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Prospective pretreatment with deliberate DST has afforded MLC reactive related donor-recipient pairs enhanced opportunity for successful transplantation. The sensitization rate in patients receiving DST prior to primary transplantation was 30%, but this sensitization has been generally specific and narrow-those patients developing a positive DSXM do not appear to be jeopardized regarding later cadaver transplantation. Graft survival rates in 86 recipients of kidneys from their blood donors are 95% (1-year) and 93% (2-year). This graft survival rate appears to outweigh the minimal risk of possible unfavorable sensitization. Potentially unsuccessful transplants in immunologically disparate related donor-recipient pairs can be avoided, and the transplants actually performed have enhanced prospects of success.

Sera from 203 recipients prior to transplantation were examined against a panel of 30 T and B lymphocytes at 5 degrees C and 37 degrees C. Those patients classified as having B-cold cytotoxins only had higher 1-year transplant survival rates from cadaver donors (82%) than patients with no antibodies (58%) or patients with antibodies reactive to T and B lymphocytes in the warm (37%). These results based on transplants from a single center confirm earlier studies derived from patients in 27 centers.

Antibody formation was monitored after buffy-coat transfusions were given at weekly intervals for 9 weeks or a single injection of buffy-coat pooled from ten different donors was given. Among patients with no prior transfusion history, 7 patients given repeated transfusions did not develop warm B or T cytotoxins. Among 25 patients receiving pooled buffy-coat, only 1 patient (who had 3 prior pregnancies) developed warm B and T cytotoxins. In contrast, approximately one fourth of patients who had prior blood transfusions developed warm B and T cytotoxins with either repeated or pooled buffy-coat transfusions. We conclude that buffy-coat from 10 donors given weekly or as a single pooled injection does not produce warm B and T cytotoxins in nontransfused patients, but does function as a secondary stimulus in primed patients.

Thoracic duct lymphocytes from patients receiving thoracic duct drainage as a pretransplant therapy were examined for cell surface markers. Patients followed over the drainage time period showed a variable but decreasing percentage of E-rosette-positive cells in the lymph fluid. A substantial percentage of these E-rosette-positive cells also had C3 receptors on their cell surface. Reactions of the whole lymphocytes with a heteroantisera to human B-lymphocyte antigens reflected the increasing proportion of B cells in the samples, but also indicated that a fraction of the T cells have Ia-like antigens on their surface marker characteristics. Significance of these cells with respect to graft survival is discussed.

1. In the long-term period, the half-life effectively measured loss rate. For HLA-identical sib donors the half-life was 25 years; for parental donors, 13 years; and for cadaver donors, 8 years (now possibly 11 years). 2. HLA-A,B,DR matching exerted the greatest effect on half-life, for a half-life of 17 years was achieved for cadaver donors. This rate was not quite as high as that for A,B,DR matched siblings but was higher than the one haplotype mismatched parental donor transplants. 3. Caucasian recipients had a half-life of 8 years compared to 5 years for black recipients. 4. Excellent centers had a 10-year half-life compared to 5 years for fair centers. 5. Cold ischemia time over 24 hours, recipient age over 55, and donor age of 50-60 had a small effect on the half-life in the order of 1 to 3 years. 6. Among the short-term factors that affect the 1-year graft survival, there was a 12% difference between excellent and fair centers. An 11% difference between A,B,DR matched transplants and 6 A,B,DR mismatched grafts was noted. First-cadaver donor grafts had a 10% higher graft survival at 1-year than second grafts. Other factors together with the difference in 1-year graft survival between the extremes were as follows: sensitization 9%, race 8%, transfusion 6%, donor age 6%, diabetic 3%, recipient age 3% and cold ischemia 1%. Thus more factors affect short-term survival than long-term survival.

In this study, pretransplant transfusions significantly improved the survival of first cadaver kidney transplants. Large numbers of transfusions had the same influence on graft survival as small number of transfusions. Graft survival was not influenced by pretransplant antibody levels, and the beneficial effect of transfusions was also independent of highest pretransplant antibody levels. The positive relationship between transfusions and cytotoxic antibodies was shown to be highly significant. B-warm and T-warm antibodies were both increased by transfusions and tended to occur together. B-cold antibodies occurred independent of transfusions, B-warm and T-warm antibodies. The results of this study suggest, but do not confirm, that B-cold antibodies benefit graft survival, while T-warm antibodies adversely influence graft survival. Transfusions and B-cold antibodies appear to influence graft survival by different mechanisms.

Monitoring of 25 first cadaver transplant recipients was carried out weekly after transplantation. A total of 441 sera were tested from these patients against B and T lymphocytes at 4 degrees C and 37 degrees C for development of cytotoxic antibodies. Thirteen of the 25 patients (52%) developed B-cold antibodies as their first antibodies and all had functioning kidneys. Five of the patients developed B-warm antibodies initially, and all 5 rejected their transplants within 24 days. Of the seven patients who did not develop antibodies, 3 rejected their kidneys within 72 days. We conclude that it is important to distinguish between two types of antibodies to B lymphocytes--those reactive in the cold and those reactive in the warm--since they have opposite effects. Of the 17 successful grafts, 13 first developed B-cold cytotoxins.

Pretreatment with deliberate DST has not resulted in hyperacute or irreversible rejection in patients receiving kidneys after negative donor-specific crossmatches, but has afforded immunologically disparate related recipients enhanced opportunity at successful transplantation. Additionally, with a post-transplant course paralleling that of HLA-identical siblings, high-dose immunosuppressive therapy for rejection has been spared in many recipients. Transplantation, however, proved unsuccessful in a patient receiving a kidney from his positive B-warm crossmatch blood donor in a protocol departure. This case experience and subsequent antibody studies have reconfirmed our initially established criterion of not proceeding with transplantation against a persistently positive B-warm donor-specific crossmatch. By pursuing the initially established DST protocol, it appears that a potentially unsuccessful living related transplant can be avoided, while the transplants actually performed have enhanced prospects of success. The nature of the various immunologic responses in this patient population remain to be more clearly defined.

Six serial dilutions of 51 sera from pretransplant patients were reacted against T and B lymphocytes at 5 degrees C and 37 degrees C. By the use of defined panels of T and B lymphocytes it could be shown that 10% of the 51 positive sera contained T-warm antibodies against HLA-A, -B, and -C specificities. There were 28% of the sera that had antibodies against non-HLA antigens reactive to B lymphocytes in the cold. Other sera contained mixtures of HLA and non-HLA antibodies. By dilution analysis of the sera, the mixtures could be detected and the HLA specificities identified. This ability to distinguish between HLA and non-HLA antibodies should be important in classifying pretransplant patients into high- and low-risk patients. Prior evidence that we have presented suggests that the non-HLA antibodies may be enhancing antibodies.