In an effort to answer many unresolved questions concerning orthotopic homotransplantation of the canine liver, a complete reappraisal of this preparation was under-taken in early 1964 in both the untreated and modified host. A particular effort was made to (A) reduce the operative mortality; (B) interpret the significance of pathologic changes in the homograft and in the recipient tissues; (C) define the presence or absence of a graft-host reaction; (D) study the effect of variations in therapy upon results; (E) assess the hepatotoxic properties of azathioprine; (F) determine if and with what regularity hepatic rejection could be reversed and chronic survival attained; and (G) find if and when a state of relative host-graft non-reactivity developed some time after homotransplantation. METHODS Mongrel dogs weighing 8.3 to 27.3 kilograms were used. All animals had hematologic and liver function determinations before and at regular intervals after the experiments were begun. Red cell survival studies were performed with a Cr 51 technique. 6 Tetracycline and chloramphenicol were routinely administered. Azathioprine * was employed in most experiments with a dose of 2 to 8 mg. per kilogram per day. Insofar as possible, the induction of leukopenia was avoided. Azathioprine and antibiotic therapy was discontinued at 120 days in all surviving animals. Other variations in therapy are described below. Tissues were examined with light and electron microscopy. For homotransplantation, livers were obtained from donors of dissimilar appearance, but of approximately the same weight as the recipients. Prior to removal, the donor liver was cooled by perfusion of chilled Ringer's lactate solution through the portal vein. The technique of transplantation 24 resulted in an essentially normal blood supply (Fig. 1). The intervals of ischemia were almost all less than one hour. Cholecystoduodenostomy was established for internal biliary drainage. Azathioprine toxicity study In 18 non-transplanted dogs the effects of 40 days of azathioprine were studied. The animals were divided into 3 groups of 6 each which received: Group I. Daily azathioprine (2 to 4 mg. per kilogram).

SummaryAn attempt was made to determine whether 36 long-term kidney homograft recipients and their donors were compatible for 7 major leukocyte groups. It was found that 21 of these recipients were surviving 2 to 3 years in spite of incompatibility for 1 or 2 major leukocyte antigens. Survival of mismatched grafts does not itself indicate that the antigens being measured are not transplantation antigens, for it was shown that the 15 recipients with no groups of mismatch were clinically superior to those with group incompatibilities. Moreover, histopathologic scores given to biopsy specimens taken 2 to 3 years after transplantation were significantly correlated with the number of group mismatches. Because the leukocyte groups were determined by cytotoxicity reactions of peripheral blood lymphocytes, the results may have been influenced considerably by chimerism in chronically dialyzed uremic patients or change in lymphocyte antigenicity or susceptibility to lysis upon prolonged immunosuppressive treatment. Although the possibility of these complications could not be ruled out in all instances, it was shown that 52 dialyzed uremic patients and 49 patients who had been treated with immunosuppression for over 1 year did not possess more or less antigens than a random population of normal individuals. It is concluded that: (1) the major leukocyte antigens are histocompatibility antigens and (2) since survival can be attained at times despite mismatches for these groups, the antigens are of intermediate strength and kidney homograft rejection may occur if excessive numbers of antigens are incompatible or if particular combinations of antigens are mismatched.

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