BACKGROUND Pretransplant blood transfusion has a well-known beneficial effect on posttransplant graft survival. Recently, it has been proposed that the clinical benefit of transfusion is due to HLA-DR antigen sharing between the blood donor(s) and the recipient. Immunological studies have suggested that this might result from a functional deletion of donor-reactive cytotoxic T lymphocytes. METHODS We investigated frequencies of alloreactive lymphocyte precursors with cytotoxic or interleukin-2-producing helper function by limiting dilution analysis in 10 renal dialysis patients before and after transfusion with fresh, allogeneic whole blood. Five patients received blood transfusions from donors matched for one HLA haplotype (or one HLA-B-DR antigen) and the other five patients received blood from fully HLA-mismatched donors. RESULTS Contrary to some previous reports, frequency analysis of cytotoxic T lymphocyte precursors revealed no significant differences between the two treatment groups in terms of development of blood donor-specific hyporesponsiveness after transfusion. Split-well analysis of cytotoxic T lymphocyte precursors reactive with single-mismatched HLA antigens demonstrated that the effects of transfusion on alloreactive specificity are complex and may vary depending on the particular antigens mismatched between the recipient and blood donor. Analysis of donor-specific helper T lymphocyte precursor frequencies revealed a significant decrease of interleukin-2-producing cells 3 months after transfusion in the total patient population. This effect was most prominent in the recipients of HLA-mismatched blood, but it also exhibited some degree of nonspecificity, as frequencies of third-party reactive helper T lymphocyte precursors were also significantly reduced. CONCLUSIONS Our overall results suggest that the degree of HLA matching between blood donor and recipient does not greatly influence the effect of blood transfusion on the T lymphocyte allorepertoire. The apparent induced down-regulation of helper T lymphocyte activity may play a role in the reported immunosuppressive effects of allogeneic blood transfusion.

The efficacy of HLA-DR matching in cadaveric renal transplantation is controversial in the cyclosporine (CsA) era. Reports have questioned both the reliability of serological HLA-DR typing as well as the benefit of matching in terms of improved graft survival. Analysis of 1,000 consecutive cadaver donor transplants performed at Oxford between 1975 and 1992 has shown that with improved immunosuppressive regimens and increased transplant success there has been a steadily diminishing influence of HLA-DR matching measured in terms of first graft outcome. For patients treated with azathioprine and prednisolone (n = 278) overall one-year first graft survival was 65%, but there was a 20% improvement associated with HLA-DR matching which has been maintained for up to 15 years. With the introduction of CsA, used either alone or in conjunction with low dose steroids (n = 96), one-year first graft survival was 69% and the difference between HLA-DR-matched and -mismatched transplants was 14%. Our current maintenance immunosuppressive protocol is triple therapy (N = 425) with an 81% one-year first graft survival for both matched and mismatched transplants. However, we do continue to find a marked correlation between HLA-DR matching and clinical course. HLA-DR-mismatched patients suffer more rejection episodes, spend a longer time in the hospital, and have higher creatinine levels at 3 months. This costs, on average, an extra 1,500 pounds for each mismatched transplant. The effect is most apparent in unsensitized males. For cadaveric regrafts, one-year graft survival for patients on triple therapy is 80% (n = 116) which does not differ from first graft survival rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Two types of K channel regulated by ATP were observed in pancreatic β cells from a type-2 diabetic man. One type had a conductance of 67 pS at-70 mV in symmetrical 140 mM KCl and was inhibited by intracellular ATP with a half-maximal concentration of 40 μM. ATP inhibition was antagonised by ADP. Tolbutamide inhibited the whole-cell K currents half-maximally at 25 μM. This channel has properties similar to those found for the ATP-sensitive K channel in rodent and normal human β cells. The second channel type observed was an ATP-activated K channel. It had a conductance of 37 pS at -70 mV in symmetrical 140 mM KCl and was activated half-maximally by 9 μM intracellular ATP. This channel was unaffected by 1 mM tolbutamide. In cell-attached patches, one β cell out of four tested responded to 20 mM glucose with depolarization. The role of the ATP-activated K channel with respect to the (patho)physiology of the β cell is uncertain.

Successful transplantation of the endocrine pancreas in Type I diabetes with complete correction of the glucose metabolic abnormalities may prevent progression or development of the microangiopathic complications of the disease. This could be achieved by transplantation of the whole pancreas as a vascularized graft (the only available clinical approach at present), transplantation of isolated islets or of fetal pancreas. Since transplantation of the pancreas as a vascularized graft is associated with a significant peri-operative morbidity and requires immunosuppression to prevent rejection it is unlikely to be applicable at a relatively early stage of the disease, before microangiopathic complications become irreversible. For this reason transplantation of pancreatic islets or fetal pancreas is the only approach likely to be acceptable. Transplantation of isolated islets in the rodent does correct experimental diabetes, but recurrence of disease is seen in the spontaneous diabetes of the Biobreeding (BB) rat and the non-obese diabetic (NOD) mouse. Furthermore suppression of rejection of allogenic islets has proved difficult. In large mammals, including man, the lack of a technique to prepare isolated islets in a relatively pure form has been a further obstacle to development. Recently this problem has been overcome, allowing separation of islets in relatively large numbers with adequate purity, bringing closer the time when clinical trials might be considered. However, rejection and disease recurrence are likely to remain major obstacles, although experimental work suggests that both can be overcome.

The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 μmol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 μmol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.