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S K Takemoto

Publications and source records attributed to S K Takemoto.

15 recordsLinked to original sources
PubMed2000

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection.

BACKGROUND: Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS: PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS: By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS: Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

Antibodies↗
PubMed2000

Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation.

BACKGROUND: In October 1987, the United Network for Organ Sharing (UNOS) established a national kidney-sharing program to increase the number of HLA-matched transplantations. Since then, over 7500 cadaveric kidneys have been shipped to centers in 48 states for transplantation to HLA-matched patients. We evaluated the efficacy of the program during its first 12 years of operation. METHODS: We compared the rates of rejection and actuarial graft survival for 7614 HLA-matched and 81,364 HLA-mismatched cadaveric kidney transplantations reported to the UNOS Scientific Registry between October 1987 and September 1999. To assess the effects of the extended period of ischemia associated with shipping HLA-matched kidneys, we identified 3562 pairs of cadaveric kidneys in which one kidney went to an HLA-matched recipient and the other went to an HLA-mismatched recipient. RESULTS: The estimated 10-year rate of graft survival was 52 percent for HLA-matched transplants, as compared with 37 percent for HLA-mismatched transplants. The estimated half-lives of the transplants were 12.5 years and 8.6 years, respectively, and the mean duration of cold ischemia was 23 hours and 22 hours, respectively. After adjustment for the effects of demographic characteristics, at 10 years the overall rates of graft survival and the rates of functional-graft survival (with data censored on patients who died with a functioning graft) were 10 percent and 11 percent higher, respectively, for HLA-matched transplants than for HLA-mismatched transplants. Among 3562 pairs of kidneys, HLA-matched transplants had higher rates of survival, a lower incidence of episodes of rejection, and a lower risk of loss as a result of rejection. CONCLUSIONS: A superior graft outcome with little increase in the duration of cold ischemia justifies national sharing of HLA-matched kidney transplants.

Actuarial Analysis↗
PubMed2000

Anti-HLA antibodies after solid organ transplantation.

We have cited more than 23 studies showing that de novo development of anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants. Antibodies to both HLA class I and class II antigens seem to be detrimental. Antibodies of the IgG isotype and possibly the IgM isotype were clinically relevant. Most studies showed that donor-specific antibodies were associated with rejection and graft loss. Therefore, HLA antibodies provide a clinical readout for patient alloreactivity that may have the ability to distinguish graft dysfunction due to immunologic and nonimmunologic causes. Antibody may act as a critical trigger for rejection of allografts and may serve as an early indicator of a slowly smoldering chronic rejection that is not manifested at a given time by biochemical measures such as serum creatinine levels. The effectiveness of various drugs on chronic rejection should be evaluable by their effects on HLA antibody production. We predict that recently developed ELISA and flow cytometry techniques using purified HLA antigen will increase the clinical relevance of posttransplantation HLA antibody monitoring by (1) allowing the detection of low levels of donor antibody; (2) easily distinguishing the isotype and target (HLA class I or class II) of the antibodies; and (3) correlating the antibody with specific graft pathology.

Animals↗
PubMed1999

Transplant risks.

1. Changes in serum creatinine is a potentially useful predictor of chronic rejection. Patients with 2 10% increases in creatinine values in 3 consecutive years between 1-5 years had 4 times the risk of chronic rejection graft loss than patients with stable creatinine. 2. Formation of HLA antibody may correlate with graft rejection since losing a kidney increased the risk of broad sensitization 5-fold and losing multiple kidneys increased the risk ten-fold. 3. Sensitization increased the risk of acute and chronic rejection while pregnancies decreased the risk of acute and chronic rejection suggesting that pregnancy may result in "beneficial" sensitization. 4. HLA matching was the most potent factor decreasing the risk of acute rejection 2-fold and chronic rejection by 62%. 5. The incidence of acute and chronic rejection have both decreased significantly since 1994.

Acute Disease↗
PubMed1997

Evaluation of the transplant recipient and donor: molecular approach to tissue typing, flow cytometry and alternative approaches to distributing organs.

An enzyme-linked immunosorbent assay test for measuring and characterizing anti-human leukocyte antigen antibodies in recipient sera received mixed evaluations. Enzyme-linked immunosorbent assay and flow cytometry crossmatch tests using solubulized donor human leukocyte antigens were introduced New methods for allocating kidneys included permissible human leukocyte antigen mismatch, human leukocyte antigen amino acid residue match, and kidney size/human leukocyte antigen match algorithms.

Enzyme-Linked Immunosorbent Assay↗
PubMed1997

Class I peptides involved in the indirect pathway of allorecognition.

1. Donor HLA class I peptides that best "fit" the recipient's HLA-class II antigen peptide motifs were determined as peptide scores. 2. Transplants with high-scoring donor peptide mismatches had reduced long-term outcome. 3. Peptides identified in this analysis may be useful for induction of tolerance, diagnosis of rejection, and improvement in allocation of more histocompatible kidneys.

Amino Acid Sequence↗
PubMed1996

HLA matching.

1. HLA matching exerts a profound influence on graft outcome. The difference in 3-year graft survival rates between best and worst matched cases was 17% for first grafts and 18% for retransplants. This HLA matching effect persists despite recent improvements in graft outcome. The matching effect at 3-years was 12% for transplants since 1991. 2. Surprisingly, HLA matching is especially important for recipients over age 60. The increase in the HLA matching effect to 20% in patients older than 60 can be attributed to the additive effects of HLA matching on both functional and patient survival. Consequently, graft survival for zero-MM recipients is similar for patients older and younger than age 60. 3. The difference in 3-year survival between zero and 0-MM kidneys was 10% for White and 15% for Black recipients. 4. Transplants with zero-broad but split A,B mismatches had graft outcomes similar to one-A,B,DR MM kidneys. Split DR MM did not affect the outcome of zero-MM kidneys. 5. HLA-matched transplants can be classified according to the degree of identity between the donor and recipient: 6-antigen match, phenotypic match, and zero-MM. Outcome for zero-MM was lower in transplants before 1990, but the 3 types have similar outcomes in recent transplants. The change in UNOS matching policy in 1995 to include zero-MM kidneys doubled the number of shared kidneys. 6. HLA typing from over 150 centers resulted in an error rate for shipped kidneys of less than 5%. Donor antigens retyped at the recipient center resulted in identical antigens for 70% of cases, a broad DR MM for 2.2%, and an A,B MM in 2.6% of the retyped cases. 7. Although increasing cold ischemia time (CIT) had a deleterious effect on survival of MM kidneys, no effect was seen for zero-MM kidneys. 8. An effect of a possible sex-linked minor histocompatibility antigen was demonstrated with improved outcome for male to male zero-MM cadaveric and parent-to-child transplants. 9. Zero-MM kidneys from pediatric donors and donors older than 60 years of age had poorer outcome than MM kidneys before 1991, but the recent experience shows a matching effect even with these marginal donors.

Adult↗
PubMed1996

HLA amino acid residue matching.

1. HLA amino acid sequences have been defined for 77 A- and 176 B-locus antigens. Amino acid polymorphisms occurred at 80 A- and 74 B- sequence positions. 2. The majority of amino acid substitutions occurred in regions involved with peptide binding. A surprisingly large number of substitutions were in the alpha-3 regions of the molecule. 3. Graft outcome in cadaveric and living donor transplants was calculated for mismatches for every possible amino acid allele. 4. Two-thirds of the HLA-A and -B locus antigens used for solid organ allocation had disparate frequencies in White and Black recipients. Only 6 antigens were found in over 20% of White recipients. 5. Five-year survival for first transplants was 66% for zero-DR, zero-residue mismatched kidneys compared to 59% for kidneys with mismatches. Half-life for residue matched kidneys was 11 years compared with 8 years for kidneys with mismatches. 6. Mismatches for all of the A-locus residues and the majority of B-locus residues were correlated with positive crossmatches. 7. None of the crossmatches for highly sensitized patients with zero-A,B,DR mismatches were positive; 30% of zero-residue mismatched patients had a positive crossmatch compared to 70% of cases with mismatches.

Amino Acid Sequence↗