Iwaki, Y

Iwatsuki, S

Kano, T

Klintmalm, G

Koep, LJ

Starzl, TE

Weil, R

English

PubMed

D-Scholarship@Pitt

Successful Liver Transplantation From Crossmatch-Positive Donors S. Iwatsuki, Y. Iwaki, T. Kano, G. Klintmalm, L. J. Koep, R. Weil, and T. E. Starzl W E HAVE published before that liver transplantation can be performed suc-cessfully in spite of positive anti-donor cross-matches detected with the standard cytotoxic-ity test.'·2 These so-called positive crossmatch cases were compiled before the classification of the responsible antibodies3 was possible. In the present study, ten previously reported recipients whose sera contained anti-donor cytotoxic antibodies were reviewed. The quantity and type of antibodies in the recipient sera were determined from their reactions to a panel of lymphocyte donors. From the results, an educated guess became possible as to whether the previous positive crossmatches against the organ donors were caused by warm anti-T antibodies or by less dangerous varieties. Finally, a fresh transplant was performed in a patient whose preoperative serum contained warm anti-T-Iymphocyte antibod-ies that reacted with heavy killing against the liver donor. MATERIALS AND METHODS In II of 179 cases of orthotopic liver transplantation in Denver, the patients received liver homografts from From the Department of Surgery, Denver Veterans Administration Medical Center and the School of Medi-cine of the University of Colorado Health Sciences Center, Denver, Colo. and the Department of Surgery, School of Medicine, University of California, Los Angeles, The Center for the Health Sciences, Los Angeles, Calif. Supported in part by research projects from the Veter-ans Administration; by USPHS Grants AM-17160 and AM-07771; and by Grants RR-00051 and RR-00069 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Reprint requests should be addressed to Dr. T. E. Starzl. Department of Surgery, University of Pittsburgh, 1084 Scaife Hall, Pittsburgh, Pa. 15261. ©1981 by Grune & Stratton, Inc. MM4/~1P4R1U111 301-0065$01.00/0 286 donors to whom the recipients' sera showed strong lymphocyte cytotoxic activity by standard cytoxicity crossmatch tests. One of the II patients (OT 168) had proven strong anti-T- and anti-B-Iymphocyte cytotoxicity against the donor. Clinical and pathologic observations of these II patients are listed in Table I. Pretransplant sera of these II patients were tested for anti-T- and anti-B-Iymphocyte antibody under warm and cold temperatures against a random lymphocyte panel of 30-40 donors by a previously reported method.3 Sera from the first 10 patients had been stored at -80°C for long periods before testing against the lymphocyte panel. I n the most recent case (OT 168), the cytotoxicity was tested with fresh sera against the organ donor lympho-cytes as well as against a random lymphocyte panel. Immunologic observations in these II patients are summarized in Table 2. RESULTS Immunologic Observation Preoperative sera of all 11 patients had Iymphocytotoxic antibodies against the spe-cific donors by standard cytotoxic testing at the time of transplantation. In the most recent case (OT 168), the pretransplant serum had strong anti-T - and anti- B-lymphocytotoxicity against the actual liver donor. The results of retrospective anti-T - and anti-B-Iymphocyte cytotoxicity against a ran-dom cell panel are shown in Table 2 for all I I patients. Excluding the most recent case, OT 168, whose serum was tested against the specific donor cells, five (OT 63, OT 101, OT 114, OT 119, OT 122) of ten previously reported patients possessed strong and wide cytotoxic antibody against both T and B lymphocytes. Four more (OT 58, OT 71A, OT 138, OT 151) had narrow but definite antibody against T lymphocyte and wider antibody against B lymphocytes. One patient (OT 103B) did not have anti-T-Iymphocyte antibody against the random cell panel, but she had anti-B-Iymphocyte antibody. None of the 11 patients had transplanta-tion across an ABO blood group barrier. Transplantation Proceedings, Vol. XIII, No.1 (March). 1981 LIVER TRANSPLANTATION FROM CROSSMATCH-POSITIVE DONORS 287 Table 1. Clinical Observation OT No. Age Sex Diagnosis 58 34 M Chronic aggressive hepatitis 63 49 Primary biliary cirrhosis 71A 2 M Biliary atresia Survival (Days) 407 26 (Homograft) Removal at 10 days Main Cause of Death Refused medication; hepatic insuffi-ciency Gastrointestinal hemorrhage Pathologic Changes in Liver Resolution of previous obstructive changes at 8.5-month biopsy (no autopsy) Normal liver Acute rejection, cellular and hu-moral (Heterograh) 14 days after Pulmonary edema; bronchial hem or- No evidence of cellular rejection; retransplantation 101 28 Primary biliary cirrhosis 189 114 27 Liver tumor of undetermined type Alive over 4 years 119 23 M Sclerosing cholangitis 33 122 28 Chronic aggressive hepatitis 131 1038 21 Primary biliary cirrhosis 403 138 42 M Sclerosing cholangitis 108 151 M Biliary atresia 72 168 33 Chronic aggressive hepatitis 23 Clinical and Pathologic Observation Despite the probable presence of donor-specific anti-T -lymphocyte antibody 10 the pretransplant sera of at least half of the previous ten liver recipients and despite defi-nite existence of such antibody in the most recent recipient (OT 168), hyperacute rejec-tion such as seen in renal homografts was not observed in any case. Early graft dysfunction rhage centrilobular cholestasis Hepatic insufficiency; renal and cardiac Biopsy 5 days prior to death failure showed hepatocyte swelling, Alive suggesting hepatitis; no rejec-tion Obstructed cholecystojejunostomy to Biliary obstruction, intrahepatic choledochajejunostomy; subse- sludge and cholangitis; no rejec-Quent rupture of mycotic hepatic ar- tion tery aneurysm into jejunum Pneumococcal meningitis; liver failure; Chronic rejection liver abscesses Cholecystojejunostomy to choledocho- Chronic rejection; massive liver ne-jejunostomy; liver failure crasis Leak of colonic anastomosis after Chronic cholangitis; no rejection emergency colectomy; liver and pul-monary failure; CMV infection Chicken pox; fresh portal vein throm-basis Pulmonary sepSis Hepatitis group viruses seen by EM in necrotic tissue and in some of the adjacent cells Biopsy on the 15th day showed no rejection within 10 days after transplantation was observed only in two cases (OT 71A and OT 168). The liver pathology of the first case (OT 71A) on the tenth posttransplant day revealed acute rejection of a cellular and humoral nature, and this could be interpreted at most as a modified type of hyperacute rejection in liver homograft. The second case (OT 168) had significant periopcrative ischemic dam-Table 2. ImmunOlogic Profile Nonspecific Cytotoxic Blood HLA-A.B Donor-Specific Antibody Screening (% of Panel Cells) Type Mismatch Cytotoxic Antibody (Donor to Recipient) Number (Standard C,ossmatch) T-Warm B-Warm B-Cold OT 58 OtoO 4 Pos. (1:2) 3 43 6 OT 63 OtoO 3 Pos. (1 :64) 76 100 0 OT 71 A OtoA 2 Pos. (1: 16) 23 96 3 OT 101 OtoO 4 Pos. (7) 84 100 0 OT 114 OtoA 3 Pos. (7) 88 96 0 OT 119 OtoO 4 Pos. (7) 92 100 0 OT 122 OtoA 2 Pos. (7) 84 100 0 OT 1038 OtoA 3 Pos. (7) 0 3 0 OT 138 OtoA 3 Pos. (1:4) 15 31 D OT 151 AtoA 4 Pos. (1:8) 3 43 3 OT 168 OtoO Pos. (1 :64)* 100 100 0 * Positive T-warm and 8-warm. 288 age to the graft, but the graft produced bile on immediate posttransplant days. The liver biopsy obtained on the 15th posttransplant day did not show any rejection of either a cellular or humoral nature. The remaining nine patients did not have early graft dysfunction, and one (OT 114) is still alive and well over 4 years after trans-plantation. Two (OT 58 and OT 103B) lived more than a year. The liver pathology of these nine patients did not show acute rejection (Table 1). DISCUSSION The pathophysiology of hyperacute rejec-tion has been well studied in recent years. Fixation of antibody to the graft is apparently the initial event followed by entrapment of clotting factors and formed blood elements in the microvasculature of the graft and conse-quent graft necrosis. The antibodies that are known to cause hyperacute rejection in kidney allografts are anti-A and -B red cell isoagglu-tinins 4 and cytotoxins against T lympho-cytes. 3,5,6 Heterospccific antibody in the het-erograft system can also have the same effect.7 Accumulated clinical and experimen-tal evidence indicates that kidney grafts are unusually prone to the irreversible conse-quences of hyperacute rejection and that the liver graft, in contrast, is unusually resis-tant. 1,2,7 The difference in microvascular structure between the kidney and the liver (capillary versus sinusoidal system) may be responsible. We have previously reported ten patients who did not have hyperacute rejection of liver grafts in spite of the detection in their sera by standard cytotoxicity testing of antibody against the specific donor. I ,2 With recent advances in transplantation serology, it is now IWATSUKI ET Al. known that anti-T-lymphocyte antibody is responsible for hyperacute rejection, but that anti-B-Iymphocyte antibody is not responsi-ble. 3,6 As the donor lymphocytes were no longer available in the previous ten cases, the sera were tested for anti-T - and anti- B-lymphocyte toxicity against a random lym-phocyte panel. In retrospect, five of the patients who did not possess warm anti-T antibodies were not at risk from hyperacute rejection. However, five (OT 63, OT 101, OT 114,OT 119, and OT 122) of ten patients had strong and wide (greater than 75% of panel cells) anti-T-lymphocyte antibody. It is reasonable to conclude from this infor-mation that at least some of these five patients had anti-T-lymphocyte antibody against the donor, but did not reject liver homografts hyperacutely. One (OT 114) of the five patients is still alive and well with normal liver function over 4 years after trans-plant. In the additional recent case (OT 168) such speculation is not necessary. The liver transplant was known to have been performed in the presence of strong cytotoxic antibody against the donor T lymphocytes. The liver homograft did not undergo hyperacute rejec-tion and the biopsy on the 15th day did not show any sign of rejection, either of humoral or of cellular type, CONCLUSION The data presented above are consistent with previous reports that the liver is unusu-ally resistant to hyperacute rejection and that a positive anti-T-lymphocyte crossmatch is not an absolute contraindication for liver homotransplantation. Further investigations are needed to explain the unusual resistance of the liver to hyperacute rejection. REFERENCES I. Starzl TE, Ishikawa M, Putnum CW, et al: Trans-plantProc6:129,1974 2, Starzl TE, Koep LJ, Halgrimson CG, ct al: Gastro-enterology 77:375, 1979 3, Tcrasaki PI, Bernoco D, Park MS, et al: Am J Clin Pathol 69:] 03, 1978 4. Starz] TE: Experience in Renal Transplantation, Philadelphia, W.B. Saunders, 1964 5. Terasaki PI, Marchioro TL, Starzl TE: Histocom-patibility Testing. Washington DC, National Academy of Sciences-National Research Council, 1965, pp 83-96 6. Ettenger RB, Terasaki PI, Opelz G, et al: Lancet 2:56, 1976 7. Giles GR, Boehning HT, Lilly J, et al: Transplant Proc 2:522, 197 I 

Successful liver transplantation from crossmatch-positive donors.

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Successful liver transplantation from crossmatch-positive donors

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Successful liver transplantation from crossmatch-positive donors.

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