG 항체의제거효과는혈관내로재유입되는항체의양에따라다양하게나타날수있다. 일반적으로임상적으로유의한 HLA 항체는대부분 IgG 항체로구성되어있어 [5], 고농도의항체가존재하는경우 PP만으로항체를제거하기에는어려 움이있다. PP에서는제거된혈장성분을대신해항체가없는대체용액을주입하며, 알부민이나신선동결혈장이대체용액으로선택된다. IA법은 PP로혈장을분리한뒤칼럼 (column) 을통과시켜 IgG 성분의항체만흡착시키고나머지혈장성분은다시재주입하는형태의탈감작방법이다. IA법에사용되는칼럼은 Staphylococcal protein A 혹은 protein G가들어있는것이주로사용된다. S. aureus 세포벽의일부성분이 IgG 항체의 Fc 부위와 IgG를함유한면역복합체에강한친화력을보인다는특징을활용한칼럼으로 IgG1, IgG2, IgG4 항체의제거는효과적으로이루어지지만, 상대적으로 IgG3, IgM, IgA 항체의제거효과는약한것으로알려져있다. 고농도 IVIG (2 g/kg) 투여를이용한탈감작은면역억제기능이비교적적으며, 약물투여가용이하다는장점이있으나, 감염등면역학적부작용과고농도 IVIG 투여에대한독성반응이있을수있고, 탈감작효과를예측하기어려운단점이 Table 1. Mechanisms of various medication and procedures used for desensitization Category Medication or procedure Target Mechanism of action Antibody removal Plasmapheresis HLA antibody Antibody removal, exchange plasma into replacement fluid Immunoadsorption HLA antibody Staphylococcal protein A or protein G, IgG antibody removal IdeS HLA antibody IgG-degrading enzyme of Streptococcus pyogenes, cleavage of IgG to F(ab ) 2 and Fc portion Intravenous Various Unclear, F(ab ) 2 and Fc dependent pathway etc. immunoglobulin Blocking antibody Rituximab Pre, mature, Anti-CD20 formation memory B cells Bortezomib Plasma cell Proteasome inhibitor Tocilizumab B cell, Plasma cell IL-6 receptor antagonist Inactivation of complement system C1-INH Complement system C1 esterase inhibitor Eculizumab Complement system C5 convertase inhibitor - 3 -
Korean J Blood Transfus Vol. 30, No. 1, 1-14, Apr. 2019 있다 [6-8]. 현재국내뿐아니라세계적으로가장널리사용되는항체제거방법은 PP와저농도 IVIG (100 300 mg/kg) 를병용하는탈감작방법이다. 일반적으로리툭시맙과함께탈감작치료에사용되고있으며, PP/ 저농도 IVIG 탈감작으로 ABMR의치료에효과를보인후, 현재까지도이식전후 HLA 항체제거에가장보편적으로사용되는방법이다 [9,10]. 탈감작치료효과를나타내는 IVIG의작용기전은아직명확하지는않지만, F(ab') 2 을매개로하여항체매개표적세포살해, 세포간상호작용억제, 시토카인과자가항체를중화하는기전이제시되어있고, 항체결합부위 (Fc receptor) 를포화 (saturation) 시키거나, 조절 T 세포 (regulatory T cell) 를증가시키고, 면역복합체의결합을저해하며, 가지세포 (dendritic cell) 의활성을조정 (modulation) 하는등복합적인기전이작용할것으로제시되었다 [11]. 2. 생존신장이식전 HLA 탈감작치료의예후 고전적으로 HLA 항체가있는경우, 보체의존성세포독성교차시험 (complement dependent cytotoxic crossmatching, CDC-XM) 에서양성을나타내고, 신장이식후초급성거부반응이일어날수있으므로이식의금기로여겨져왔다 [12]. 그러나, 고도로감작된신장이식대기환자에서이식전 PP나 IA법으로 HLA 항체를제거하고, 초급성거부반응을예방하고자하는시도는 1980년대부터이미시작되었다 [13,14]. 초기에는일부항체역가가매우높은환자에서항체의음전을실패하기도하였고, 탈감작으로항체역가를낮춰이식수술을시행하는데는성공했으나, 탈감작치료의부작용으로심한감염을겪은사례가보고되기도하였다 [13,14]. 국내에서는 2002년교차시험양성환자에서탈감작치료후성공적인신장 이식을시행한바있다 [4]. 탈감작을시행하는환자는이미감작된상태에있었기때문에, 항체가없었던환자와비교해 ABMR의발생빈도는높아질수있다 [15]. 일부, 공여자특이항체 (donor specific antibody, DSA) 가제거되지않고지속되는경우이식후 ABMR을일으키게되는데, HLA-DR, -DQ와같은 class II HLA 항체가 HLA-A, -B 와같은 class I HLA 항체에비해 2배이상더높은비율로지속적인양성반응을나타내는것으로나타났다 [16]. 그러나, ABMR 빈도가증가함에도불구하고, 감작되지않은환자와장기적인예후가유사하다는보고나, 생존공여자에게 HLA 불일치신장이식을받은경우뇌사자에게이식을받거나, 이식을받지않은경우와비교할때장기생존예후가유의하게좋다는보고들이발표되면서생존신장이식에서적극적으로탈감작치료를시행하는근거가되고있다 [17,18]. 방법에따른예후를살펴보면, IA법을통한탈감작치료효과는 HLA 항체를제거하고, 초급성거부반응을예방할수는있었지만, 항체제거효과가오래가지않아, 1달후항체역가가재상승했다는초기보고가있으며 [14,19,20], 소규모이지만이식후 5년이식신생존율에서도장기적으로좋은예후를나타낸보고도있다 [19]. 그러나, IA법을사용한탈감작치료는유럽등의국가에서일부사용되고있으며국내에서는널리사용되지못하고있다. 고농도 IVIG 투여방법은, 이식전 CDC-XM 양성이었던환자에서도 1달에한번씩고농도 IVIG 를투여하여성공적으로이식을시행하고좋은예후를보였으며 [21,22], 대규모연구에서도리툭시맙과고농도 IVIG가성공적인예후를보인결과등을볼때 [23], 고농도 IVIG를이용한적절한탈감작시도는긍정적인효과를나타낼것으로 - 4 -
박금보래 : HLA 불일치장기이식의탈감작치료 생각할수있다. 또한, 고농도 IVIG 치료에의한항체제거효과는보체결합 HLA 항체에서더빠른감소효과를나타내는것으로알려져있어 CDC-XM 양성인고감작환자에서도치료효과를기대할수있다 [24]. 그러나, 일부 cpra (calculated PRA) 가높은환자에서고농도 IVIG치료가실패한사례들이있어, cpra가 100% 에이르는고감작환자에서는탈감작성공여부를기대하기어려운측면도있을수있다 [25]. PP/ 저농도 CMV-IG (cytomegalovirus immunoglobulin) 를병용하는탈감작치료에서도반복적인시술로교차시험양성결과를보이는환자에서성공적으로항체를제거할수있었으며, 많은경우일정기간항체의재상승이관찰되지않아, 긍정적인치료효과를보인것으로보고되었다 [26]. 특히 HLA 적합공여자를기다리며투석을시행하다이식을시행한환자군과비교했을때, HLA 부적합공여자에대해 PP/ 저농도 IVIG 병합요법으로탈감작치료를시행한뒤생존신장이식을시행한환자에서예후가더우수하다는결과가보고되어, 생존신장이식에서탈감작치료를적극적으로시도하는근거가될수있었다 [27]. 최근에는탈감작치료에드는고비용과리툭시맙투여등의투여로인한과면역억제 (over-immunosuppression) 로감염관련사망율이증가할수있는단점도제시된바있다 [28]. 3. HLA 탈감작치료방법의선택고농도 IVIG 투여로탈감작을시행한경우, 항체의음전후이식을시행하였음에도 ABMR 비율이높다는보고등으로인해, 고농도 IVIG 치료보다는 PP/ 저농도 IVIG를이용한항체제거를시행하는기관이더많은것이사실이다 [29]. 국내에서는처음탈감작치료가시작될때부터 PP/ 저농도 IVIG 병합치료가우선적용되었고, 세부적 인프로토콜에서는차이를보이기는하지만, 현재까지도 PP/ 저농도 IVIG를병합하는방법이항체제거를위해주로사용되고있다 [4,30]. 그러나, 이식전탈감작치료에고농도 IVIG 치료와 PP/ 저농도 IVIG 병합요법시행을비교한결과에서는, 두방법모두우수한항체제거효과를보이고, 비교적항체의재상승도적다는측면에서유사한치료효과를보인다고할수있을것이다 [8,25]. 다만, 고농도 IVIG 치료는대개 1달에한번정도를주기로투여하기때문에탈감작치료에보다긴기간이필요할수있고, PP/ 저농도 IVIG 병합치료는프로토콜에따라다양할수있지만, 대개주 3회이상의시술이가능하기때문에, 상대적으로짧은기간에항체제거가가능하므로, 이러한차이가치료방법선택에고려사항이될수있을것이다. 4. 탈감작치료에사용하는약제 1) 리툭시맙 (rituximab) 리툭시맙은 B세포및전구세포표면에표현되는 CD20에대한단클론항체이다. 악성림프종의치료제로처음사용되었으나, 저용량으로도말초혈액과비장에존재하는 B세포제거기능이있다는것이밝혀지면서, B세포를미리제거하여형질세포로분화될수없도록막아줌으로써항체생성을억제하는역할을한다. 고감작환자의탈감작에서리툭시맙투여후이식을시행하는경우수술후 HLA 항체의재상승이유의하게줄어드는것이보고되었다 [31]. 그러나, 형질세포의경우 CD20을거의발현하지않기때문에리툭시맙에의해제거되지않아, 동일항원에노출된적이있었던환자들에서는리툭시맙을투여했음에도불구하고항체의재상승이있어, 지속적으로항체를생성하는세포에서는리툭시맙의효과가충분하지않음을확인할수있었다 [31]. 그럼에도 - 5 -
Korean J Blood Transfus Vol. 30, No. 1, 1-14, Apr. 2019 불구하고, 현재까지 ABO 혈액형불일치이식과더불어 HLA 불일치이식의탈감작치료에서리툭시맙은항체생성억제를위해가장많이사용되는약물이다. 2) 보르테조밉 (bortezomib, proteasome inhibitor) 보르테조밉은 26S proteasome의기능을차단하여 nuclear factor-kappa B (NFkB) 가자유롭게핵내로들어갈수없도록하여형질세포의자살을유도하는약물로알려져있다. 일반적으로 ABMR 에서지속적으로 HLA 항체를생성하는세포는골수주위에남아오랫동안생존하는형질세포 (bone marrow niche resident long lived plasma cell) 이다. 형질세포는 CD20을표현하지않아리툭시맙치료에반응하지않으며, 이러한세포에서생성되는 HLA항체는탈감작치료에의해효과적으로제거되지않는다. 따라서형질세포를표적으로하는보르테조밉치료를탈감작에도시도하게되었다 [32,33]. 그동안보르테조밉은이식후 ABMR 치료에사용하는것이주로시도되었으나, 최근에는이식전 cpra% 가매우높아공여자를찾기힘든경우, 탈감작에일부효과가있다는발표들이등장하면서, 이식전보르테조밉탈감작치료에대한연구가이루어졌고 [34], 국내에서도보르테조밉을포함한탈감작치료를통해이식전항체제거나 ABMR의탈감작치료에성공한사례들이보고되고있다 [35,36]. 또한, 고도로감작된뇌사신장이식대기자에서이식전보르테조밉, 리툭시맙, 고용량 IVIG의병합투여로탈감작을시행해 DSA 역가를낮추고, 뇌사신장이식가능성을높힌연구도보고되어, 탈감작치료에서보르테조밉의적용이증가되는추세이다 [37]. 3) 그외새로운약제에쿨리주맙 (eculizumab) 은보체중 C5a에대한단클론항체로항원-항체반응에의해이루어지는보체의활성을저해하여이식장기의손상을 막을것으로기대할수있을것이다. 교차시험음성이지만, DSA가양성인환자를대상으로한연구에서이식후 1년간에쿨리주맙을투여한결과 PP로탈감작을시행한환자군과비교했을때, 탈감작효과는유사했고, 에쿨리주맙치료군에서조직학적으로 ABMR이더적은것으로보고된바있으나 [38], 아직은대규모연구가부족한실정이다. 보체계의활성을억제할수있는 C1 esterase inhibitor (C1-INH) 는이식후탈감작이필요한경우 PP와 C1-INH를병행했을때, 투여하지않은군과비교해 ABMR의발병률이적은것으로나타났으며, 고용량 IVIG 탈감작치료에반응이없는급성 ABMR 환자군에서 C1-INH를병행하면신기능개선에다소효과를보인것으로나타난바있다 [39-41]. 토실리주맙 (tocilizumab) 은인터루킨-6 수용체길항체 (IL-6 receptor antagonist) 로류마티스관절염의치료제로사용되던약제였으나, B 세포와형질세포를효과적으로조절하여혈액내항체를감소시킬수있는것이보고되면서탈감작치료에반응하지않는고도감작환자를대상으로한임상연구가진행되어대조군에비해이식신장의기능을양호하게유지하는것이보고된바있다 [42]. 가장최근에는 IgG를 F(ab ) 2 와 Fc로분할 (cleavage) 하여항체를중화시키는것으로알려진 IgG-degrading enzyme of Streptococcus pyogenes (IdeS) 를탈감작치료에사용하여, 6시간이내에 IgG 항체를성공적으로제거한임상연구결과가보고되어, 추가임상연구가진행중이다 [43]. 5. HLA에감작된정도의평가와해석 HLA 항체는이전의수혈, 임신, 장기이식등으로인해동종항원에미리감작된환자에서주로 - 6 -
박금보래 : HLA 불일치장기이식의탈감작치료 생성된다. 이식전 HLA 항원에감작된정도를평가하기위한방법으로는교차시험, PRA (panel reactive antibody) 검사, DSA 평가, 가상교차시험 (virtual crossmatch, VXM) 등의방법이활용된다. 1) 교차시험과 PRA 검사교차시험은공여자의림프구와환자의혈청을반응시키는방법으로 CDC-XM와유세포분석교차시험 (flow cytometry crossmatching, FCXM) 검사가주로시행되고있다. CDC-XM 양성인경우, 초급성거부반응과밀접한관계가있는것으로알려져있다 [12]. CDC-XM 에서는음성을보이고, FCXM 에서만양성을보인경우초급성거부반응이일어날가능성은낮다고알려졌지만, 이식후 ABMR의위험도가높아져좋지않은예후를나타내기때문에, 신장이식에서는 FCXM 양성인환자에서탈감작치료없이이식을시행하지는않는다 [44]. FCXM은 CDC-XM에비해 100배정도까지예민하고 IgG와 IgM 항체를구별할수있으며, 세포를따로분리하지않아도형광염색을통해 T/B 세포의구별이가능한장점이있는검사법이다. FCXM에서도보체를활용해항체의세포독성여부를감별할수있는검사를시행하기도하지만 [45], 일반적으로시행하는 FCXM에서는보체를사용하지않기때문에, 항체의세포독성여부를감별할수없는것이 FCXM 검사의단점으로여겨지고있다. PRA 검사는이미알고있는 HLA항원으로구성된패널을이용하여, HLA에감작된정도를평가하는검사법이다. 최근에는세포를이용하지않고 Luminex 기기와다중비드 (bead) 에 HLA를부착시켜사용하는다중비드면역측정법이 PRA 검사에주로이용되고있다 [46]. PRA 검사의종류는선별, 동정, 단일항원동정의세가지검사법이있다. 단일항원동정검사는 대립유전자수준에서서로다른수십종이상의 HLA class I 및 class II 재조합항원 (recombinant antigen) 을각각서로다른비드에부착시켜검사하기때문에, 많은종류의 HLA 항체를가지고있는사람에서도단일항원수준에서항체의정확한동정이가능하다 [46]. 일반적으로단일항원동정검사결과를활용해 DSA를평가하고, 탈감작치료시행여부를결정하거나, 치료효과를평가한다. 2) 공여자특이항체와가상교차시험이식받는환자의혈청내에존재하는 HLA 항체중기증자가가지고있는 HLA에대한항체를 DSA라고한다. 일반적으로신장이식에서는이식전존재하는고역가의세포독성 DSA는 CDC-XM 양성을나타내고, 신장이식의금기가된다 [12]. 그러나저역가의 DSA 역시이식신의손상을통해 ABMR을초래할수있어, 최근에는이식전에 DSA를평가해신장이식여부를결정하는데활용하고있다 [47]. VXM는환자의 HLA 항체검사결과와기증자의 HLA형별검사결과로 DSA를평가하고, 실제로교차시험을시행하지않고교차시험결과를예측하는일종의가상교차시험이다. 그동안의연구에서단일항원항체검사 DSA MFI (median fluorescence intensity) 의평균혹은중앙값과 CDC- XM 양성결과사이의상관관계가보고된바있으나, 교차시험양성결과를나타내는 DSA MFI 값의기준이기관에따라다양하게보고되어있어, 이식의금기로적용하는부적합항원 (unacceptable antigen) 을판단하기위한 HLA 항체의강도는의료기관에따라달라질수있다 [47]. 서로다른검사기관에서입력한결과를동일하게적용하더라도장기배분의공정성이유지되기위해서는각검사기관사이의결과에차이가없다는전제가있어야한다. 국내외에서시행된비교평가에서기관별 DSA MFI는유사한양상을나타냈지 - 7 -
Korean J Blood Transfus Vol. 30, No. 1, 1-14, Apr. 2019 만, MFI 자체의변이계수 (coeffience of variation) 가 20% 를넘는경우가있으므로해석에유의해야할것이다 [48,49]. MFI 값은형광신호강도이며, 변이계수가 20% 를넘는검사는정량검사의범주에속한다고보기어렵고, MFI 값도희석할수록증가하는전지대반응 (prozone reaction) 을나타낼수있다는점등으로인해 DSA MFI 값으로교차시험결과를예측하기에는제한점이있다 [49-51]. 다만, DSA MFI 2,000을기준으로교차시험결과를예측하는경우양성결과예측율은 79% 에불과하지만, 교차시험음성결과예측율은약 92% 를나타내므로, 이식전부적합항원을교차시험양성을보이는항원으로기준을삼고자한다면, DSA MFI 2,000이부적합항원의기준으로추천될수도있을것이다 [47,52]. 6. 탈감작치료목표일반적으로 HLA 교차시험양성결과를음성으로전환시키는것이탈감작치료의 1차목표로여겨져왔다. 대개 T 세포 CDC-XM는완전한음성결과를보여야이식에적합한기준으로평가하지만, B세포교차시험은리툭시맙을사용하는경우지속적으로양성결과를나타내기때문에탈감작치료지표로삼는데어려움이있다 [53]. 일부프로토콜에서는 FCXM를기준으로 T-FCXM <70 MCS (median channel shift), B-FCXM<130 MCS를치료목표로제시한바있으나 [42], FCXM 결과도리툭시맙에의해영향을받을수있으며, 매검사마다기증자의혈구세포가필요한어려움이있으므로, PRA 검사로 HLA 항체를측정하고, 기증자 HLA 항원에대한 DSA를평가해탈감작치료효과를판단하는것이추천된다 [54]. 최근에는교차시험양성뿐아니라, 교차시험은음성이지만, DSA 양성인낮은역가의항체를가지는경우에도 ABMR의위험도가증가해이식 신장의생존율이낮아지므로 [55], 낮은역가의 DSA만가지고있는경우에도탈감작치료를시행하는것이더좋은예후를나타낸다고알려져이식전치료의대상이되고있다 [56]. 이에따라 PRA 검사의의미가더욱강조되고있다. 항체의강도는대개 PRA 단일항원항체검사에서제시되는항체의 MFI 값을사용해유추한다. 과거에는이식전탈감작치료목표를 DSA MFI <5,000 혹은 3,000 MFI로보고한경우가있는데, 이는 FCXM 에서양성을보이는 DSA MFI와유사한값을치료목표로설정한것이다 [57]. 그러나, 앞서언급한바와같이 MFI 결과는정량값이아니며, 이식후거부반응이나이식실패를예측하는 MFI 값의기준에대해서도보고자마다범위가다양하며, 항체측정결과에서전지대반응, IgG 항체의종류 (subclass) 에따른항체반응의차이, 다중비드항체반응이실제인체와는다른항체반응을나타내거나, 제조사에따라 MFI 결과에차이가있을수있는등의검사에제한점이있으므로연구마다다른 DSA MFI 값이치료목표로제안되고있으며, 임상정보를고려하여 MFI 값을모니터링해야할것이다 [46,58]. 최근에는 Luminex 보체결합단일항원항체검사 (complement binding HLA antibody test, C1q or C3d binding HLA antibody assay) 로측정한 C1q DSA가탈감작치료에의해더효과적으로감소하며, IVIG 에의한간섭현상을받지않기때문에, 탈감작효과를평가하는데적용하여성공적으로이식을시행한결과가보고되고있어 C1q DSA의음성전환을탈감작치료의목표로삼을수있는가능성이제시되었다 [24,35,58,59]. 탈감작치료로교차시험음성을만들기위해요구되는탈감작치료횟수는 AHG-CDC XM를기준으로 1:128일때 10회, FCXM 양성, AHG- CDC XM 음성인경우는 2회정도의 PP를시행하 - 8 -
박금보래 : HLA 불일치장기이식의탈감작치료 여, 성공적으로탈감작을시행한프로토콜이제시된바있다 [27]. 그러나임상적으로유의한 HLA 항체는대부분이 IgG 항체로혈관외에존재하는항체와생성되는정도에따라항체제거율에영향을미칠수있기때문에교차시험결과나 DSA 역가에따라 PP 시행횟수를특정짓기에는어려움이있다. 또한 class I과 class II 항체가성상이다르기때문에항체의제거율역시다를수있는데, HLA 항체의종류나항체의강도및이전이식력과같은임상정보를종합하여 DSA 제거율을예측하는확률을계산하는공식이제안되기도하였다 [16]. 그러나, 이는특정탈감작프로토콜에대한항체제거율을예측하는공식이며, 이식후투여하는다양한면역억제치료나능동적하향조절 (active down regulation) 현상, 이식직후일어나는허혈-재관류 (ischemic reperfusion) 와염증반응 (inflammation) 등에의해일어날수있는항원발현 (antigenic expression) 의증가등면역학적으로다양한변수를반영하지못하였기때문에, 항체제거율과이식후예후를예측하는데이러한공식을보편적으로적용하기에는무리가있다 [60]. 7. 기타장기이식에서탈감작치료심장이식에서도이식전후 HLA 항체는거부반응을유발하여이식장기의예후에영향을미치기때문에, 이식전양성교차시험결과는이식의금기가되며, 이식후에도일정간격으로 DSA를추적관찰하는것이추천되고있다 [61-63]. 그러나, 심장이식은뇌사장기이식으로만가능하며, 적합한공여자를찾았을때응급으로수술을시행할수있어야한다. 심장이식에서는적합한공여자를찾는것이어려운실정이기때문에, 아직공여자가선정되지않아 DSA 여부를알수없는경우에도 PRA가높다면미리탈감작을시행하고자하는시도가있다 [64,65]. 심장이식에서이식 후 C1q DSA가음전된경우 ABMR을나타내지않은보고에근거해, C1q DSA가음전되는것을탈감작치료의목표로삼기도한다 [66,67]. 폐이식에서도이식후새롭게생성된 DSA는 ABMR을유발할수있고, 기관지폐쇄증후군 (bronchiolitis obliterans syndrome) 을증가시켜, 수혜자의생존율을감소시키는것으로알려져있으며, 이식전후 HLA 항체를측정하는것이추천된다 [68,69]. 그러나폐이식에서탈감작치료의임상적인효과는아직미미한것으로보고되어적극적인탈감작치료가추천되지는못하고있다 [70]. 간이식에서는재생력이뛰어나고대식세포 (macrophage) 가풍부한간의특성때문에다른장기에비해 DSA가예후에미치는영향이적을것으로생각되어왔으며, 실제예후에미치는영향에대한연구결과에서도논란의여지가있었다 [71]. 그러나, 이식후새롭게생성된 DSA는거부반응이나생존율과관련이있는것으로여겨지고있으며 [72], 소수의환자를대상으로하였지만, 이식후생성된 DSA를제거하기위한탈감작치료에대한임상적효과는긍정적인것으로평가된바있다 [73]. 결론탈감작치료를통해고감작된환자에서도 HLA 불일치신장이식을가능하게하여, 환자의생존율을높이고삶의질을향상시킬수있을것이다. 그러나, 고비용과과면역억제로인한감염의증가등의단점이있을수있고, HLA 항체의특성상탈감작치료에따른항체의생성및제거의변화를정확히예측하기어려운측면이있으므로, 탈감작치료효과의예측과평가는환자에따라임상상을고려하여신중하게이루어져야할것이다. 더불어심장이식에서도탈감작치료의시도 - 9 -
Korean J Blood Transfus Vol. 30, No. 1, 1-14, Apr. 2019 를긍정적으로고려할수있겠지만, 간이식과폐이식에서탈감작치료의효과를판단하기위해서는추가연구가필요할것으로사료된다. 요약 말기환자의치료로이식이추천되는경우, 이식대기자수에비해부족한뇌사자장기기증현황으로인해우리나라는신장, 간등의이식은뇌사기증자보다생존기증자의장기이식을많이시행하고있다. 생존기증자를대상으로한이식에서는혈액형불일치이식이나 HLA 불일치이식이큰장벽이될수있다. 현재탈감작치료로혈액형불일치이식을시행하는비율이생존장기이식의 20 25% 정도에달하며, 혈액은행은혈장교환술의시행으로활발한역할을하고있다. 고감작된환자에서이식을시도하는 HLA 불일치이식의탈감작치료는혈액형불일치이식에비해항체의제거가쉽지않고, 감작을예방하는것도어려운측면이있다. 또한, 검사결과를토대로치료목표를설정하거나치료결과를예측하는데에도어려움이있다. 따라서, 다양한방법으로탈감작치료가시도되고, 다양한치료목표가제시되고있다. 본종설에서는 HLA 불일치장기이식에서시도되는다양한탈감작치료방법을신장이식을중심으로소개하고, 항체제거를위해시도되는다양한탈감작방법의예후에대해문헌을토대로소개하였다. References 1. Opelz G. Impact of HLA compatibility on survival of kidney transplants from unrelated live donors. Transplantation 1997;64:1473-5 2. Kim YN, Chung BH, Yang CW. Current issues in ABO-incompatible kidney transplantation. J Korean Transplant Soc 2014;28:5-12 3. Lee SH, Choi HJ, You YK, Kim DG, Na GH. ABO incompatible living donor liver transplantation: a single center experience. J Korean Transplant Soc 2018;32:84-91 4. Kwon KH, Moon JI, Chang HJ, Kim BS, Choi KH, Kang SW, et al. The results of renal transplantation after lymphocyte cross - match negative conversion by combination therapy with plasmapheresis, intravenous gamma globulin and potent immunosuppresants in patients with positive LCM. J Korean Transplant Soc 2002;16:172-7 5. Roy R, Belles-Isles M, Paré M, Lachance JG, Noël R. The importance of serum dithiothreitol treatment in crossmatching selection of presensitized kidney transplant recipients. Transplantation 1990;50:532-4 6. Tyan DB, Li VA, Czer L, Trento A, Jordan SC. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 1994; 57:553-62 7. Vo AA, Cam V, Toyoda M, Puliyanda DP, Lukovsky M, Bunnapradist S, et al. Safety and adverse events profiles of intravenous gammaglobulin products used for immunomodulation: a single-center experience. Clin J Am Soc Nephrol 2006;1:844-52 8. Kahwaji J, Sinha A, Toyoda M, Ge S, Reinsmoen N, Cao K, et al. Infectious complications in kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin. Clin J Am Soc Nephrol 2011;6:2894-900 9. Montgomery RA, Zachary AA, Racusen LC, Leffell MS, King KE, Burdick J, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to - 10 -
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