Case report: binding of a clinically relevant human leukocyte antigen-DQα-specific antibody in a kidney graft recipient is inhibited by donor-type human leukocyte antigen-DQß chain.

In this case report, we have found what may be an immunization with donor-specific human leukocyte antigen (HLA)-DQα in combination with recipient-specific HLA-DQß. A renal allograft recipient who did not comply with immunosuppressive therapy during pregnancy had graft failure 23 months posttransplantation with biopsy-proven humoral and cellular rejection. Sera were tested in a Luminex-based single-antigen bead assay. We compared Luminex reactivity with the degree of eplet mismatching between the recipient's own HLA-DQ chains and the HLA-DQ chains bound to the Luminex beads. Eplet calculations were done with the HLAMatchmaker. HLA-DQ similarities were compared further by dissimilarity scoring in HistoCheck. We observed that Luminex beads with donor-type HLA-DQα and HLA-DQß bound less antibody than beads with donor-type HLA-DQα combined with recipient HLA-DQß. In HLAMatchmaker, we identified all eplet mismatches between donor and recipient HLA-DQ. Next, we counted how many of these eplets were represented on the various Luminex beads. We found that antibody binding to the bead increased with the number of such mismatches for HLA-DQα. Surprisingly, antibody binding decreased as the number of eplet mismatches for HLA-DQß increased, from a mean fluorescence intensity (MFI) value of 18,800 for no mismatched eplets to approximately 10,000 for 12 mismatched eplets. These findings were confirmed by comparing antibody binding with the structural dissimilarity score between the recipient HLA-DQ type and the HLA-DQ bound to the Luminex beads. In this patient, clinically relevant antibodies bound strongly to donor-like HLA-DQα chains when combined with recipient-like HLA-DQß. HLA-DQß chains more similar to those of the donor reduced the binding of donor- specific HLA-DQα antibody.

Increased plasminogen activator inhibition levels in malignancy.

Plasminogen activator(PA)-tissue and urokinase type-and PA-inhibition in plasma were investigated in 52 consecutive cancer patients with a variety of tumors. At first patients were analyzed as one group. Secondly patients were subdivided into two groups, one with (n = 42) and one without (n = 10) metastasis. Our results show that tissue-type-PA antigen (t-PA-antigen) and PA-inhibition were both significantly increased irrespective of the presence or absence of tumor metastasis (p less than 0.001 compared to age matched healthy controls. In the group without metastasis a significantly decreased level of t-PA activity was found (p less than 0.001) but in the group with metastasis t-PA activity was normal. These data seem to reject the hypothesis that decreased plasma fibrinolytic activity is one of the prerequisites for tumor metastasis.

Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model.

Purified human radioiodinated antithrombin III (125I-AT III) was used to study its metabolism in six members from three different families with a known hereditary AT III deficiency. Six healthy volunteers served as a control group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and crossed immunoelectrophoresis (CIE) showed the purified AT III to be homogeneous. Amino acid analysis of the protein revealed a composition identical to a highly purified internal standard. The specific activity was 5.6 U/mg. Analysis of plasma radioactivity data was performed, using a three-compartment model. Neither plasma disappearance half-times nor fractional catabolic rate constants differed significantly between patients and control subjects. The mean absolute catabolic rate in the patient group was significantly lower than that of the control group at 2.57 +/- 0.44 and 4.46 +/- 0.80 mg/kg/day, respectively. In addition, the mean patient alpha 1-phase, flux ratio (k1,2 and k2,1) of the second compartment alpha 2-phase and influx (k3,1) of the third compartment were significantly reduced as compared with control values. It has been tentatively concluded that the observed reduction in the second compartment may be caused by a decrease in endothelial cell surface binding.

Antithrombin III metabolism in two colitis patients with acquired antithrombin III deficiency.

125I-Antithrombin III metabolism studies were performed in 2 patients with ischemic and ulcerative colitis, respectively. Both patients had acquired antithrombin III deficiency and objectively diagnosed deep venous thrombosis. A decreased 125I-antithrombin III plasma disappearance halflife and an increased fractional catabolic rate was found in both patients. The transcapillary flux ratio was elevated in the patient with ischemic colitis. A follow-up study of the first patient during a period when no signs of an ischemic colitis were present and no medication was taken showed completely normal tracer data. The data are consistent with both gastrointestinal loss and intravascular consumption of antithrombin III. The antithrombin III deficiency could not be explained by other causes such as proteinuria, liver dysfunction, or obvious disseminated intravascular coagulation. Reduced antithrombin III plasma levels were considered to have contributed to the development of deep venous thrombosis in both patients.

alpha 2-Plasmin inhibitor metabolism in patients with liver cirrhosis.

We describe the metabolism of purified human alpha 2-plasmin inhibitor in patients with liver cirrhosis to determine whether low plasma concentrations of alpha 2-plasmin inhibitor are the result of impaired synthesis or increased catabolism or both. A kinetic study was performed with 131I-alpha 2-plasmin inhibitor as a sensitive parameter of fibrinolysis in 14 patients with histologically proved liver cirrhosis compared with six healthy control subjects. Eight patients had macronodular cirrhosis (with positive hepatitis B surface antigen), and six had micronodular cirrhosis as a result of alcohol abuse. None of the patients had clinical signs of ascites, and in all the disease was stabilized. alpha 2-Plasmin inhibitor levels biologically and immunologically measured were decreased in all patients. Ten microCi 131I-alpha 2PI was injected intravenously, the disappearance of plasma radioactivity was measured, and turnover data were calculated according to the function x(t) = A1e-alpha 1t + A2e-alpha 2t + Be-beta t. Mean (+/- SD) turnover data in the control subjects were plasma radioactivity half-life 60.1 +/- 5.3 hours, fractional catabolic rate constant of the plasma pool 0.0318 +/- 0.0106 hr-1, and absolute catabolic (synthetic) rate constant 2.10 +/- 0.60 mg/kg/day. The alpha 1-phase was 1.26 +/- 0.23, and the transcapillary influx constant (k2,1) was 0.974 +/- 0.109 hr-1. In the patients, plasma radioactivity half-life was 58.7 +/- 12.09 hr, and fractional catabolic rate constant of the plasma pool 0.0283 +/- 0.0043 hr-1. The alpha 1-phase 4.74 +/- 6.48 and the transcapillary influx (k2,1) 3.08 +/- 3.9 hr-1 were both significantly increased compared with control values (p less than 0.05 and p less than 0.05, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)