Demetris, AJ

Fontes, P

Fung, JJ

Rao, AS

Starzl, TE

Trucco, M

PubMed

Name not available

Explanation for loss of the HLA matching effect

D-Scholarship@Pitt

---------------_. Explanation for Loss of the HLA Matching Effect T.E. Starzl. A.S. Rae. M. Trucco. P. Fontes. J.J. Fung. A.J. Demetris M y MAIN purpose today is to explain why HLA matching is so crucial for bone marrow transplanta-1 ion on one hand. and yet so relatively IIl1imponallf for urgan transplantation on the other. THE ONE-WAY PARADIGM OF TRANSPLANTATION IMMUNOLOGY The one-way paradigm of transplantation immunology shown in Fig I was of course directly derived from our patron saints-Billingham. Brent. and Medawar. In their original model. I or in the defenseless parent to offspring FI hvhrid experiments. and after recipient cytoablation. the ;Ivoidance of graft-vs-host disease (GYHD) after bone marrow or spleen cell transplantation was found to be dependent on good MHC compatibility. In analogous experiments. the same rules of histocom-p;ltibility apply to immunologically defenseless recipients of Immunologically active whole organs as was emphasized by Billingham and Brent~ and demonstrated in detail for the Illtestine bv Monchik and Russell.' However. the usual immunologic context of whole organ transplantation is actually a mirror image of the bone marrow experiments. hut still involving a one-wav reaction. Now. the graft is the defenseless victim instead ;)1' being the aggresso;. This false conceptualization has been the paradigm of transplantation immunology for more than 40 years. In spite of its fatal intellectual flaw. the concept of an essen-tially unidirectional immune reaction proved useful. It was translated into successful clinical bone marrow transplanta-tion in I YfJiI by Robert Good and Fritz Bach. emphasizing ahove all the need for HLA compatibility if engraftment was to be accomplished without the complication of liVHD. THE 2-WAY IMMUNOLOGIC PARADIGM The one-way paradigm has never explained what we see daily in our whole organ clinics. exemplified by the failure of HLA matching to influence more profoundly the survival of whole organ grafts. This was recognized earlv bv trans-plant surgeons who bv the time of the first succes~fulD clinical bone marrow cases' had already recorded thousands of successful whole organ transplantations (mostly kidneys) using continuous immunosuppression-without host pre-conditioning. without dependence on MHC matching. and with no problems with GYHD. The avalanche of whole urgan cases began after a characteristic postoperative cycle II ;IS identified when azathioprine was systematically com-Illncd with prednisone:' Kidney rejection could be reversed 'lirprisingly easily with prednisone. More importantly. the Ilt:t:d later on for maintenance immunosuppression fre-yuently declined. The same sequence has been seen since with all other organs transplanted and with all of the immunosuppressive regimens. Something appeared to have changed in the host. the graft. or both. But what? Thirty years and a revolution in immunology later. this question was answered. Donor leukoCYtes of bone marrow origin. which are part of the structure of all complex grafts (the so-called multilineage "passenger leukocytes"). had migrated from the organs and survived ubiquitously in the recipients.s," Thus. successful organ transplantation was a cryptic example of cell transplantation. whereby a small fragment of disseminated extramedullary donor bone mar-row (shown in Figure 2 as a bone silhouette) was assimi-lated into the overwhelmingly larger immunologic network of the host. The cdl movement was in both directions. In this bidirectiollal paradigm. the immunologic confrontation following whole organ transplantation involves a GYH as well as HYG reaction in which the two cell populations an: mutually cancelling. providing both can survive. The um-brella of immunosuppression that covers both equally al-lows this. The number of chimeric donor cells is small."·" Recent research has suggested how such a small numher of chi-meric leukocyte~ can uown regulate the donor-specific reactivity of the vast army of recipient cells against which they are arrayed \ a veto clrcct: Fig 2). The uendritic cells of Steinman and Cohn 7 are thought to be key participants. With the paradigm of a two-way immune reaction. virtually every previously enigmatic problem seen clinically after experimental or clinical whole organ transplantation be-comes either transparent or susceptible to experimental inquiry. THE BLINDFOLDING OF HLA This includes the loss or blunting of an HLA matching effect. With the two-way cancellation. it is easy to under~ stand how the expt!cted matching influence is blind folded. With each further level of histoincompatibility. the cancel-ling effect is postulated to escalate both ways providing the process is chaperoned with an effective immunosuppressive From the Pittsburgh Transplantation Institute. and the Depart-ments of Surgery (T.E.S., A.S.R .. P.F., J.J.F.), Pathology (A.S.R .. A.J.D.), and PediatriCS (M.T.), UniverSity of Pittsburgh Medical Center. Pittsburgh. Pennsylvania. Supported by research grants from the Veterans Administra-tion and project grant DK 29961 from the National Institutes of Health. Bethesda. Maryland. Address reprint requests to Thomas E. Starzl. MD. PhD, Department of Surgery, 3601 Fifth Ave. 5C Falk Clinic. University of Pittsburgh, Pittsburgh. PA 15213. '9 1995 by Appleton & Lange 0041-1345/95/$3.00/ + 0 57 Transplantation Proceedings, Vol 27, No 1 (February). 1995: pp 57-60 ij 58 STARZL. RAO. TRUCCO ET AL One-Way Paradigm (Spleen) GVH umbrella. with a consequent dwindling of the matching effect as donor-specific and recipient-specific nonreactivity evolves. In this context. suppressor and veto cells. changes in cytokine profiles. and the development of enhancing antibodies are derivative from the primary event of mutual cdl engagement (Fig 2). The importance of the sponruneous chimerism and its densitv has been demonstrated by Robert Keenan and Adriana Zeevi (Universitv of Pittsburgh). They stratitied 15 lung transplant recipients. with follow-up of I to 5 years. into a clinical and histopathologically favorable group of eight with no bronchiolitis obliterans and seven who had this ominous tinding of chronic rejection. The patients without bronchiolitis llbliterans had dense chimerism-positive in eight of eight lymph nodes. seven of eight skin biopsies. and six of eight blood samples.x Chimerism also was demonstrable in several patients of the less favored group but less regularlv and with a generally lower quanti-tative grade. Using the stored donor spleens. donor-specitic nonreactivity was demonstrated in all but one of the highly chimeric recipients. but in only two of the less favored group. These results had no correlation with the preopera-tive HLA match. In addition to explaining whv the HLA matching effect is hlind folded. this bidirectional mechanism explains why GVHD does nO[ develop after liver. intestinal. multivis-cera!. and heart-lung transplantation. It also explains why all whole organs have the inherent capabilitv of toleroge-nicitv. Calne's brilliant studies with Sells in pigs" and with t Defenseless Recipient Blilingham-Brent-Medawar Cytoablation (x-ray, drugs) Parent-. Offspring F1 Hybrid Fig 1. Transplant model used in the first demonstration by Billingham. Brent. and Med-awar' to demonstrate the ac-quisition of immunologic toler-ance. Zimmerman and Kamada in rats of the leukocyte-rich liver provided the most clear examples-called hepatic tolero-genicity. However. Corry et al lo and Russell et al" showed long ago the tolerogenicity of even the leukocyte-poor heart and kidney in mice but ollly with less difficult MHC barriers. Finally. the once vast gap between the bone marrow and whole organ transplantation tields was further closed when it was shown bv the teams of Donnall Thomas in Seattle 12 and others l.1 u~ing sensitive detection techniques that there is a trace population of recipient cells in patients whose hone marrow was previously thought to have been com-pletely replaced. Thus. in these patients. as in whole organ recipients. the appearance of MHC restricted veto and suppressor cells. enhancing antibodies. and changes in cytokine profiles could be construed as by-products of and accessory to the seminal event of mixed chimerism. similar to the depiction of Fig 2. The difference in principle hetween the bone marrow and whole organ recipients turns on which of the coexisting cell populations is present at trace levels. DONOR LEUKOCYTE AUGMENTATION :\t a practical clinical level. the observations establishing the two-way paradigm exposed a perioperative window of llpportunity. which is not HLA dependent during which unahcred HLA incompatible hone marrow can be en-graltcd safely in organ recipients without recipient condi-tioning. without T-cell depletion. and with no deviation , LOSS OF HLA MATCHING EFFECT 59 Two-Way Paradigm (Organ) \mmunosuppression dse---I~ Mutual Natural ~ Immunosuppression @ . @ . @ , ~ ° .o® @ooo o@ @ ® o@ ° G 0 ~@ o® ~o o@o ~K @ D~Do~ o@ 2 o@o 0° ~f@D ~ Fig 2. Bidirectional mecha-nism of whole organ graft ac-ceptance involVing a graft-vs-host (GVH) reaction by the bone marrow denved donor leuko-cytes in the graft that are pitted against the whole recipient im-munologic apparatus (host-vs-graft [HVGJ rejection). For con-ventional whole organ clinical transplantation. the recipient IS not preconditioned. Not Quite 'efenseless Graft Veto/Suppressor Cells Cytokine Profile Changes Enhancing Antibodies HVG (Rejection) from the standard practices of postoperative immunosup-pression used in whole organ centers. This has been done in Pittshurgh with the infusion of 3 x lOx/kg unaltered donor hone marrow cells perioperatively in M consecutive pri-mary recipients of cadaveric kidneys. livers. hearts. and 11In!!s (Fig 3). Immunosuppression was with the standard \tralc!,'Y developed a third of century ago with azathioprine and prednisone but now with the combination of FK 501i and prednisone instead. All 1i4 of these patients are well except for a cardiac recipient who died with a normal heart of nonimmunologic complications 9 months after transplantation (Table I). Chimerism. estimated to be more than I UOO times greater than that occurring spontancously. could bc reliably pro-duced and sustained. The first 18 of these patients were recently reported in The Lancer. 14 The familiar events were ohserved of crisis and recovery that are also seen in Illlnmarrow augmented control recipients. The notable ~fhsence of serious GYHD. and the presence Dt well-Ilinctioning grafts in all of the patients. has marked these rC'ciplents as an advantaged cohort. Although drug weaning 111 these densely chimeric patients is expected to take \everal years. they are the tirst recipients to undergo HLA mismatched cadaveric whole organ transplantation with the reasonable prospect of eventually becoming drug free. Unconditioned Recipient TERASAKI'S SEMINAL OBSERVATION In closing. it is worth reflecting on the previous work of Paul Terasaki. who in 1970 announced at the Third Transplan-tation Congress at The Hague that tissue typing did not accurately predict outcome atter kidney transplantation except when there was a perfectlv matched donor (unpuh-lished manuscript). This courageous report was treated as a scandal by the HLA community and was the beginning of a dispute that has never come to closure. Now we can explain Terasaki"s results as well as those obtained by us from a 6-year prospecti\'e trial of HLA matching for kidney transplan-tation carried out in collaboration with Terasaki at the Uni-versity of Colorado heTWeen 19M and 1970. 15 This was the first such matching trial ever done. When matching proved to he non predictive of outcome except when there was a perfect match. we were stunned. because we had no explanation. Ironically. the explanation was published as early as 1953 at least in concept. hy Simonsen-one of this years' Med-awar laureates-who wrote: " ... our only real hope of making homotransplantation of the kidnev a clinically feasible procedure ... must actually be based on the follow-ing conditions: First. that the most important individual-specific antigens are shared by the kidney and the blood cells. so that a gross biological incompatibility can be eliminated by detailed blood determination. Second. that -~----------~-I---60 STARZL. RAO. TRUCCO ET Al + --Slowly Evolving Donor and Recipient-Specific Nonreactivity (Bidirectional Tolerance) Fig 3. Strategy for donor leu-kocyte augmentation in recipi-ents of whole organ allografts. 14 The bone marrow is given at the time of the surgical transplant procedure. the kidney's defense reaction against the recipient's anti-bodies and/or antigens can check a less significant biological incompatibility ... and thus provide a more or less com-plete adaptation to the recipient.'''/> As it has turned out. the tirst of these conditions. histocompatibility matching. is apparently less important in the whole organ field than the second which is the primitive outline of what we now call the two-way paradigm. CONCLUSIONS As in Edgar Allen Poe's ( IX(N to IX4lJ) famous short story. n,e Pllr/oilled Lmer. the reason for the failure of an HLA matching etfect was not found for such a long time because it Table 1. Whole Organ Transplantation With 3 x 108 /kg Bone Marrow Cells (December 14, 1992 to August 5,19941 SUlVlval Organ Pallent Graft Kidney 17 17 Kidney .,. Islets 6 6 Kidney .,. pancreas 2 2 Liver 28 28 Liver - Islets 1 1 Heart 8 r Lung 2 2 Total 64 63 Nole: The torst 18 pallents were reponeo In The Lancer. July 17. 1994. There was no nost conOlll00ln9. 'NonlmmunOloglc oeatn. 9 montns-carOfac aHogren normal. was hidden in such obvious locations-throughout the body of the recipient in the form of donor chimeric cells (Fig 2). REFERENCES 1. Billingham R. Brent L. Medawar P: Philos Trans R Soc Lond' [Bioll 239:357. 1956 2. Billingham R. Brent L: Philos Trans R Soc Lond [BioI] O~O:4P9K 1959 3. Monehik GJ. Russell PS: Surgery 70:fl93. 1971 ~K Starzl TE. Marchioro TL. Waddell WR: Surg Gynecol ObSICI 117:385. 1%3 5. Starzl TE. Dcmetris AJ. Murase N. ct al: Lancet 339:1579. 1992 (]. Starzl TE. Dcmclris AJ. Truccu M. et al: Hepatology 17: 1127. 1993 7. Steinman RM. Cohn ZA: J Exp Med 1.37: 1142. 1973 ii. Starzl TE. Dcmctris AJ. Rau AS. cl al: Transplant Proc (in press) lJ. Caine R Y. Sclls RA. Pena Jr. cl al: Nature 223:472. 1%1.) III. Curry RJ. Winn HJ. Russell PS: Transplantation fll:g~PK 1973 II. Russell PS. Chase CM. Colvin RB. ct al: J E,p Med l~T:1~41FK 197R 12. Przepiorka D. Thomas ED. Durham DM. et al: HemalOpa-Iholub'Y '15:201. 1991 13. Wessman M. Popp S. RUULU T. cl al: Bone Marrow Trans-plant II :279. 1993 14. Fontes 1'. Rao A. Dcmc:trlS AJ. ct al: Llncet 344: 151. 1 \1'}4 15. Starzl TE. Purter KA. Andres G . .:t al: Ann Surg 17::!:-B7. 1'171l I ll. Simonsen M: Acta I'athul Micruhiol Scand 32:36. 1953 , I ~ , 

http://d-scholarship.pitt.edu/5133/1/31735062126044.pdf

Explanation for loss of the HLA matching effect

Abstract

Similar works

Full text

Available Versions

Name not available

Name not available

D-Scholarship@Pitt