대한내과학회지 : 제 78 권제 5 호 2010 특집 (Special Review) - 개원의를위한혈액검사와혈액질환의이해 혈액질환에서의새로운조혈모세포이식기법 가톨릭대학교의과대학내과학교실 김정아 New therapeutic modalities on hematopoietic stem cell transplantation Jeong Kim, M.D., Ph.D. Division of Hematology, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea Hematopoietic stem cell transplantation (HSCT) has been used to treat a variety of non-malignant and malignant lymphohematopoietic disease. ut, there are many obstacles in performing HSCT for patients who do not have a human leukocyte antigen (HL)-matched donor or are not eligible for HSCT because of old age and comorbidities. better understanding of transplantation biology led to the development of non-myeloablative stem cell transplantation, HL-haploidentical stem cell and umbilical cord blood (UC) transplantation. Non-myeloablative stem cell transplantation is being commonly used in older patients as well as in disorders due to their safety and therapeutic effect. For patients without a matched HL-identical sibling or unrelated donor, other graft sources, such as UC and HL-haploidentical donors, have been used. Transplantation using UC is used in child transplantation, but it is not always suitable for adult transplantation because of insufficient cell doses. Transplantation of the stem cells from HL-haploidentical donors emerges as an alternative source for acute leukemia patients without matched donors, but it is faced with the difficulties of graft rejection, GVHD and delayed immune reconstitution. It is necessary to overcome these difficulties through further studies. (Korean J Med 78:552-556, 2010) Key Words: Stem cell transplantation; HL; Engraftment; Graft versus host disease 서론조혈모세포이식은재생불량성빈혈등의골수기능부전이나백혈병과같은혈액암환자들을대상으로고용량의골수억제치료를시행한후, 조혈모세포를주입하여골수기능을회복시키는치료방법이다. 불과 50여년전에시작된조혈모세포이식은비약적인발전을거듭하며혈액질환치료에크게기여해왔다. 초기에골수만을이용한골수이식 (bone marrow transplantation) 의영역을넘어현재는말초혈액과제대혈내의조혈모세포를사용하게되었고, 조직적합항원 (human leukocyte antigen, HL) 불일치시의면역학적장벽을극복할수있는방법들 이소개되면서공여자와수혜자간의 HL 일부가불일치하더라도이식이가능해졌다. 이글에서는조직적합항원과동종조혈모세포이식 (allogeneic stem cell transplantation) 을중심으로이식에관한전반적인사항을먼저살펴보고조혈모세포이식분야에서의새로운치료방법을소개하고자한다. 1. 조직적합항원조직적합항원복합체 (HL complex) 는 6번염색체의단완에위치하고 200여개의유전자로구성되어있으며그중 40 개의유전자가조직적합항원을부호화 (encoding) 하는데관련된다. HL 시스템은자기 (self) 와비자기 (non-self) 를구분하 - 552 -
- Jeong Kim. New therapeutic modalities on hematopoietic stem cell transplantation - T cell Helper T cell Peptide PC Cytotoxic T cell Figure 1. ntigen presentation by antigen presenting cell. PC, antigen presenting cell. 여항원에대한면역반응에관여하고세포면역과체액면역을조절한다. HL 유전자좌는사람마다다양한유전적다형성 (genetic polymorphism) 을보이며, 동종이식에서이식편의생착과이식편대숙주병 (graft versus host disease) 의발생을결정짓는중요한인자이다. HL 대립유전자는기능과구조가다른 HL-, -, -C 항원 (class I) 과 HL-DR, -DQ, -DP 항원 (class II) 을부호화한다 1). HL 불일치조혈모세포이식 (HL mismatched stem cell transplantation) 시에는공여자와수혜자간에한두개의 HL 분자만일치하지않는것이아니라수천가지의항원성 peptide가일치하지않아, 공여자의 T세포가이를항원으로인식하여이식거부반응이나타난다 ( 그림 1). 1990년대이전까지 HL 검사는혈청학적방법을사용한저해상도검사 ( 두자리검사, 예 : *02) 였으나근래에는분자생물학적방법을이용한고해상도 HL 검사 ( 네자리검사, 예 : *2010) 가사용된다. HL 검사는 HL-, -, -C, -DR1 및 DQ1 유전자위의분석이권장되며환자와공여자간의대립유전자가모두일치하는경우를완전일치 (full match, 10/10 일치 ) 라고한다. 동종조혈모세포이식에가장적합한공여자는 HL가완전히일치하는형제자매이지만이러한경우는전체환자의 15~30% 에불과하다. HL 가일치하는형제자매가존재하지않을경우차선책은 HL가일치하는비혈연공여자를선택하는것이다. 상기두조건에합치하는공여자를찾을수없을때는 HL 부분불일치혈연이식 (HL haploidentical hematopoietic stem cell transplantation) 이나 HL 부분불일치제대혈이식 (HL partially mismatched cord blood transplantation) 이대안이될수있다 2). 2. 조혈모세포이식 1960년대초 HL 개념이알려지면서면역결핍환자에게 HL 일치혈연간동종조혈모세포이식 (HL matched related allogeneic stem cell transplantation) 이시도되었고, 1970년대후반 Thomas 등 3) 이백혈병환자들에게 HL 일치혈연간동종조혈모세포이식을시행하였다. 이후이러한임상결과를 바탕으로조혈모세포이식이혈액질환치료에폭넓게사용되게되었다. 조혈모세포이식은공여자와수혜자와의관계및조혈모세포를채취하는이식원의위치에따라분류한다. 이식전환자자신의조혈모세포를채집, 냉동보관하였다이식하는경우를자가조혈모세포이식 (autologous stem cell transplantation) 이라고한다. 다른사람으로부터조혈모세포를이식받는경우를동종조혈모세포이식 (allogeneic transplantation) 이라고한다. 또, 공여자와환자가혈연관계인경우는혈연간동종조혈모세포이식, 공여자와환자가혈연관계가아닌경우는비혈연동종조혈모세포이식 (unrelated allogeneic stem cell transplantation) 이라고한다. 이식원을기준으로골수이식, 말초조혈모세포이식 (peripheral stem cell transplantation) 그리고제대혈이식 (umbilical cord blood transplantation) 으로분류한다. 전통적으로이식에사용되는조혈모세포는후장골능에서채취한골수세포를사용하였다. 그러나최근에는조혈촉진인자를이용하여골수조혈모세포를말초혈액내로가동화 (mobilization) 시켜혈액내에서조혈모세포를수집할수있게되었고, 이러한말초혈조혈모세포수집은전신마취가필요없고간편하여많이사용된다 3). 조혈모세포이식은전처치 (conditioning), 세포이식, 생착 (engraftment) 및면역학적재구성 (immunoreconstitution) 의네단계로구성된다. 전처치는악성세포를제거하고면역반응을억제하여이식된세포에대한거부반응이생기지않도록하는치료이다. 주로고용량의전신방사선조사와 cyclophosphamide, busulfan같은알킬화제를병합하여사용한다 4). 생착은이식된조혈모세포가골수내에서새로운혈액성분을생성하여절대중성구수가 0.5 10 9 /L 이상으로회복되는상태로 5) 거부반응은이식받은환자의 5% 이내에서발생한다 6). 생착후환자의면역기능이점진적으로회복되는단계를면역학적재구성이라고한다. 세포독성및포식기능은이식 100일후부터회복되기시작하지만 T 림프구와 림프구의기능이완전히회복되려면 1년이상걸린다 7). 전처치에사용되는약물과전신방사선조사로인해범혈구감소증과비혈액학적합병증이일어날수있다. 가장흔한문제는점막염으로구강인두의통증, 구토, 복부통증등의증상을유발한다. 약 10% 의환자에서간비대, 황달및체액저류를동반한정맥폐쇄성간질환 (veno-occlusive disease) 이발생하는데치명적인합병증이다. 생착전가장흔한합병증은감염이며, 발열증상이있을때광범위항생제의즉각적인투여와항진균제및항바이러스제의예방적투여가필요 - 553 -
- 대한내과학회지 : 제 78 권제 5 호통권제 597 호 2010 - Donor Leukemic cell Graft -versus-leukemic effect Preparative regimen HSCT DLI Donor T lymphocyte Graft- versus- host disease Normal cell in Skin, Liver, GI Figure 2. Graft-versus-leukemic effect and graft-versus-host disease. 하다. 생착후가장흔한합병증은이식편대숙주병이다. 공여자의 T 림프구가환자의항원을인식하여피부, 위장관및간에염증반응을일으켜발진, 복부통증, 설사, 황달등이나타난다. 또한공여자의 T 림프구는체내에서잔존백혈병세포를공격하는이식편대종양효과 (graft versus leukemic effect) 도유도하여병의재발을낮추는역할도한다 ( 그림 2). 이식관련사망률은 HL 일치혈연간조혈모세포이식의경우 20~30% 에이르며, 비혈연간조혈모세포이식의경우는이보다더높아합병증과재발을줄이는것이향후극복해야할문제이다 8). 3. 비골수제거조혈모세포이식 (Non-myeloablative hematopoietic stem cell transplantation) 기존의조혈모세포이식은전신방사선조사나고용량화학요법같은전처치로인한합병증때문에고령자나기왕증이있는환자들에게시술하기어려웠다. 최근에는전처치의강도를낮추어살아남아있는환자의조혈모세포와공여자의조혈모세포가공존하는혼합키메라 (mixed chimerism) 를유도하고, 공여자의림프구를다시수혈하여완전공여자키메라 (complete donor chimerism) 상태를만드는비골수제거조혈모세포이식이시행되고있다 ( 그림 3) 10). 비골수제거조혈모세포이식은전처치의강도를낮춰이식편대숙주반응등의전처치관련독성을감소시키고 11), 림프구를수혈하여이식편대종양효과를유도하는비교적안전하고효과적인치료방법이지만기존의동종조혈모세포이식에비해재발이나생착부전 (graft rejection) 은더많이발생한다 11,12). 그러나고령자나기왕증이있는환자에서안정성과유효성이입증되어 60세이상의환자들에게는가장흔히사용되는조혈모세포이식방법이다 13). L L L Recipient Mixed Chimera Complete Chimera Figure 3. Non-myeloablative stem cell transplantation., patient derived cells; L, Leukemic cells;, donor derived cells; HSCT, hematopoietic stem cell transplantation; DLI, donor lymphocyte infusion. 4. HL 불일치조혈모세포이식 (HL mismatched hematopoietic stem cell transplantation) 1) HL 부분불일치혈연조혈모세포이식 (HL partially mismatched/haploidentical hematopoietic stem cell transplantation) 대부분의환자는유전자형과표현형이동일한일배체 (haplotype) 와 HL 항원이일치하지않는다른일배체를가진부모, 형제또는자녀가있기때문에 HL 부분불일치혈연조혈모세포이식이가능하다. 그러나 HL 불일치로인한생착부전과심한이식편대숙주병때문에이식관련사망률이높아진다 14-16). 비교적양호한 HL 불일치혈연간조혈모세포이식성적은 22개월의추적기간중관해상태급성골수성백혈병의무병생존율이약 50% 정도로 HL 일치비혈연조혈모세포이식에필적할만한결과이다 17). HL 불일치혈연간조혈모세포이식은아직해결되지않은문제들이있으나 HL 일치공여자가없는경우에는치료대안으로시도되고있으며, 앞으로이식성적을더향상시키기위해서는생착을증가시키고이식편대숙주병을예방하기위한새로운면역조절방법에대한연구가필요할것으로생각된다. 2) HL 부분불일치제대혈조혈모세포이식 (HL partially mismatched cord blood transplantation) 제대혈은골수나말초조혈모세포이식에비해구하기쉽고이식편대숙주병이심하지않은장점이있어새로운조혈모세포이식의공급원으로주목받고있다 18,19). 소아환자에서 HL 부분불일치제대혈조혈모세포이식은골수를이용한 - 554 -
- 김정아. 혈액질환에서의새로운조혈모세포이식기법 - 조혈모세포이식과비교할때생착이지연되고, 이식초기사망률이높지만전체적인생존율은비슷하다 20). 성인의경우제대혈내의세포수가부족하므로여러공여자의제대혈을동시에이식하거나제대혈조혈모세포의생체외배양에대한연구가진행되고있다 18). 결 조혈모세포이식은재생불량성빈혈과같은골수기능부전환자의조혈기능을회복시킬수있는치료이며, 혈액암환자에서는잔존백혈병세포를제거하고이식편대항종양효과를유도하여완치율을증가시킬수있는치료방법이다. 이전에는 HL 일치공여자를구할수없거나, 고령이나기왕증등의문제로강력한전처치를받을수없는환자들은이식이불가능하였으나, 이를극복하기위한노력과연구의결과로비골수제거조혈모세포이식과제대혈이식, HL 부분불일치혈연간조혈모세포이식이가능해져치료영역이확대되었다. 그러나생착부전, 감염, 이식편대숙주병등의문제는완전히해결되지않았기때문에앞으로보다많은연구가필요하다. 중심단어 : 조혈모세포이식 ; 조직적합항원 ; 생착 ; 이식편대숙주반응 론 REFERENCES 1) Klein J, Sato. The HL system. First of two parts. N Engl J Med. 343:702-709, 2000 2) Nowak J. Role of HL in hematopoietic SCT. one Marrow Transplant. 42 Suppl 2:S71-76, 2008 3) Copelan E. Hematopoietic stem-cell transplantation. N Engl J Med. 354:1813-1826, 2006 4) Hennessy J, Orchard KH, Potter MN. Novel approaches to transplant conditioning. Hematol Oncol. 19:43-57, 2001 5) ensinger WI, Martin PJ, Storer, Clift R, Forman SJ, Negrin R, Kashyap, Flowers ME, Lilleby K, Chauncey TR, Storb R, ppelbaum FR. Transplantation of bone marrow as compared with peripheral-blood cells from HL-identical relatives in patients with hematologic cancers. N Engl J Med. 344:175-181, 2001 6) Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. one Marrow Transplant. 29:545-552, 2002 7) Lum LG. The kinetics of immune reconstitution after human marrow transplantation. lood. 69:369-380, 1987 8) Leger CS, Nevill TJ. Hematopoietic stem cell transplantation: a primer for the primary care physician. CMJ. 170:1569-1577, 2004 9) Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer, uckner CD, Storb R. ntileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 300:1068-1073, 1979 10) Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, Read EJ, Carter C, ahceci E, Young NS, arrett J. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. lood. 94:3234-3241, 1999 11) Pollack SM, O'Connor TP, Jr., Hashash J, Tabbara I. Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review. m J Clin Oncol. 32:618-628, 2009 12) Levine JE, Uberti JP, yash L, Reynolds C, Ferrara JL, Silver SM, raun T, Yanik G, Hutchinson R, Ratanatharathorn V. Loweredintensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. iol lood Marrow Transplant. 9:189-197, 2003 13) Giralt S. Reduced-intensity conditioning regimens for hematologic malignancies: what have we learned over the last 10 years? Hematology m Soc Hematol Educ Program. 384-389, 2005 14) Szydlo R, Goldman JM, Klein JP, Gale RP, sh RC, ach FH, radley, Casper JT, Flomenberg N, Gajewski JL, Gluckman E, Henslee-Downey PJ, Hows JM, Jacobsen N, Kolb HJ, Lowenberg, Masaoka T, Rowlings P, Sondel PM, van ekkum DW, van Rood JJ, Vowels MR, Zhang MJ, Horowitz MM. Results of allogeneic bone marrow transplants for leukemia using donors other than HL-identical siblings. J Clin Oncol. 15:1767-1777, 1997 15) Clift R, Hansen J, Thomas ED, uckner CD, Sanders JE, Mickelson EM, Storb, R, Johnson FL, Singer JW, Gooddell W. Marrow transplantation from donors other than HL-identical siblings. Transplantation. 28:235-242, 1979 16) Ciceri F, Labopin M, versa F, Rowe JM, unjes D, Lewalle P, Nagler, Di artolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V. cute Leukemia Working Party (LWP) of European lood and Marrow Transplant (EMT) Group. survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. lood. 112:3574-3581, 2008 17) versa F, Terenzi, Tabilio, Falzetti F, Carotti, allanti S, Felicini R, Falcinelli F, Velardi, Ruggeri L, loisi T, Saab JP, Santucci, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 23:3447-3454, 2005-555 -
- The Korean Journal of Medicine: Vol. 78, No. 5, 2010-18) Gluckman E. Ten years of cord blood transplantation: from bench to bedside. r J Haematol. 147:192-199, 2009 19) Hwang WY, Ong SY. llogeneic haematopoietic stem cell transplantation without a matched sibling donor: current options and future potential. nn cad Med Singapore. 38:340-346, 2009 20) arker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. lood. 97:2957-2961, 2001-556 -