Rose Payne

Cardiac Transplantation in Man VII. Cardiac Allograft Pathology

To date, 12 of 18 patients receiving cardiac allografts at the Stanford Medical Center have died. Five of these died with some degree of graft failure resulting from rejection injury. The remaining seven demonstrated some morphologic evidence of rejection, but death was due to other causes including pulmonary hypertension in two, hemorrhage and sepsis in one, infection in two, cerebral embolism in one, and hepatic failure in one. Acute rejection injury was defined in 10 allografts, accelerated acute rejection in one, and chronic rejection in nine.The clinical signs of allograft rejection and their morphologic correlates were essentially as predicted from the study of orthotopic canine cardiac allografts. The clinical features and most of the anatomic lesions of acute rejection were usually reversible by current methods of immunosuppressive therapy. Chronic rejection, manifested primarily by obliterative intimal proliferation in coronary arteries, was present in most allografts obtained from patients surviving at least 1 month. Its severity was apparently not related to the quality of the host-donor leukocyte antigen match, and it was not routinely detectable clinically. This intimal thickening may limit long survival of patients undergoing cardiac transplantation.

Nonhemolytic Febrile Transfusion Reactions

The conditions under which nonhemolytic febrile transfusion reactions developed in eight afebrile patients were investigated. Recipients invariably developed a reaction on transfusion of incompatible white cells if a sufficient quantity of leukocytes was infused. The sensitivity of each patient differed with respect to the number of incompatible white cells which could be tolerated without a reaction. In general, the in vivo reaction to blood from an individual donor could be predicted by the routine leukocyte agglutination test. Mild febrile reactions were inconstantly observed in three patients transfused with presumably compatible leukocytes. Further investigation suggested that the cells inducing reaction were probably incompatible, and that in vivo reactions were a more sensitive index than the in vitro test. Granulocytes, lymphocytes or platelets, separately administered, all induced febrile reactions, provided that the routine leukocyte agglutinin test demonstrated an incompatibility. There was no direct evidence that febrile reactions had occurred in response to plasma infusion. It is concluded that white cell antibodies were the primary cause of nonhemolytic febrile transfusion reactions in this series, and that the detection of white cell antibodies and preparation of leukocyte‐poor blood continue to be procedures of practical importance in modern transfusion therapy.

The association of febrile transfusion reactions with leuko-agglutinins.

Leuko‐agglutinins were demonstrated in 32 of 49 or 65% of sera from patients with febrile transfusion reactions. In contrast, the incidence of red cell antibodies was small. Transfusion reactions and leuko‐agglutinins developed at approximately the same time in 13 of 15 patients receiving repeated transfusion therapy. The use of “leukocyte‐free” blood failed to provoke febrile transfusion reactions in patients with a history of reaction.

GENETICS OF “4” AND “LA” HUMAN LEUKOCYTE GROUPS*

The possible significance of leukocyte antigens for human histocompatibility typing underlines the need to establish the genetic determination of these antigen systems. The analysis of the pairwise associations of the reactions of a set of primarily multispecific sera with a panel of random donors has, up to now, formed the main basis for the definition of antigenic specificities on human leukocytes (van Rood, 1962; Payne et al. 1964; see also Histocompatibility Testing, 1965). The reason for this approach is that the technical problems of large-scale absorption of multispecific sera hinder the simple definition of antigenic specificities by more conventional immunological procedures. In this paper, the analysis of the population associations between the antigenic specificities (as opposed to the associations between individual sera), which has formed the basis for the preliminary definition of the relationships between the genes controlling these specificities, will be discussed (Payne et al. 1964; Bodmer and Payne 1965). A family that clearly demonstrates the independence of the LA and 4 systems will be described. A new antigen, LA3, of the LA system will also be described. Predictions of the prevailing allelic combinations to be found in Caucasian populations will be made by application of the analysis of associations to the LA and 4 systems, using our own data and that of others.

Fate of HL-A antigens in aging cultured human diploid cell strains☆

Abstract The expression of HL-A antigens was found to remain unchanged throughout the finite in vitro lifetime of three human embryonic diploid cell strains (WI-38, WI-26 and MRC-5) and twelve adult skin fibroblast cultures. It is unlikely, therefore, that any immunological theory of senescence would be tenable if it depends on in vitro changes in HL-A specificities with age. One practical result of this finding is the possibility of distinguishing between human diploid cell populations derived from normal individuals of the same sex.

HLA C and D antigens associated with psoriasis.

The frequency of two newly defined HLA antigens, HLA CT7 and DMA, was found to be greatly increased in patients with psoriasis. These two antigens and those previously found to be associated with the disease, B13, BW16 and BW17, frequently occurred together. The disease may be primarily associated with HLA DMA, or with the HLA haplotypes CT7‐B13/W16/W17‐DMA.

Histocompatibility antigens in leprosy.

Abstract. Results of HL‐A typing are presented in 82 patients with leprosy and 50 normal Filipinos from Cebu, and 144 normal Filipino immigrants from the Luzon area. Comparisons of HL‐A antigen frequencies among the total patients and normals of Cebu showed no statistically significant differences; however, HL‐A10 was increased in frequency among the patients with lepromatous disease compared to the normals, and HL‐A5 was increased among the tuberculoid patients compared to the lepromatous patients. None of these comparisons was statistically significant when corrected for the number of antigens tested. Comparisons of HL‐A antigen frequencies between normal Filipinos of the Cebu and Luzon regions showed increased W‐5 in the Luzon population (corrected p < 0.025).

CORRELATION OF HISTOCOMPATIBILITY MATCHING WITH GRAFT REJECTION AND SURVIVAL AFTER CARDIAC TRANSPLANTATION IN MAN

Abstract Lymphocytes of donors and recipients were HL-A typed for 20 specificities in thirty cases of cardiac transplantation. ABO blood-group compatibility and a negative lymphocyte crossmatch were present in all cases. Standard postoperative immunosuppression including azathioprine, prednisone, and antilymphocyte or antithymocyte globulin was used. The number of HL-A incompatibilities ranged from one to four. There was no significant relationship between number of mismatches and postoperative survival, rejection history, or clinical status. The most striking finding was that HL-A mismatching does not preclude long-term survival with satisfactory graft function. Three of four recipients living more than 2 years after transplantation were mismatched for four antigens.

Distribution and Quantity of Leukocyte Antigens in the Formed Elements of the Blood

The capacity of platelets, lymphocytes, leukocytes (mixed lymphocytes and granulocytes) and erythrocytes to absorb 12 leukocyte agglutinins from multiparous women was investigated. Erythrocytes did not absorb these agglutinins. Platelets, lymphocytes and granulocytes appeared to share antigens identified by representative antisera belonging to the Group 4 and the LA antigen systems. Leukocyte antisera specific for a single blood cell line were not encountered. Approximately 20 times as many platelets as lymphocytes or leukocytes were required to absorb an aliquot of serum. The quantities necessary for absorption indicate that whole blood is an inefficient source of antigen for large scale production of monospecific from multi‐specific leukocyte antisera.

Association of Hla Antigens and Primary Open-Angle Glaucoma

HLA testing of 55 patients with primary open-angle glaucoma revealed no increased frequencies of any of 17 HLA-A and 29 HLA-B antigens. However, the subgroup with a known family history of primary open-angle glaucoma had an increase in the frequency of the HLA-B12 antigen (48%). Intrafamily studies might further define the strength and importance of this association.