Imnmnosuppression after Experimental and Clinical I-Iomotmnsplantation of the Liver

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Abstract
The influence of immunosuppressive drugs upon rejection was evaluated in 40 dogs which received orthotopic or auxiliary hepatic homografts, and in 5 clinical cases of orthotopic liver transplantation. The effectiveness of azathioprine and steroid therapy was judged upon serial measurements of function, upon duration of survival, and upon findings at pathologic examination. Definite mitigation of rejection was demonstrated in all 3 groups. From a histologic point of view, immunosuppression was most successful in the human cases despite the employment of badly ischematized cadaveric organs. Orthtopic canine homografts were less completely protected, presumably because of a species difference in the vigor of rejection. The most severely damaged specimens were the canine auxiliary livers which were placed in the right paravertebral gutter without removal of the recipient''s own liver. In dogs treated with immunosuppressive agents, rejection was often observed in the absence of mononuclear cell invasion. The homografts in such dogs commonly had central necrosis and diffuse vascular lesions, with selective preservation of the duct system, the general location of principal hepatocyte loss being the same as previously reported in non-treated animals. The pathophysiologic mechanisms in such non-cellular rejection are considered. It seems possible that the hepatocyte is the primary target of attack by recipient antibodies. Alternatively, the vascular lesions may cause secondary ischemic injury to the parenchyma, in spite of the fact that angiograms in this study failed to support this possibility. In dogs, the use of optimally preserved homo-grafts makes possible the accurate identification of rejection with biochemical measurements. This diagnosis was made difficult in the clinical cases because of the employment of cadaveric organs, which do not function normally as a consequence of agonal and postmortem ischemic injury. Nevertheless, the results of serial liver tests suggested that rejection was not functionally present in any but Case 5 of the human series during survival periods of 6. 5 to 23 days. Several previously unrecorded observations are described concerning more esoteric biochemical changes alter hepatic homotransplantation including alterations in serum or plasma immunoglobulins, amino acids, pyruvates and lactates. In addition, a case is documented in which the haptoglobin genotype of the receipient converted to that of the donor, a finding which supports the concept that the liver is the only source of this substance.