Michiko Taniguchi

Donor‐specific human leukocyte antigen antibodies of the immunoglobulin G3 subclass are associated with Chronic rejection and graft loss after liver transplantation

In a previous study, we found that 92% of patients with chronic rejection had donor‐specific human leukocyte antigen antibodies (DSAs), but surprisingly, 61% of comparator patients without rejection also had DSAs. We hypothesized that immunoglobulin G (IgG) subclasses were differentially distributed between the 2 groups. A modified single‐antigen bead assay was used to detect the presence of individual IgG subclasses against human leukocyte antigen in 39 chronic rejection patients and 66 comparator patients. DSAs of the IgG1 subclass were most common and were found in 45% of all patients; they were followed by IgG3 DSAs (21%), IgG4 DSAs (14%), and IgG2 DSAs (13%). The percentage of patients with multiple IgG subclasses was significantly higher in the chronic rejection group versus the comparator group (50% versus 14%, P < 0.001). Patients with normal graft function in the presence of DSAs mostly had isolated IgG1, whereas patients with chronic rejection had a combination of IgG subclasses. Patients who developed DSAs of the IgG3 subclass showed an increased risk of graft loss (hazard ratio = 3.35, 95% confidence interval = 1.39‐8.05) in comparison with patients with DSAs of other IgG subclasses or without DSAs. Although further study is needed, the determination of the IgG subclass in DSA‐positive patients may help us to identify patients with a higher risk of chronic rejection and graft loss. Liver Transpl, 2012.

Association of anti-human leukocyte antigen and anti-angiotensin II type 1 receptor antibodies with liver allograft fibrosis after immunosuppression withdrawal.

Background Many pediatric patients who receive a living-donor liver transplant undergo withdrawal of immunosuppression (IS). For them, the high incidence of long-term progressive graft fibrosis is of particular concern. Methods We conducted a cross-sectional study including 81 pediatric patients who underwent IS withdrawal after living-donor liver transplant at Kyoto University Hospital and whose serum samples and pathological data could be obtained during the analysis period. We examined the association of donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) and angiotensin II type 1 receptor antibody (anti-AT1R Ab) with posttransplant graft fibrosis. Normalized mean fluorescence intensity (MFI) 5,000 or higher and anti-AT1R Ab concentrations 17 U/mL or higher were both considered high level. The patients were classified into an advanced fibrosis group (AFG) (Ishak score≥3) and a control group (CG) (Ishak score⩽2). Results Only one patient demonstrated DSA class I. Among those who demonstrated DSA class II, more AFG patients than CG patients demonstrated high-level mean fluorescence intensity, although the difference was not significant (64% vs. 39%; P=0.053). The incidence of high-level DSA-DRB1, however, was significantly higher in the AFG than that in the CG (40% vs. 4%; P<0.001), but there was no significant difference in DSA-DQB1 or DSA-DRB345. High-level anti-AT1R Ab was significantly more frequent in the AFG than in the CG (65% vs. 36%; P=0.02). All patients with both high-level DSA-DRB1 and high-level anti-AT1R Ab were found to have advanced fibrosis (P<0.001). Conclusion Anti-AT1R Ab and DSA-DRB1 may be candidates as biomarkers of graft fibrosis; both HLA and non-HLA immunity may be involved in graft fibrosis after IS withdrawal.

Higher Risk of Kidney Graft Failure in Patients with Rejection Episodes in the Presence of Anti-Angiotensin II Type 1 Receptor Antibodies: 2168

Rejection Episodes in the Presence of AntiAngiotensin II Type 1 Receptor Antibodies Taniguchi M., Rebellato L.M., Catrou P.G., Briley K.P., Hopfield J., Terasaki P.I. One Lambda, Inc., Los Angeles, United States, East Carolina University, Brody School of Medicine, Greenville, United States, Terasaki Foundation Laboratory, Los Angeles, United States Purpose: Anti-Angiotensin II Type 1 Receptor (AT1R) antibodies have been shown in patients with acute rejection of kidney and chronic rejection of heart transplants. In this study, we sought to determine if AT1R antibodies are associated with graft failure. Methods: The study subjects were 132 kidney transplant recipients (transplanted between 1999 and 2007) having biopsy-proven rejection episodes. Sera from these patients collected during rejection episodes were tested for the presence of both anti-AT1R and HLA antibodies. The detection of AT1R antibodies was done using ELISA (cell based), and the detection of HLA antibodies with LABScreen Single Antigen. The anti-AT1R level was categorized into three: high (>16.5 IU/ml), moderate (16.5 9.5 IU/ml), and low (< 9.5 IU/ml). Results: The high and moderate AT1R antibody levels were observed in 24% (32/132) of the patients with rejection episodes (12% high and 12% moderate). Co-occurrence of positive HLA antibodies was 78%. In the patients with high anti-AT1R, (i) biopsy-proven chronic rejection was more prevalent than biopsy-proven acute rejection (50% vs. 31%); (ii) co-occurrence of HLA-donor specific antibodies (DSA) was higher than the patients with low anti-AT1R (50% vs. 33%). The graft survival of the patients with high anti-AT1R was the worst compared with the patients with moderate and low anti-AT1R (Log-rank P=0.007, Figure 1). Moreover, the lowest survival was observed with high anti-AT1R alone, followed by concurrence of high anti-AT1R and HLA-DSA, HLA-DSA alone and absence of both antibodies (P=0.005, Figure 2)