Kendrick A. Porter

REVERSIBILITY OF LYMPHOMAS AND LYMPHOPROLIFERATIVE LESIONS DEVELOPING UNDER CYCLOSPORIN-STEROID THERAPY

Post-transplant lymphomas or other lymphoproliferative lesions, which were usually associated with Epstein-Barr virus infections, developed in 8, 4, 3, and 2 recipients, respectively, of cadaveric kidney, liver, heart, and heart-lung homografts. Reduction or discontinuance of immunosuppression caused regression of the lesions, often without subsequent rejection of the grafts. Chemotherapy and irradiation were not valuable. The findings may influence policies about treating other kinds of post-transplantation neoplasms.

Liver Transplantation with Use of Cyclosporin a and Prednisone

THE difficulties in consistently prolonging survival after orthotopic liver transplantation have been documented by us1 and by Calne.2 In this report we describe a new trial of orthotopic liver tra...

Portal diversion for the treatment of glycogen storage disease in humans.

Seven patients with Types I, III, or VI glycogen storage disease were treated with portal diversion from 5 1/2 mth to 9 1/2 yr ago. The first 2 patients had portacaval transposition with 1 early death. The last 5 patients had the technically safer procedure of end to side portacaval shunt without any deaths and with no late findings of hepatic encephalopathy. The convalescence of the patients with either kind of portal diversion was characterized by accelerated body growth and bone mineralization, incomplete relief of hypoglycemia and metabolic acidosis, striking amelioration of the hyperlipidemia of Type I disease, liver shrinkage in Types I and VI disease, and variable relief of such diverse other derangements as abnormal bleeding and elevated serum uric acid concentrations. The liver concentrations of glycogen were not affected by portal diversion. Hepatocytes were decreased in size in subsequent biopsies, thereby accounting for the reduction of liver size in most of the cases without a major alteration in glycogen. There was a high incidence of pre existing coincidental liver disease in patients, including transaminase elevations and hepatic fibrosis or even cirrhosis. These abnormalities were particularly striking in Type III patients but did not appear in any of the cases to be made worse by portal diversion. The observations in these 7 patients and in 6 more reported from other centers and followed up with personal examination indicate that portal diversion should have an important role in carefully selected cases of glycogen storage disease. Recent work was reviewed which suggests that the effects of portacaval shunt are due more to the rerouting of pancreatic hormones around the liver than to the bypassing of alimentary glucose.

AUGMENTATION OF RAT LIVER REGENERATION BY FK 506 COMPARED WITH CYCLOSPORIN

The immunosuppressive drug, FK 506, increased the regeneration response that follows 40% and 70% hepatectomy in rats. The effect was similar to that obtained with cyclosporin.

Chronic Survival After Human Renal Homotransplantation Lymphocyte-antigen Matching, Pathology and Influence of Thymectomy

FRO?^^ November 24, 1962 to March 30, 1964, 64 uremic patients were treated with renal homografts obtained from living volunteer donors other than identical twins. Thirty-seven of the original group lived for at least 1 year and 36 are still alive 13% to 30 months after operation. Numerous post-transplant function studies have been obtained, and in the 8 patients with the longest follow up, homograft biopsies were performed from 21 to 24 months postoperatively. The recipients who are still alive were esamined with a lymphocyte cytotoxicity test for the degree of antigenic matching with their respective donors to determine by retrospective analysis whether this method might be helpful in evaluating the results as well as in the selection of donors for future cases.

Liver regeneration in dogs: morphologic and chemical changes.

Forty-four percent and 72% hepatectomy were carried out in dogs and the animals were sacrificed for biochemical and pathologic studies from 0.5 to 6 days later. Compensatory hypertrophy and hyperplasia (“regeneration”) were evident within 1 day, reached a maximum in 3 days, and were almost complete by 6 days. Coincident with the histologic events of regeneration were decreases in responsiveness of receptor adenyl cyclase to glucagon stimulation, increases of cyclic AMP, inconsistent changes in plasma insulin, and increases in plasma glucagon. These studies have standardized hepatic resection in dogs and they have focused attention upon some possible mechanisms that will require further study.

HEPATOTROPHIC EFFECTS OF FK506 IN DOGS

Portacaval shunt (Eck fistula) in dogs causes hepatocyte atrophy and organelle disruption, as well as tripling of hepatocyte mitoses. After submitting dogs to this procedure, FK506 was infused into the tied-off left portal vein. The size, anatomic quality, and replication of hepatocytes were enhanced in the portion of liver infused with FK506, with a significant spillover effect in the noninfused portion. These hepatotrophic qualities of FK506 may explain part of FK506s efficacy for the treatment of chronic liver rejection. Also, the observations support a trial with this drug for the treatment of autoimmune liver diseases because, in addition to turning off the immunologic genesis of such disorders, repair and regeneration of the damaged liver may be augmented. Finally, these hepatrophic qualities are part of an emerging spectrum of biologic effects caused by drugs that may modulate the enzyme cis-trans peptidyl-prolyl isomerase (PPIase), the principal constituent of the cytosolic binding sites of FK506, repatomycin, cyclosporine, and presumably other immunosuppressive drugs as yet undiscovered.

Serotyping for homotransplantation V. Evaluation of a matching scheme

SUMMARY An 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.

Use of OKT3 with Ciclosporin and Steroids for Reversal of Acute Kidney and Liver Allograft Rejection

OKT3 monoclonal antibody therapy was added to preexisting baseline immunosuppressive treatment with ciclosporin and steroids to treat rejection in 52 recipients of cadaveric livers and 10 recipients of cadaveric kidneys. Rejection was controlled in 75% of patients treated, often after high-dose steroid therapy had failed. Rejection recurred during the 17-month follow-up period, after completion of OKT3, in only 25% of the patients who had responded. The safety and effectiveness of this monoclonal therapy, added to ciclosporin and steroids, has been established in this study.

SEROTYPING FOR HOMOTRANSPLANTATION. VII. SELECTION OF KIDNEY DONORS FOR THIRTY‐TWO RECIPIENTS*

An attempt was made to select donors for human kidney transplantation on the basis of lymphocyte antigen matching. Compatibility was assayed by reactions of individual antisera on donor and recipient lymphocytes, as well as by matching on the basis of the six recognized leukocyte groups. The donor judged to be the best match was chosen from pools of related and unrelated donors. Although the choice was often limited, a group of donors was selected which, as a whole, was slightly more compatible than that achieved by random matching. Mismatches which were extremely high or from group 6 were avoided whenever possible. Eighteen transplants were done from related donors: sixteen of these recipients lived for at least 4 months postoperatively; three more died after 1012, 812 and 8 months. Thirteen of the original 18 patients are still alive, 6, after 4 to 8 months, four, after 8 to 21 months and three, after more than one year. This represents a slight improvement over the first unmatched Denver series treated 2 to 312 years ago. Of the 14 recipients in the present series who received kidneys from matched unrelated donors, ten lived for more than 4 months; two more died after 5 and 10 months respectively. Eight of the original patients are still alive with a minimum follow-up of 612 months; four of these patients are surviving 9 to 12 months after operation, and the other three, more than one year. These results are improved over that of an original nonselected series of unrelated homotransplants performed in Denver. Furthermore, the survival curve in these nonrelated donors and recipients now approximates that which was obtained in the past Denver experience with randomly selected related donors. Because of the relatively small numbers involved, however, this improvement is not statistically significant. Pathological studies of the kidneys from the recipients who died were compared to the kidneys of the dead recipients of the first Denver series in which donors were randomly selected. Acute vascular lesions which result from severe rejection were less frequent in this series as compared to the earlier un-matched series. It was concluded that coincidental to matching for provisional leukocyte types, an improved early clinical outcome of transplantation was obtained with respect to survival and minimization of pathologic changes associated with rejection. Whether the improvements are attributable to the matching procedure or to other unrecognized factors in the clinical management of the patients could not be determined.