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A Tale of Two Kidneys Overcoming the Immunological Barrier in Organ Transplantation by Roxanna Haghighat

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A Tale of Two Kidneys Overcoming the Immunological Barrier in Organ Transplantation by Roxanna Haghighat 375Focus: Illuminating Science Years of Science at Harvard A Tale of Two Kidneys Overcoming the Immunological Barrier in Organ Transplantation By Roxanna Haghighat rgan transplantation becomes from one person and implant it into Harvard Medical School (now known Oa pesonal rather than scien- a separate human being at the outset as Brigham and Women’s Hospital), WLÀFPDWWHUDWWKH'09·VRIÀFHZKHUH seemed overwhelmingly complicated 'U0XUUD\SHUIRUPHGWKHÀUVWVXF- newly-licensed drivers are faced with DQGDOPRVWOLNHVFLHQFHÀFWLRQ³DPRUH cessful transplant of a major organ, for the crucial choice of whether or not humanistic Frankenstein, perhaps. Yet, which he received the Nobel Prize in to be an organ donor. Organ dona- decades of research later and count- Physiology in Medicine in 1990. More tion carries two seemingly polarized less obstacles overcome, organ trans- VSHFLÀFDOO\LQKHSHUIRUPHGWKH LPDJHV³RQHRI DJULHYLQJIDPLO\ plantation stands as the gold standard ÀUVWUHQDOWUDQVSODQWEHWZHHQLGHQWLFDO choosing to give life to sick patients therapeutic approach for patients with twins without organ rejection result- sitting at the top of the transplant list failing organs. ing in recipient mortality. Beyond this with no other treatment options and the While transplantation remains con- successful demonstration, Dr. Murray other of the global organ black market troversial in some cultures, as it is seen sought further to link his medical ac- by which scarce tissue resources are DVFRPPRGLÀFDWLRQRI KXPDQEHLQJV FRPSOLVKPHQWWRWKHEDVLFVFLHQWLÀF smuggled across borders. Perceptions the ability to perform organ transplants principles underlying it, investigating DVLGHWUDQVSODQWDWLRQ³ZKLOHWRGD\D LVDUHPDUNDEOHVFLHQWLÀFDFKLHYHPHQW genetics, the immune system, and organ VHWRI URXWLQHVXUJLFDOSURFHGXUHV³ that is due largely to the efforts of Dr. rejection. His discoveries, both in the UHPDLQVDQLQFUHGLEOHVFLHQWLÀFIHDW Joseph E. Murray. During his time at operating room and at the bench, have The capacity to remove a live organ the Peter Bent Brigham Hospital of the forever opened up the possibility of a credit:The National Archives of Plastic Surgery, Francis A. Countway LIbrary of Medicine Francis Archives of Plastic Surgery, credit:The National 8 Harvard Science Review fall 2011 375Focus: Illuminating Science Years of Science at Harvard curative therapy for end-stage disease. use of the transplantation of organs for therapeutic purposes.” (3). Given the The Immunological Barrier The History of Transplantation limited understanding of the immune Yet, following a common thread 7KHILUVWVXFFHVVIXODOORJUDIW³D system at the time, in the history of transplant between individuals of the this conclusion, at- medical advances, VDPHVSHFLHV³ZDVSHUIRUPHGLQ tained through his physician scientists (1). This crude operation, however, was extensive experi- refused to accept limited to bone transplantation. Nearly ence with grafts WKLVXOWLPDWXPLQ- WZRFHQWXULHVODWHUWKHÀUVWKXPDQWLV- and transplants, is VWHDGLQWKHV sue graft was performed in Switzerland, especially remark- DQGVUHVHDUFK but advancements to full, solid organ able. Carrel him- uncovered the transplants consistently failed through- self had pioneered source of immune RXWWKHHDUO\thFHQWXU\ 7KHÀUVW the first vascular rejection, known meaningful step toward a successful suturing technique, as HLA antigens organ transplant was the allograft of a known as “trian- (Human Leukocyte FRUQHDLQ$XVWULDLQLQVSLUHGE\ gulation,” which Antigens). In par- this success, surgeons in France began entails connecting ticular, after clini- credit:(7) attempting kidney transplants begin- blood vessels from cal experience in QLQJLQ2I DWRWDOIRUW\SDWLHQWV the living recipi- France with hema- all passed away due to organ rejection, ent and deceased tology and research XVXDOO\ZLWKLQWKHÀUVW\HDUZKLFKVW\- donor (3). This Figure 1. Dr. Joseph E. Murray at Harvard Medi- mied physician willingness to perform method, inspired cal School, French and patient willingness to receive such and perfected by his work with a immunologist Jean Dusset attempted DQRSHUDWLRQ seamstress, enabled the short-term suc- to transfer techniques in immunohae- Given the repeated failures of these cess of organ transplants. By the late matology, or blood banking, to white WUDQVSODQWVLQ)UHQFKVXUJHRQ VIHOORZ1REHO/DXUHDWH6LU3HWHU EORRGFHOOVDQGSODWHOHWV $IWHURE- and Nobel Prize Laureate in Physiology Medawar expressed the frustration of serving the agglutination of leukocytes or Medicine Alexis Carrel realized that physicians towards the seemingly in- and thrombocytes, he eventually identi- there must be some “biological force” surmountable challenge of transplanta- ÀHGWKHÀUVWOHXNRF\WHDQWLJHQLQ inhibiting a successful operation be- tion, declaring that the biological force NQRZQDV+/$$ +XPDQ/HXNRF\WH tween individuals of the same species: described by Carrel would “forever… Antigen), for which he received the ´&HOOVDUHVSHFLÀFRI WKHLQGLYLGXDOWR inhibit transplantation from one indi- 1REHO3UL]HLQ 7KHUHFLSLHQW·V whom they belong. This peculiarity of YLGXDOWRDQRWKHUµ immune system recognizes the HLA our body has so far prevented the wide antigens on the cell surfaces of the donor’s organ, which induces the host cells’ immunological response to reject the foreign cells. This process, known as the “graft-versus-host” reaction *9+ XQGHUOD\WKHIDLOXUHRISUHYLRXV transplantation attempts. The discovery of Carrel’s infamous “biological factor” immediately sparked renewed interest in transplantation, HVSHFLDOO\LQWKHÀHOGRIQHSKURORJ\ With the help of Dr. Carl W. Walter, Dutch physician Willem Kolff devel- oped the first “artificial kidney,” or GLDO\VLVPDFKLQHLQKRZHYHU dialysis treatment was not only tem- porary but also expensive and painful 7KHODFNRISHUPDQHQWWKHUDS\IRU patients with renal disease beckoned plastic surgeon Dr. Joseph Murray to Figure 2. A basic overview of the immune system response to an antigen credit:http://pathmicro.med.sc.edu/book/immunol-sta.htm fall 2011 Harvard Science Review 9 375Focus: Illuminating Science Years of Science at Harvard Figure 3. A ureteroneocystostomy Chief of Plastic Surgery, Dr. Murray was inspired by his men- tor’s breakthrough operation. 7KHVLJQLÀFDQFHRI DJHQHWLFUH- lationship between the donor and host implicated a genetic factor in the immunological response to organ transplantation. Two IXUWKHUH[SHULPHQWVFRQÀUPHG WKLVSRVWXODWLRQ)LUVWLQ Drs. Billingham and Medawar of the University of Birmingham induced acquired immunological tolerance in various mammals, including cows, through a neo- natal injection of donor cells into a future allograft host (10). Second, Sir Michael Woodruff of the University of Edinburgh successfully skin grafted between dizygotic, or fraternal, twins who had shared placental blood, explore the increasingly realistic pos- allow the transplanted organ to survive. which led to a protection against sibility of a successful renal transplant. Drs. Merrill and Hume attempted to immune response (11). Armed with After graduating from Harvard Medical use corticosteroids as post-operative knowledge of these results, Dr. Murray 6FKRROLQKHWUDLQHGLQSODVWLF treatment to decrease inflammation sought to overcome the immunological VXUJHU\WKURXJKWKH86$UP\DW9DO- and downregulate the immune response barrier in humans that now seemed to ley Forge General Hospital, where he following surgery, but supplies lasted be manipulable. gained extensive experience with skin for only a few days (9). First, however, Dr. Murray had to autographs and allografts (7). Given Meanwhile, Dr. Murray had wit- prove that the transplantation itself of WKLVEDFNJURXQGKHLGHQWLÀHGWKURXJK nessed the outcomes of skin allografts, a kidney would not be fatal to the re- his training the potential to cross-apply which rarely survived permanently, but cipient. An autograft, the transfer of a ongoing research in skin grafts between exhibited patient’s own tis- identical twins with surgical attempts at g r e a t e r ´7KHVLJQLÀFDQFHRIDJHQHWLF sue or organ to human renal transplants. s u c c e s s UHODWLRQVKLSEHWZHHQWKHGRQRUDQG another part of w h e n KRVWLPSOLFDWHGDJHQHWLFIDFWRU his body, would function as a Revival of Interest g r a f t e d LQWKHLPPXQRORJLFDOUHVSRQVHWR At the Brigham Hospital, encour- between negative control. aged by success in the canine model, family RUJDQWUDQVSODQWDWLRQµ After repeated Drs. John Merrill and David Hume members, experiments in had begun experimenting with cadav- rather than between an unrelated donor the canine model, at Brigham Hospital, HULFGRQRUNLGQH\V%HWZHHQDQG and recipient. In 1937, Dr. J.B. Brown Dr. Murray mastered the technique WKHWZRFRQGXFWHGQLQHVXFK at Barnes Hospital in St. Louis took this of grafting the kidney into the lower operations, whereby the cadaveric kid- observation one step further by grafting abdomen, internally connecting the neys were grafted into the recipients’ skin between monozygotic, or identical, donor kidney blood vessels to those IHPRUDOYHVVHOV +RZHYHUGHVSLWH WZLQVDV'U%URZQKDGK\SRWKHVL]HG of the recipient’s abdomen. Also, a technical achievement in four of the this operation resulted in permanent ureteroneocystostomy, by which he surgeries, the most successful host died graft survival. Having worked closely placed the upper end of the ureter within six months of the transplant due with Dr. Brown during his time at into the bladder, enabled urine drain- age (11). To date, this technique is credit: http://www.cpmc.org/learning/documents/kidney-ws.html WRLQVXIÀFLHQWLPPXQRVXSSUHVVLRQWR 9)*+ZKHUH'U%URZQZDVWKH
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