이종이식에서의 면역학적 장벽 극복: 이전 연구와 향후 방향에 대한 역사적 고찰 = Overcoming Immunological Barriers in Xenotransplantation: A Historical Review of Previous Research and Future Directions

국문 초록 (Abstract)

공여장기 부족은 임상이식의 큰 문제 중 하나이다. 이 문제를 해결하기 위한 대안으로 동물의 장기를 사람에게 이식하는 이종이식이 제시되었다. 하지만 이종이식은 오랜 시도에도 불구하고 매우 실망적인 결과로 그저 담대한 아이디어 차원에 머물렀다. 이종이식의 수많은 어려움 중 면역학적 장애와 이종 간의 분자적 부조화가 가장 극복하기 어려운 문제이다. 최근 타겟 면역억제제 개발과 유전자 편집기술의 발전에 힘입어 이종이식은 임상진입에 한층 가까워졌다. 2022년 미국에서 처음으로 사람이 돼지의 심장을 이식받고 초급성거부반응 없이 생존하였다. 생존기간이 길진 못했지만 이 시도는 여태까지 이종이식 분야에서 이루어진 연구결과들이 임상에 적용되었을 때도 의미 있는 과학적 사실임을 증명하였다. 이제 이종이식은 안전한 임상적용으로 향하는 첫 아기걸음을 시작하였고 아직 길고 험한 여정이 남아있지만 충분히 가치 있는 길이 될 것이다. 이 글에서는 이종이식 연구의 지난 과학적 탐구를 소개하고 앞으로의 방향에 대하여 다루고자 한다.

다국어 초록 (Multilingual Abstract)

The shortage of human donor organs is a major concern in clinical transplantation. Xenotransplantation, the transplantation of animal organs into humans, is a procedure that aims to solve this problem. Unfortunately, this ambitious idea has a long, fascinating, but disappointing history. Among the many obstacles to xenotransplantation, immunological barriers and molecular incompatibility between species are the most challenging. Recent advances in gene editing techniques and the development of targeted immune suppressive agents have pushed xenotransplantation closer to clinical application. In 2022, the first patient that received porcine heart transplantation in the United States showed no sign of hyperacute rejection. Although the patient did not survive for a long time, this controversial clinical trial proved that previous research data have been crucial in improving the viability of porcine donor organs in clinical transplantations. Xenotransplantation has shown a slight progress in its clinical application. However, further progress necessitates extensive and challenging research, but is worth pursuing. This article covers previous scientific endeavors and future directions in xenotransplantation research.

참고문헌 (Reference)

• 1 Shimizu A, "Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1, 3-galactosyltransferase gene-knockout pigs in baboons" 172 : 1471-1481, 2008
• 2 Gaca JG, "The role of the porcine von Willebrand factor : baboon platelet interactions in pulmonary xenotransplantation" 74 : 1596-1603, 2002
• 3 Kang HJ, "The role of the alternative complement pathway in early graft loss after intraportal porcine islet xenotransplantation" 97 : 999-1008, 2014
• 4 Doudna JA, "The new frontier of genome engineering with CRISPR-Cas9" 346 : 1258096-, 2014
• 5 Galili U, "The human natural anti-Gal IgG. III. The subtlety of immune tolerance in man as demonstrated by crossreactivity between natural anti-Gal and anti-B antibodies" 165 : 693-704, 1987
• 6 Cozzi E, "The generation of transgenic pigs as potential organ donors for humans" 1 : 964-966, 1995
• 7 Lee SJ, "Seven years of experiences of preclinical experiments of xeno-heart transplantation of pig to non-human primate(cynomolgus monkey)" 50 : 1167-1171, 2018
• 8 Fishman JA, "Risks of infectious disease in xenotransplantation" 387 : 2258-2267, 2022
• 9 Cooper DK, "Recent advances in understanding xenotransplantation : implications for the clinic" 11 : 1379-1390, 2015
• 10 Shah JA, "Prolonged survival following pig-to-primate liver xenotransplantation utilizing exogenous coagulation factors and costimulation blockade" 17 : 2178-2185, 2017
• 11 Phelps CJ, "Production and characterization of transgenic pigs expressing porcine CTLA4-Ig" 16 : 477-485, 2009
• 12 Kim YT, "Pre-treatment of porcine pulmonary xenograft with desmopressin : a novel strategy to attenuate platelet activation and systemic intravascular coagulation in an ex-vivo model of swine-to-human pulmonary xenotransplantation" 15 : 27-35, 2008
• 13 Kang HJ, "Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient" 28 : 149-156, 2005
• 14 Kim SC, "Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion" 19 : 2174-2185, 2019
• 15 Yoon CH, "Long-term survival of full-thickness corneal xenografts from α1, 3-galactosyltrans-ferase gene-knockout miniature pigs in non-human primates" 27 : e12559-, 2020
• 16 Shin JS, "Long-term control of diabetes in immunosuppressed nonhuman primates(NHP)by the transplantation of adult porcine islets" 15 : 2837-2850, 2015
• 17 Ma D, "Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques" 22 : 46-57, 2022
• 18 Watanabe H, "Intra-bone bone marrow transplantation from hCD47 transgenic pigs to baboons prolongs chimerism to >60 days and promotes increased porcine lung transplant survival" 27 : e12552-, 2020
• 19 Galili U, "Interaction of the natural anti-Gal antibody with α-galactosyl epitopes : a major obstacle for xenotransplantation in humans" 14 : 480-482, 1993
• 20 Lee KG, "Increased human tumor necrosis factor-α levels induce procoagulant change in porcine endothelial cells in vitro" 19 : 186-195, 2012
• 21 강희정 ; 이한율나리 ; 박은미 ; 김종민 ; 신준섭 ; 김중식 ; 박정규 ; 김상준, "Increase in Anti-Gal IgM Level is Associated With Early Graft Failure in Intraportal Porcine Islet Xenotransplantation" 대한진단검사의학회 35 (35): 611-617, 2015
• 22 Schuurman HJ, "Incidence of hyperacute rejection in pig-to-primate transplantation using organs from hDAF-transgenic donors" 73 : 1146-1151, 2002
• 23 Jung KC, "In situ induction of dendritic cell-based T cell tolerance in humanized mice and nonhuman primates" 208 : 2477-2488, 2011
• 24 Denner J, "Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival" 10 : 17531-, 2020
• 25 Good AH, "Identification of carbohydrate structures that bind human antiporcine antibodies : implications for discordant xenografting in humans" 24 : 559-562, 1992
• 26 Cooper DK, "Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies : relevance to discordant xenografting in man" 1 : 198-205, 1993
• 27 Rose AG, "Histopathology of hyperacute rejection of the heart : experimental and clinical observations in allografts and xenografts" 10 : 223-234, 1991
• 28 Kuwaki K, "Heart transplantation in baboons using α1, 3-galactosyltransferase gene-knockout pigs as donors : initial experience" 11 : 29-31, 2005
• 29 Griffith BP, "Genetically modified porcine-to-human cardiac xenotransplantation" 387 : 35-44, 2022
• 30 Phimister EG, "Genetic modification in pig-to-human transplantation" 387 : 79-82, 2022
• 31 Shin JS, "Failure of transplantation tolerance induction by autologous regulatory T cells in the pig-to-non-human primate islet xenotransplantation model" 23 : 300-309, 2016
• 32 Najarian JS, "Experimental xenotransplantation : a personal history" 10 : 10-15, 2003
• 33 Park EM, "Early interferon-gamma response in nonhuman primate recipients of solid-organ xenotransplantation" 53 : 3093-3100, 2021
• 34 Kang HJ, "Dissociation between anti-porcine albumin and anti-Gal antibody responses in non-human primate recipients of intraportal porcine islet transplantation" 22 : 124-134, 2015
• 35 Bach FH, "Delayed xenograft rejection" 17 : 379-384, 1996
• 36 Längin M, "Consistent success in life-supporting porcine cardiac xenotransplantation" 564 : 430-433, 2018
• 37 Kim J, "Comparative efficacy of anti-CD40 antibody-mediated costimulation blockade on long-term survival of full-thickness porcine corneal grafts in nonhuman primates" 18 : 2330-2341, 2018
• 38 Aristizabal AM, "Clinical xenotransplantation, a closer reality : Literature review" 95 : 62-72, 2017
• 39 Ekser B, "Clinical xenotransplantation : the next medical revolution?" 379 : 672-683, 2012
• 40 Huai G, "Characteristics of α-Gal epitope, anti-Gal antibody, α1, 3 galactosyltransferase and its clinical exploitation(Review)" 37 : 11-20, 2016
• 41 Zirlik A, "CD40 ligand mediates infiammation independently of CD40 by interaction with Mac-1" 115 : 1571-1580, 2007
• 42 Choi HJ, "Blockade of CD40-CD154 costimulatory pathway promotes long-term survival of full-thickness porcine corneal grafts in nonhuman primates : clinically applicable xenocorneal transplantation" 15 : 628-641, 2015
• 43 Ariyoshi Y, "Antibody reactivity with new antigens revealed in multi-transgenic triple knockout pigs may cause early loss of pig kidneys in baboons" 28 : e12642-, 2021
• 44 Korea Network for Organ Sharing, "Annual report of the transplant 2019"
• 45 Cooper DKC, "A brief history of clinical xenotransplantation" 23 : 205-210, 2015