Banner, B

Demetrius, A

Duquesnoy, R

Griffin, M

Makowka, L

Ramsey, G

Starzl, TE

Tzakis, A

English

PubMed

Demetris, A

Name not available

The definition of ABO factors in transplantation: Relation to other humoral antibody states

D-Scholarship@Pitt

I , The Definition of ABO Factors in Transplantation: Relation to Other Humoral Antibody States T.E. Starzl, A. Tzakis, L. Makowka. B. Banner, A. Demetrius, G. Ramsey, R. Duquesnoy, and M. Griffin T HE GUIDELINES for solid organ trans-plantation from donors to recipients of different blood types were established by observations in a relatively small number of renal transplantations carried out in 1962 and 1963. 1•3 In this presentation. we will retrace these steps, suggest how lessons with ABO mismatches are applicable to other preformed antibody states (including those of xenotrans-plantation). and show how modern day strategies with antibody depletion and phar-macologic manipulation of mediators of the inflammatory response could be exploited therapeutically to prevent hyperacute rejec-tion. HYPERACUTE REJECTION Kidney Transplantation The first experience was reassuring. On January 31, 1963, a 38-year-old man of A + blood type was given a kidney from his sister whose blood type was B +. Despite a moder-ately severe rejection at 25 days, the kidney survived and still functions perfectly more than 24 years later. On March 19 and July 29 of the same year, two A to 0 transplantations were performed, one from a cadaveric donor and the other from a mother. also without perioperative incident. It looked as if ABO matching was irrele-From the Departments of Surgery, Parh%g.\'. and Medicine. Universiry of Pil1shurgh HealrhCenler. Supporred br research grams from rhe Veterans Adminisrrarion and ProjeCl Gram /\io AM-2996i from rhe Nationallnsrirute of Health. Bethesda, MD. Address reprint requesl5 /0 Dr Thomas E. Star=/. M D, PhD. 360! Fljth A\.<'. ca/~K Climc·. 5 West. PiIlsburgh. PA /5213 e 1987 br Grune & Srral1on. Inc. 0041-1345/87//906-002 j S03.00/0 vant in renal transplantation and a manu-script with this conclusion was accepted by Surgen'.' While the article was still in press its message was changed drastically by tw~ catastrophic experiences. one with an A to 0 transplantation and the other witr a B \0 0 transfer. Both kidneys were hyperacutel} rejected within minutes. Arteriograms of the removed specimen showed nonfilling of the small vessels and this correlated histopathologically with wide-spread throm botic occlusion of the microvas-culature. It was concluded that the immediate rejection had been precipitated by high affin-ity isoagglutinins in the recipient sera. which had bound with A or B antigens in the mis-matched kidneys. The logic of the conclusion was supported by the documentation 2 or 3 years earlier by pzulman~ and by Hogman 5 that the ABO antigens were widely distrib-uted throughout human tissues and organs. An addendum was added to the Surgery article including the now familiar table show-ing permissible patterns of tissue transfer that were designed to a void placing kidneys into an environment containing antigraft isoaggluti-nins (Table 1). Data on isoagglutinin titers was subsequently provided.] Later. in a classi-cal report. Rapaport et al" showed how sensiti-zation of human volunteers with purined A or B antigens caused increased titers of isoagglu-tinins and accelerated (white graft) rejection of subsequent"!y transplanted skin grafts. The circle of evidence seemingly was complete. However. it is worth emphasizing that not all of the mismatched kidneys had rejected and that those that escaped immediate destruction did not seem to pay a later penalty. Much of the recent interest in the ABO system by transplanters has been focused on 4492 Transplantation Proceedmgs, Vol XIX, No 6 (December), 1987: pp 4492-4497 0 r' 0 I 0 I p It t~ fr I t! a: 0 yl k. is Ul m Sl bl W iiI sa I A If , t th I ~ ~ i - ani I , f"} t J inU-by ess, two )0 )0 ely len his le-tS-Ie n-f ;h s-'n 3 15 I HUMORAL ANTIBODY STATES Table 1. Direction of Acceptable Mismatched Tissue Transter o to non-0 Rh - '0 Rh.;.. Rh-'- to Rh-A to non-A B to non-B AS to non-AB Safe Safe Relatively Safe Dangerous Dangerous Dangerous NOTE. 0 is universal donor: AS IS universal recipient. reliably surmounting the acute antibody bar-rier. thereby expanding the available pool of organs. The recent use of Az kidneys for 0 recipients is an example. The practice is based on the reports by Breimer and Brynger et a1 7.8 of Sweden who showed that the A antigen is poorly represented in the kidneys of nonsecre-tor individuals or in patients with A2 blood type, The assumption has been that kidneys from such donors would not be the target of the anti-A isoagglutinins in 0 or B recipients. However, this newest attempt to ride over an ABO barrier may not be completely safe. On December 28, 1986 in Pittsburgh, a 39-year-old male of 0 blood type was given a kidney from an A2 cadaveric donor. Cold ischemia time was 351/2 hours. The kidney underwent hyperacute rejection within five minutes. The anti-A isoagglutinin titers are summarized in Table 2. The anti-A, titers of both IgG and [gM were high by co~parison with those in other candidates for kidnevs. livers. or hearts (Table 3). -Histopathologic examinations showed the same lesions as in the hyperacutely rejected ABO incompatible kidney 25 years previously lFig I), IgM and complement were found in the vessel walls (Fig I). Fortunately, an 0 4493 Table 2. Isoagglutinin Titers Before and After Hyperacute Rejection of a Kidney From an A, Nonsecretor Donor to an 0 Recipient Antt- Before After A, IgM 128 64 IgG >512 512 A2 IgM 128 128 IgG 1,024 512 B IgM 256 64 IgG 512 256 kidney became available while the wound was still open and it was inserted with a perfect result. Extrarenal Organs How much relevance the guidelines sum-marized in Table I will have to do with other organs is still being determined. For many years, it has been appreciated that the liver is resistant to hyperacute rejection.9 Today reports will be given from three different centers about what the risks and probabilities actually are in using ABO incompatible liv-ers. There have been a few accidental heart transplantations across ABO barriers. In Pittsburgh, there have been two such cases. One recipient has a perfect result after 18 months, but the other died in less than a day with accelerated rejection (Table 4). To leave this underdeveloped subject, our opinion is that there is a small but real jeopardy in crossing these forbidden ABO barriers in heart and liver recipients unless some specific provisions such as depletion of isoagglutinins or pharmacologic therapy is carried out as we will mention later. Table 3. Isohemagglutinin Titers in Group a liver, Heert, or Renal Transplant Candidetes Anti-A, In - 53! Ant,-A, In - 24) Anti-S In - 521 IgM IgG IgM IgG IgM IgG -------------------------------------------------------------------------------Median 128 256 J2 64 128 256 ~ected range" 32-256 64-1,024 s 16-256 s 16-512 s 16-256 s 16-1,024 NOTE. IgM, 60-mlnute room temperature saline incubation; IgG, 60-minute 37"C salme 'ncubation, then anti-lgG antiglObulin. *90% of patients are In these ranges. 4494 STARZL ET At. Fig 1: (AI Glomerulus with congested capillary loops. which contain platelet-fibrin thromb, and many neutrophils (hemotoxylin-eosin: origlnai magnification" 4001. {BJ Immunofluorescent stain for anti-Igm (o"ginal magnIficatIon, 4001 with dense deposition of IgM in polar arteriole. c H hy m~ de gr: ies tic We N, al. th di: sit h) TI Ct p~ al n g s h 5 HUMORAL ANTIBODY STATES Table 4. Hearl Transplants Across ABO Barrier IPittsburgh) ABO Case Donor ReClp!em Outcome !l,B A Good. 18 mo 2 A 0 Died of ,ejection 12 h HYPERACUTE REJECTION WITH NON-ABO ANTIBODIES It was not long after the description of hyperacute renal rejection with ABO mis-matches that a similar phenomenon was described by Terasaki in a patient with anti-graft preformed Iymphocytotoxic antibod-ies. lo The concept that immediate graft rejec-tion could be caused by preformed antibodies was confirmed and extended by Kissmeyer Neilsen,II Patel and Terasaki,I2 Williams et aI, IJ and many others. Other systems, such as the anti-vascular endothelial cell antibodies discussed by Cerilli elsewhere in this sympo-sium, appears to precipitate the same kind of hyperacute rejection of various organs. l4 Thus, the initiating antibodies or other cir-cumstances have differed. but a final common pathway of destruction has been involved in all. THE EFFECTOR CASCADE About 20 years ago, we made serious ~ttempts to delineate that common pathway In a series of inquiries in patients and animals t?at were strongly intluenced by collabora-tIOns with the experimental pathologist, Frank J. Dixon of La Jolla, CA and the immunolo-gist, Paul 1. Terasaki. I5.2l Two experimental models were used. One was the dog that was hypersensitized with multiple surface or buried skin grafts.Io.zo.::1 Kidney, liver, or spleen transplantation from the sensitizing donor was then performed. The other experi-mental model was the pig to dog xeno-graft. 18 ,19.21 The dog had preformed hetero-specific cytotoxic antibodies that led to hyperacute rejection of the pig kidney within 5 to 30 minutes. IS 4495 In addition, an opportunity presented to observe the events of hyperacute rejection in a small number of hypersensitized human kid-ney recipients. !S.i7 From these observations the hypothesis was developed that the initiat-ing step of hyperacute rejection was antibody induced. but that the irreversible injury pat-terns resulted from a cascade of secondary and nonspecific events. It was shown that antibodies, clotting factors, and formed blood elements were rapidly cleared by the grafts as estimated by gradient measurements.I6-i8.20 Fibrinolysis from the renal vein also was a consistent finding, and in extreme cases, a disseminated intravascular coagulation (DIC) could be produced. I6 .!7 Va rious descriptive terms have been applied to hyperacute rejection and its dif-ferent aspects have been emphasized by com-parison to the Arthus reaction,13 inverse ana-phylaxis, lJ and the generalized Swartzman reaction. IS Each of these classic immunologic phenomena is, or can be, initiated by interac-tion of antibody and antigen, and in each there are multiple secondary events including inflammation and coagulation. It was our conclusion that hyperacute rejection was "an immunologically mediated coagulopathy that led to the devascularization and destruction of a transplanted organ. and which sometimes resulted in systemic coagulation abnormali-ties."I) At the time this work was going on, there was little detailed information about the mediators of the inflammatory response. The modern understanding of the inflammatory response following a variety of initiating events including antigen-antibody reactions is summarized by Makowka elsewhere 10 this symposium. THERAPEUTIC INTERVENTION FOR HYPERACUTE REJECTION Antibody Removal Almost two decldes ago, therapeutic efforts to treat preformed antibody states were made in spite of the above described lack 4496 of knowledge. The most obvious approach was to eliminate the offending antibodies. The first attempt to our knowledge was made by Merkel and Bier et a1. 19•22 Using a primitive plasmapheresis machine, it was possible to extend many times the life of the pig to dog renal xenografts. A number of clinical trials of plasmapheresis to reduce antibodies have been reported through the years but with unpredictable and often uninterpretable re-sults. Plasmapheresis has been used by the group at the Catholic University of Louvain for reduction of isoagglutinin titers before transplantation across ABO barriers (sum-mary report elsewhere in this volume). Thoracic duct drainage is an alternative technique to reduce antibodies. Even though thoracic duct drainage removes T-Iympho-cytes, which are not known to effect antibody function, there is an accompanying drastic reduction by unexplained mechanisms of all of the immunoglobulin ciasses.23.24 Machleder and Paulus23 showed that isoagglutinins could be virtually eliminated with 3 or 4 weeks of thoracic duct drainage. Antibody reduction by any currently avail-able techniques is of limited value and dura-tion, but technologic developments with the so-called staphylococcal protein A adsorbent columns25 will make it possible within the next year or so to virtually remove specific classes of immunoglobulins for long periods of time peri opera livel y. Altering (he Effector Cascade When it was first appreciated that the effector cascade of hyperacute rejection was a relatively nonspecific one involving coagula-tion. the simple expedient of using heparin for anticoagulation was tried. but with no bene-fit. 26 Other means to prevent coagulation or complement activation have included the use of snake venom in experimental animals. Research of this kind came to an abrupt standstill almost 15 years ago because of the great difficulty in achieving anything of prac-tical therapeutic value. The most successful STARZL ET AL technique with either the difficult pig to dog model or after sensitization with skin homo_ grafts was the intraarterial infusion of citrate.21 Citrate in toxic doses can be a pro-found anticoagulant but it has so many other biologic effects including participation in complement activation that the specificity of action could not be clarified. With the development of new drugs with which one can intervene at specific levels of the inflammatory response, the prospect of mitigating or preventing hyperacute rejection has become more practical, as will be dis-cussed by Leonard Makowka later this mOrn-ing. The work that Dr Makowka will report should be directly applicable to the ABO questions central to this meeting. GRAFT -VERSUS-HOST CONSIDERATIONS So far, we have discussed only how pre-formed recipient antibodies can damage ABO mismatched grafts. It has become well recog-nized that grafts containing lymphoid tissue can act as B cell organs and elaborate isoag-glutinins or other antibodies that can bind with host tissues. In one of our A recipients who was given an 0 pancreatico duodenal-splenic graft, the spleen produced such high titers of anti A isoagglutinins that a hemolytic crisis was caused. 27 Livers predictably cause hemolysis under similar circumstances28 but less severely. Other syndromes such as throm-bocytopenia may result. The possibility of this kind of humoral graft-versus-host reaction exists even-with the kidneyK~9 Such observa-tions have made it less and less desirable to perform transplantation from universal do-nors and with,Dther so-called compatible but not identical combinations. especially with nomenal organs. SUMMARY The first examples of hyperacute rejection of rena! hemografts were seen almost 25 years ago when kidneys were transplanted to ABO incompatible recipients whose plasma con-tained antigraft isoagglutinins. Hyperacute HUI rej lyr tht m: th ge G: PI Ir p 4 \L g 1-r 11 1 f HUMORAL ANTiBODY STATES rejection caused in sensitized recIpIents bv lymphocytotoxic antibodies is similar in that the immune reaction triggers an acute inflam-matory reaction that leads to widespread thrombotic occlusion and devascularization of 4497 the graft. The events after xenotransplanta-tion between certain species are essentially the same. Potential strategies to avoid the precipi-tating antigen antibody reaction or to mitigate the resulting effector cascade are described. REFERENCES l. Starz1 TE. Marchioro TL. Holmes lH. et a1: Sur-gery 55:195.1964 2. Starzl TE, Marchioro TL. Holmes JH. d 011: Surg, Gynecol. & Obstet 118819. 1964 3. Starzl TE: Experience in Renal Transplantation. Philadelphia. Saunders, 1964, pp 37. H9, 317 4. Szulman AE: 1 Exp ,vIed 111:785, 1960 5, Hogman CF: Vox Sang 4: 12, 1959 6. Rapaport FT, Dausset J. Legrand L, et al: J Clin Invest 47:2206, 1968 7. Breimer ME, Brynger H, Le Pendu J, et al: Trans-plant Proc 19:226, 1987 8. Breimer ME, Samuelsson BE: Transplantation 42:88.1986 9, Starzl TE. Koep U, Halgrimson CT, et al: Gastro-enterology 77:375. 1979 10. Terasaki PI. Marchioro TL. Starzl TE: In: Histo-compatibility Testing. Washington, DC. :'-iational Acad-emy of Sciences. National Research CouncIl. 1965, p 83 II. Kissmeyer-Nielsen F, Olsen S. Peterson VP. et al: Lancet 2:662. 1966 12, Pellel R. Terasaki PI: '\jew Engl J Med 280:735, 1969 13. Williams GM. Hume DM, Hudson RP, Jr. et al: New Engl J Med 279:611, 1968 14. Brasile L, Zerbe T, Rabin B, et al: Transplantation 6:672. 1985 15, Starzl TE. Lerner RA, Dixon Fl, et .11: '\jew Engl J \fed 278:642,1968 16, Simpson KM. Bunch DL Amemiya H. et al: Surgery 68: 77, 1970 17, Starzl TE, Boehmig HJ, ,".memiya H, et al: New Engl J Med 283:383, 1970 18. Giles GR, Boehmig HJ, Lilly J. et al: Transplant Proc2:522,1970 19. Merkel FK. Bier \of, Beavers CD. et al: Transplant Proc 3:534, 1971 20, Boehmig HJ, Giles G R, Amemiya H, et al: Trans-plant Proc 3:1105,1971 21. Kux K. Boehmig J1, Amemiya H, et al: Surgery 70:103,1971 22, Bier M, Beavers CD, Merriman WG, et al: Artif Intern Organs 16:325. 1970 23. Machleder HI, Paulus H: Surgery 84: 157. 1978 24, Starzl TE, Wei I R fII, Koep LJ. et al: Ann Surg 190:474, 1979 25. Bygren P. Freilburghaus C. Lindholm T, et al: Lancet 2: 1295. 1985 26, Boehmig Hl, Amemiya H. Wilson C, et ai: In yon Kaulla KN (ed): Coagulation Problems in Transplanted Organs Springfield. IL, Chas. C. Thomas. 1972. p 65 27. Starzl TE. lwatsuki S. Shaw BW, et al: Surg. GynecolObstet 159:265. 1984 28, Ramsey G, Nusbacher J. Starzl TE. et al: New Engl J Med 31 Ll167, 1984 29. '\jajarian J •. '\scher NL: Liver transplantation ( Editorial) New Engl J Med 311: 1179, 1984 

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The definition of ABO factors in transplantation: Relation to other humoral antibody states

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