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Publications (17)22.69 Total impact

  • Transplantation 07/2010; 90(2):221-2. · 3.78 Impact Factor
  • Transplantation 01/2010; 90. · 3.78 Impact Factor
  • Nori Sasaki, Adam Idica
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    ABSTRACT: Almost all the HLA-matching effects found by the 2000 analysis were confirmed by this study. The only HLA-matching effect found in the 2000 analysis that disappeared were those of "small matching effect" found in sub-populations of type I diabetes (PRA < 10%, donor age 20-35). The 2000 analysis found a lack of HLA matching effect in non-African American kidney transplant patients with type I diabetes between 1987 and 2000. The 2000 analysis found that a patients' ethnic group was a factor in graft survival; African American patients were found to have a significantly lower 10-year graft survival in the 5 or 6 mismatched group (27%) compared to Caucasian patients (40%). In addition, Asian patients (42%) had higher graft survival compared to that of Caucasian patients. In this study, we observe a similar pattern with death-censored graft analysis for all ethnic groups with 10-year graft survivals at 72.9% for Asians, 69.5% for Caucasians, and 49.3% for African Americans. There was an overall lack of HLA-matching effect on patient survival in the 2000 analysis. In our current analysis, the patient survivals remained virtually the same despite moderate increase in graft survival over the same period of time. The HLA-C locus mismatch was found to have additive effect to the 10-year graft survival trends observed in A and B mismatch cases. HLA-DQ mismatch on the other hand, showed limited HLA-matching effect and did not show the same additive effect as C. There are various possible issues in the DQ mismatch analysis, from the consistency of DQ typing results, lack of diversity in the DQ antigen, to the possibility of DQ mismatch having little effect on the graft survival. Utilizing kidney transplant cases performed from 1995 through 2000, the 2000 analysis projected 10-year survivals of 64% and 47% for the 0 ABDR mismatch and 5 or 6 ABDR mismatched cases respectively; the 2000 projection only missed actual death-censored survivals by 9% lower for the 0 mismatch and 17% lower for the 5 or 6 mismatch cases. Utilizing the transplant cases of 2005 through 2009, we projected their 10-year graft survivals for year 2020. The 10-year graft survival for 0 ABDR mismatched patients is expected to be over 85% and nearly 70% for 5 or 6 ABDR mismatched patients. The general upward trend of graft survival we have observed in the last 10 years has been dependent upon the development of novel transplant protocols and use of novel immunomodulatory reagents. This trend is likely to continue given the promise of new drugs and personalized healthcare. The decreasing range of the differences in the 10-year graft survival between best matched and worst matched HLA groups is also likely to continue. One interesting trend that is clearly evident is the increasing difference between the best and worst HLA-matching in terms of the associated graft half-life. The positive HLA-matching effect on long-term graft survival is clearly evident and should be taken into consideration for all kidney transplants.
    Clinical transplants 01/2010;
  • Human Immunology - HUM IMMUNOL. 01/2010; 71.
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    ABSTRACT: Current treatments for autoantibody-mediated diseases (i.e., systemic lupus erythematosus) and alloantibodies (in transplant) are minimally effective. Although they deplete naïve B cells, plasmablasts, and transiently reduce antibody concentrations, they are minimally effective against long-lived, antibody-producing plasma cells. In transplantation, plasma cells produce antibodies directed against human leukocyte antigen (HLA) antigens causing poor allograft survival. We report the first clinical experience with a plasma cell depleting therapy, bortezomib, to abrogate anti-HLA antibodies in transplantation (outside of rejection) in an attempt to improve long-term allograft survival. Eleven patients with anti-HLA alloantibodies were treated with bortezomib. All patients underwent plasmapheresis to aid in removal of antibodies and to determine the effect of bortezomib. Serial measurements of anti-HLA antibody levels were conducted weekly by single antigen bead on Luminex platform. Bortezomib treatment elicited substantial reduction in both donor-specific antibody (DSA) and non-DSA levels. Antibodies were directed against DSA in 8 of 11 cases. Mean time to antibody appearance was 2 months posttransplant. Within 22 days (median) from treatment initiation, 9 of 11 patients' antibody levels dropped to less than 1000 mean fluorescence intensity. Of two patients without successful depletion, all had peak mean fluorescence intensity more than 10,000. At a mean follow-up of approximately 4 months posttreatment, all patients have stable graft function. Minimal transient side effects were noticed with bortezomib in the form of gastrointestinal toxicity, thrombocytopenia, and paresthesias. Bortezomib therapy effectively abrogates anti-HLA antibodies. Hence, removal of antibodies, by proteasome inhibition, represents a new treatment strategy for transplantation and may have benefit in autoimmune-related disease.
    Transplantation 06/2009; 87(10):1555-61. · 3.78 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Transplantation 04/2009; 87(8):1263. · 3.78 Impact Factor
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    ABSTRACT: A total of 69 individuals received a kidney from a living donor after a TLI-based clonal deletion protocol with no post-transplant maintenance immunosuppression planned. If needed, immunosuppression was started on a patient-specific basis, adding one drug at a time, a strategy we AWN". call "Drugs Added When Needed," or "DAWN. Following this strategy, at last follow-up 40 of the 69 patients (58%) had to be rescued by conventional immunosuppression, 23 (33%) had to be started on daily prednisone and six (9%) remained with no maintenance immunosuppression. The overall rate of de novo donor-specific antibody produced was 36% (in 25 of the 69 patients), and mean time to detection was about four months. The incidence of acute rejection episodes that displayed humoral components was 27% (19 cases), of which 14 were pure antibody-mediated rejection, five combined antibody- and T-cell-mediated rejection, and six were episodes (9%) of pure T-cell-mediated rejection. Finally, this study shows that although complete clonal deletion was not achieved, an important proportion of patients--42%, or 29 of the original 69--could be maintained with prednisone alone or even with no immunosuppression for a total mean follow-up of 13.3 months. Moreover, 16 patients with recent follow-up are surviving with no maintenance immunosuppression or just on prednisone. The mean serum creatinine at last follow-up for these 16 patients is 1.33 +/- 0.2 mg/dL with a mean follow-up of 19.3 months. Clonal deletion can be used to transplant patients without maintenance immunosuppression, adding drugs only as needed.
    Clinical transplants 01/2009;
  • Human Immunology - HUM IMMUNOL. 01/2009; 70.
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    ABSTRACT: Transplant patients often produce human leukocyte antigen (HLA) antibodies against their donors and produce more specificities than can be accounted for by HLA antigen mismatches. We theorize that the presence of extra, otherwise unexplainable specificities could be accounted for if antibodies reacted to more than one epitope (primary and mimetic) on distinct HLA molecules. The theory states that mimetic epitopes consist of the same three amino acids that comprise the primary, sterically placed approximately the same distance apart as are the corresponding amino acids of the primary. A mimetic epitope table containing all primary epitopes and corresponding mimetic epitopes was built. Then, the HLA specificities of monoclonal and single patient antibodies were determined. These specificities that could not be defined by unique position or amino acid epitopes alone were then used to query the mimetic epitope table. A single antibody from a transplant patient and three monoclonal antibodies produced reactions that can best be explained as the result of one antibody reacting to the same amino acids at two distinct sites on the molecule. Those position and amino acid combinations (pos/aa) are the primary and mimetic epitopes. Using computerized methods of searching, mimetic epitopes were found in five additional kidney transplant patients who produced nondonor-specific antibodies in addition to donor-specific antibodies. Epitopes on the HLA molecule that mimic the primary epitope have been found. We suggest that these mimetic epitopes explain the additional antibodies often found on HLA immunization resulting from allograft rejections, pregnancies, and transfusions.
    Transplantation 11/2008; 86(7):912-8. · 3.78 Impact Factor
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    ABSTRACT: 1. A total of 61 patients were treated with a clonal deletion protocol and transplanted without planned post-transplant immunosuppression. 2. Twenty-nine (48%) patients did not develop any donor-specific anti-HLA antibodies after the transplant, with a median follow-up of 158 days and a mean sCr of 2.1 mg/dL at the last follow-up. 3. Only 23% of the patients who received a DST of 60 mL produced DSA after the transplant, while 68% of the patients who received a bigger DST dose did. 4. Small doses of donor-specific transfusions (60 mL) elicited smaller specific responses, allowing efficient deletion of the reacting clones, creating conditions in which donor-specific anti-HLA antibodies were not produced. 5. A better deleting agent is needed to achieve higher rates of success using the clonal deletion protocol.
    Clinical transplants 02/2008;
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    ABSTRACT: 1. Immunological responses cause antibodies to be produced, and transplant patients often produce HLA antibodies against their donors' HLA. But in many cases, more antibodies are produced than just those against mismatched HLA. Many patients with zero mismatched transplants also produce antibodies, and some of these grafts fail. This study used graft survival analysis that contemplated the primary epitopes against the donors' alleles and the corresponding mimetic epitopes, less those shared with the patients' alleles. 2. A table of primary epitopes and corresponding mimetic epitopes was built in a previous study. For each case studied, here, a subset of the table was selected for all of the donor's HLA alleles. The subset was reduced by eliminating all primary and mimetic epitopes shared by the patient's own HLA alleles. The remaining mimetic and primary epitopes-the maximum pool of epitopes (MaxPEpi)-produced epitope frequency (Efr) for each allele. Using a zero-HLA-AB-mismatch subset (n = 16) of the Greenville and Holland kidney transplant data set (n = 451), the Efr for each allele in the MaxPEpi of each case was tallied and compared with the corresponding observed antibody specificities. The average frequencies were 2,869 and 1,975, respectively, and the t-test was significant at the p-value of less than 0.00001, indicating that the higher the frequency, the more likely that the corresponding allele appears as a part of the specificity. 3. The trends were used to perform survival analysis on zero-mismatch kidney transplant cases in the 2007 UNOS data file. Different variables of MaxPEpi parameters and cutoff points were tried with half of the deceased-donor cases in the file, survival rates for those below and above each cutoff point were compared by the log-rank test. The average Efr with a cutoff of 3,700 yielded the best 10-year graft survival in this subgroup of the 2007 UNOS cases. The results were supported and verified by analyzing the second half of the deceased-donor cases and the living-donor cases in the 2007 UNOS data set. 4. With the 2007 file living-donor cases, 10-year graft survival rate was 86.2% for cases below the cutoff, and 85.4% for those above, and the difference was significant at a p-value less than 0.01. A larger difference was observed for 2007 living-donor cases, excluding identical sibling transplants, but the difference was not statistically significant due to the low number of cases. 5. The same trends were found for 10-year survivals with cases in the 2008 data, but were not statistically significant. With living donors, the rates below and above the cutoff were 85.7% and 85.2%, respectively, and with deceased donors, 72.7% and 72.1%, respectively, p < 0.125. As with the 2007 data, cases in the 2008 file with living donors--excluding identical sibling transplants--had survival rates of 91.7% and 79.0%, respectively, but the 12.7% difference was not statistically significant because of the low number of cases.
    Clinical transplants 02/2008;
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    ABSTRACT: We show the ability of bortezomib to remove donor-specific HLA antibody from kidney allograft patients, the drug acting as a proteasome inhibitor, providing targeted therapy against antibody-producing plasma cells. Ten out of thirteen patients (77%) experienced primary DSA reversal, and in the remaining three patients the MFI of their primary DSA was dramatically reduced. Bortezomib is a viable therapy to treat donor-specific HLA antibody in allograft recipients. The potential for long-term benefits--and complications--are still unknown. Prospective trials are being conducted at the University of Cincinnati, Cincinnati, OH; at the Mayo Clinic, Rochester, MN; and at IKDRC-ITS, Ahmedabad, India.
    Clinical transplants 02/2008;
  • Transplantation 01/2008; 86. · 3.78 Impact Factor
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    ABSTRACT: 1. The study began with the 2007 UNOS dataset of 270,690 kidney transplant, from which were selected post-1995 first transplants with Caucasian donor/patients and available ABDR typing data, yielding 87,616 cases. These were split into cadaver donor (n=46,927) and living donor (n=40,689) populations. 2. Cases with broad antigens such as A9, A10, B12 and B17 were eliminated, as were cases that had failed within 30 days. That left 28,264 cadaver donor and 26,211 living donor cases. 3. We looked at every theoretical mismatch between donors and patients in the living donor population. Overall, 405 single, 21,269 double, and 391,325 triple position/amino acid mismatches were included in the analysis. Two tallies for each mismatch were generated: "function" and "fail" based on patient's associated graft survival. 4. We generated a list of "fail" single, double, and triple position/amino acid mismatches and computed 10-year survival curves for each of the mismatches, comparing them with the average 10-year survival curve using the log-rank test. Based on the log-rank statistics, a ranking of the bad mismatches was established. 5. We looked at the long-term graft survival of additive single, double, and triple "fail" mismatches in cadaver donor transplants. 6. Survival curves of transplants with position/ amino acid mismatches were generated and compared with the survival curves of the traditional standards: 0 ABDR mismatch; 1 A, 1 B and 1 DR mismatch; and full 6 ABDR mismatches. 7. The greatest effect was seen in first transplants with a male recipient, but that were not Caucasian-to-Caucasian. Up to 125 double mismatches resulted in a 10-year survival 29% lower than 0 ABDR mismatches. 8. In first transplants that were not Caucasian-to-Caucasian 1154 out of 1177 (98%) pos/aa mismatches (single, double, or triple) had lower 10-year survival than cases with one mismatch, each, in A, B and DR. Looking at re-grafts, we see that 498 out of 499 with single, double and triple mismatches had lower 10-year survival than that of cases with one mismatch, each, in A, B and DR. 9. Overall, position/amino acid mismatches had consistently lower 10-year survival than 1 A, 1 B, 1 DR mismatches. We believe our selection of "fail" pos/aa mismatches provide a good starting point for establishing a list of mismatches to be looked for and avoided in future transplants in order to give them a better chance of survival.
    Clinical transplants 01/2007;
  • Adam Idica, Nori Sasaki, Paul Terasaki
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    ABSTRACT: 1. Began with the 2006 UNOS dataset and then selected for Caucasian donor/patients (post-1995 transplant and first transplant kidney only with full ABDR typing data). This was then split into cadaver donor (n = 20,542) and living donor (n = 21,890) populations. 2. Looked at every theoretical mismatch between donor and patients in the living donor population. Overall, 167 single, 4601 double, and 83,655 triple position/amino acid mismatches were included in the analysis. Two tallies for each mismatch were generated: "good" and "bad" based on patient's associated graft survival. 3. Generated a list of "bad" single, double, and triple position/ amino acid mismatches. 4. Looked at associated long-term graft survivals of patient/donor pairs with additive single, double, and triple "bad" mismatches in the cadaver donor population. 5. Survival curves of transplant pairs with associated mismatches were generated and compared with traditional standards of 0ABDR mismatch, 1 or more ABDR mismatch, and full 6ABDR mismatch survival curves. 6. The greatest effect was seen in re-grafted male patients where up to 50 double mismatches were associated with a 10-year survival 27% lower than 0ABDR mismatch. 7. Many of the "bad" position/amino acid mismatches identified were the same as those identified by generation of antibodies against Class I and Class II epitopes. This is evidence that antibody-defined epitopes and those functioning as transplantation epitopes influencing long-term graft survival are the same. 8. Overall, we are disappointed that position/ amino acid mismatches were not associated with more markedly lower survivals. It appears that current immunosuppression can largely negate the effect of mismatching for immunogenic epitopes.
    Clinical transplants 02/2006;
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    ABSTRACT: 1. The resolution of single antigen beads is high enough to distinguish between a patient's own HLA phenotype and antibody specificity down to the allele level. 2. Mismatched antigens generally produce an antibody specific to that antigen. Therefore, one would naturally expect antibody specificity frequency to correlate with phenotype frequencies for any given population (e.g., rare phenotypes would rarely have an antibody generated against it). We called this the antigen mismatch model. 3. When testing the sera of 367 highly sensitized patients with single antigen beads, we found results which did not correlate with the antigen mismatch model. Antibodies specific for rare antigens occurred at surprisingly high levels within the study population. 4. We postulate that these high frequencies are due to mismatches on epitopes as defined by absorption/elution experiments (9) or NEpis. Thus, a mismatch on a common antigen could produce an antibody specific for a rare antigen as long as the two antigens share a NEpi (unique position/amino acid combination). 5. The probability of mismatching on 58 NEpis based on published phenotype frequencies was calculated. We called this the NEpi mismatch model. 6. Both the antigen mismatch model and the NEpi mismatch model were compared to observed antibody specificity frequencies in our study population. Overall, the NEpi mismatch model correlated with observed frequencies much more accurately than the traditional antigen mismatch model. 7. In conclusion, we present a probable explanation for higher-than-expected antibody specificity frequencies and propose that mismatching on NEpis has further potential clinical implications.
    Clinical transplants 02/2006;
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    ABSTRACT: 1. We utilize single-antigen beads to test 103 pre-transplant patients to discern HLA antibody specificity frequencies. 2. Overall, we found much higher levels of immunization to HLA than anticipated, particularly rare specificities. We postulate that the presence of epitopes and mismatching on epitopes are responsible for these higher levels of immunization. 3. Two models were generated: (A) The first was an antigen mismatch model representing the traditional theory that higher rates of immunization to an antigen would occur with a higher incidence of the antigen within the population. This model was based on published gene frequencies (4), which were converted into antigen frequencies. (B) The second model was an epitope mismatch model based on published gene frequencies (4) as well as experimentally proven epitopes (3). 4. These two models were then compared with observed antibody specificity frequencies. The antigen mismatch model consistently underestimated observed frequencies. On the other hand, the epitope mismatch model seems to be a much better representation of observed frequencies. 5. In conclusion, we bring attention to the occurrence of higher-than-expected frequencies of antibodies against HLA, especially rare antigens like A43 and B76, and we show that mismatched epitopes might provide a plausible explanation for these observed high frequencies.
    Clinical transplants 02/2006;