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Biomedical subjects

P I Terasaki

Publications and source records attributed to P I Terasaki.

At least 19 recordsLinked to original sources
PubMed2007

Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival.

In 2002, 1329 patients with functioning transplants were prospectively tested for HLA antibodies in the 13th International Histocompatibility Workshop. Four years after testing, deceased donor graft survival among 806 patients not having antibodies in 2002 was 81% compared to 58% for 158 patients with HLA antibodies (p < 0.0001) and 72% for 69 patients with MICA antibodies (p = 0.02). Hazard ratio (HR) using death-censored graft survival from multivariate analysis of HLA antibodies was 3.3 (p < 0.00001) and 2.04 for MICA (p = 0.01). In the 14th Workshop, at 1 year follow-up, survival for 1319 patients receiving deceased donor grafts and no HLA antibodies was 96% compared to 94% for 344 patients with HLA antibodies (p = 0.0004) and 83% survival for 33 patients with MICA (p = 0.0005). HR from multivariate analysis: HLA antibodies was 3.6 (p < 0.00001) and 6.1 for MICA (p = 0.006). Twelve patients with donor specific antibodies tested by single antigen beads had a 1 year survival of 64% (p = 0.008), and 27 patients with non-donor specific 'strong' antibodies had a 66% survival (p = 0.0003) compared to 92% survival in those with no antibodies. In conclusion, these two prospective trials, after 1 and 4 years, provided strong evidence that HLA and MICA antibodies are associated with graft failure.

Antibodies↗
PubMed2006

Soluble HLA-G expression and renal graft acceptance.

HLA-G is a potentially interesting molecule associated with immunosuppressive function. We survey here the presence of soluble HLA-G (sHLA-G) in serial serum samples of renal transplants. A total of 330 sera of from 65 patients were tested for sHLA-G with ELISA. IgG/IgM antibodies to HLA, and MICA antibodies were also previously tested. After serial analysis of the 65 patients' 330 sera, 50% of 26 patients in functioning group had consistent sHLA-G expression or became positive, in comparison to 20.5% among 39 patients who rejected their transplants (p=0.013). Thus sHLA-G was associated with functioning transplants. Eighty percent (77 of 96) of the HLA IgG positive sera had no sHLA-G expression, while 81.4% (83 of 102) of the HLA-G(+) sera had no HLA IgG (p=0.005), which showed a negative association between sHLA-G and the presence of HLA IgG antibodies (which was previously been shown to be associated with failure). In this preliminary survey, sHLA-G was found in the serum of about 30% of renal transplant patients. sHLA-G had a negative association with allograft failure from chronic rejection, and a negative relationship with the production of HLA IgG antibodies. The significance of sHLA-G in renal transplants remains to be determined.

Adult↗
PubMed2006

No improvement in long-term liver transplant graft survival in the last decade: an analysis of the UNOS data.

We analyzed change in outcomes during two successive 5-year periods (period I = 1992-1996 vs period II = 1997-2002) among 35 186 deceased adult liver transplant recipients reported to the United Network for Organ Sharing (UNOS) Registry. The 5-year graft survival was 67.4% in the first period and 67.5% in the second, though the 1-year survival had improved from 81.0 to 83.5%. Comparison of blended survival rates during the two study periods showed decreased long-term graft survival in period II, explicable by an increased number of hepatitis C virus cirrhosis (HCV) patients and an increase in patients with HCV antibodies (HCVab) during this later period. Analysis wherein these patients with HCV were excluded revealed the same long-term graft survival during both periods. Non-HCV patients who had HCVab also had worse 5-year graft survival. We conclude that hepatitis C prevented improved outcomes during period II and that improved, more effective, treatment for hepatitis C virus would have great positive impact on overall survival of liver transplant recipients.

Follow-Up Studies↗
PubMed2006

Development of nondonor-specific HLA-DR antibodies in allograft recipients is associated with shared epitopes with mismatched donor DR antigens.

Our previous studies showed that not only donor-specific antibodies (DSA) but also nondonor-specific antibodies (NDSA) were detected in the peripheral blood of allograft recipients. The molecular mechanism involved in the development of NDSA is examined here. HLA class II single antigen (SA) beads were used to determine the presence of HLA DR-specific antibodies in renal transplant recipients with failed allografts. Sequence-based antibody-epitope mapping was determined by the comparison of the reaction profiles of different SA recombinant cell lines containing unique epitope pattern. We found that 22 out of 65 recipients with failed grafts developed antibodies against donor HLA DR that is a mismatch with the recipient. Three of them had only DSA while 19 patients had not only DSA but also NDSA. An average of 77.3% of NDSA reacted with targets that share amino acid sequence with mismatched donor DR antigens. Either surface or nonsurface amino acid residues may constitute an antibody epitope. In conclusion, development of NDSA in allograft recipients may be associated with shared amino acids with mismatched donor antigens. SA beads technique not only helps to determine antibody specificities but also provides an ideal approach for the identification of potential HLA antibody epitopes.

Epitopes↗
PubMed2005

HLA antibody identification with single antigen beads compared to conventional methods.

Single antigen (SA) beads coated with Class I HLA antigens from recombinant cells lines were tested with 170 mouse monoclonal antibodies (mAbs). The HLA specificities of all mAbs were previously determined by the cytotoxicity assay (CDC). There were 100 mAbs which produced the expected reactions with the SA beads, indicating that the SA beads coated with the antigens had reacted properly. Sixty one mAbs were positive with one or more antigen(s) that shared unique amino acids (aa) possibly constituting a common epitope. Single antigen beads were then tested on 58 alloantisera analyzed by 63 laboratories of the UCLA serum exchange (UCLA-SE). Many specificities detected by the single antigen beads were missed by the laboratories employing conventional methods. Most of the missed specificities were of lower frequency, although in some instances, even common specificities were missed. These findings have important implications regarding the use of specificities to predict positive crossmatch, to selecting platelet donors for highly sensitized recipients, and analysis of sera for donor specific antibodies.

Animals↗
PubMed2001

Annual trends and triple therapy--1991-2000.

1. Although the number of cadaver donor transplants did not increase substantially over the past 10 years, unrelated living donor grafts increased from 153 in 1991 to 1,661 through 2000. Use of spousal and other unrelated donor organs contributed to this increase. There was a modest increase in living-related donor transplants from 2,328 in 1991 to 3,451 in 2000. 2. Cadaver donor graft survival at one year improved from 84% in 1991 to 90% in 2000. In contrast, one-year graft survival of living donor transplants only improved from 93% in 1991 to 95% in 2000. 3. Throughout the 10-year period, approximately 13% of transplants were repeat transplants from cadaver donors and roughly 8% were regrafts from live donors. 4. Cadaver donor transplants into White recipients declined from 68% in 1991 to 60% in 2000. For living donors, the percentage of White patients remained constant at about 70%. 5. Graft survival in patients of all races was about equal at one year but diverged at 3 years, with Asians having the highest and Blacks having the lowest 3-year graft survival rates. 6. Average donor age increased from 31.7 in 1991 to 36 in 2000 for cadaveric donor transplants and 37.9 in 1991 to 40.4 in 2000 for living donor transplants. Cadaveric kidneys from donors older than 50 years of age yielded significantly lower 3-year graft survival. 7. Average recipient age for cadaveric donor transplants increased from 42.1 in 1991 to 46.8 in 2000. The average recipient age for living donor transplants also increased steadily from 33.7 in 1991 to 42.9 in 2000. There was relatively little effect on graft survival rates for advanced age recipients. 8. The percentage of sensitized recipients receiving cadaver donor grafts declined from 27% in 1991 to 21% in 2000. Similarly, sensitized recipients receiving living donor grafts decreased from 17% in 1991 to 13% in 2000. Graft survival in patients with more than 50% PRA was lower at 3 years for patients receiving cadaveric donor grafts. Highly sensitized patients receiving living donor grafts had graft survival rates similar to those who were not sensitized. 9. Cold ischemia times decreased from an average of 24.2 hours in 1991 to 18.9 hours in 2000. Improved graft survival rates over those 10 years were noted in all groups, and even cold ischemia times more than 36 hours yielded 3-year graft survivals comparable to those with lower cold ischemia times in 1998. 10. The need for dialysis has remained constant at about 23% over the last 10 years for patients receiving kidneys from cadaveric donors. The rate of dialysis for patients receiving kidneys from living donors was about 5% for each of the 10 years examined. First day anuria increased from 11% in 1991 to 16% in 2000 for cadaver donor transplants and 3% in 1999 to 5% in 2000 for living donor grafts. 11. Cadaveric donor patients requiring dialysis had a 3-year graft survival rate of 63% if there was no first day anuria and 56% if they had first day anuria. This is in contrast to 80% 3-year graft survival for those with immediate diuresis and no need for dialysis. The 3-year graft survival rate for those receiving living donor grafts and needing dialysis was 58% if they had first day diuresis and 41% if they ware anuric on the first day. Conversely, those who had first day function and did not require dialysis had 89% 3-year graft survival. 12. Among the patients receiving cadaveric grafts with first day diuresis there was a marked reduction in those with rejection, from 21% in 1991 to 5% in 2000. Similarly, for this type of patient receiving living donor grafts, the reduction was 17% in 1991 to 5% in 2000. However, graft survival among these patients did not change significantly. The greatest improvement was noted in those with first day anuria and no rejection. 13. Patients who did not require dialysis, and had rejection prior to discharge decreased markedly from 17% in 1991 to 3% in 2000 in those receiving cadaveric grafts and 15% in 1991 to 3.9% in 2000 for those receiving living donors. Graft survival of cadaveric transplants in those needing dialysis, with and without rejection, improved the most in the 10 year period. 14. Hospitalization days for cadaveric transplant recipients were reduced from 19 days in 1991 to 10 days in 2000 and 16 days in 1991 to 8 days in 2000 for recipients of living donor grafts. There was an increase in discharge serum creatinine values from 2.3 mg/dl in 1991 to 3.3 mg/dl in 2000 for cadaver donor grafts. 15. Double therapy was utilized for about 15% of cadaveric and living donors. There was a sharp increase in induction therapy, peaking at 51% in 1994 and decreasing to 5% by 2000 for cadaveric donor transplants. Induction did not improve graft survival for either cadaver or living donor transplant recipients. 16. Triple therapy improved graft survival of White and Black patients, but did not affect the half-lives in either race. 17. The lower graft survival from older donors was not affected by triple therapy for cadaver donor transplants. Triple therapy removed the donor age effect for recipients of living donor grafts. 18. Triple therapy practically eliminated the effect of sensitization for cadaveric donor grafts. Both double and triple therapy virtually eliminated the sensitization effect for living donors. 19. Triple therapy significantly improved the survival of kidneys with more than 36 hours cold ischemia time so that 3-year graft survival was 76% at 3 years compared with 81% for kidneys stored 1-12 hours. 20. Triple therapy improved the 3-year graft survival of kidneys with first day anuria from 50% for double therapy to 69% for triple therapy in cadaver donor transplants. For living donor transplants, there was a similar improvement from 57% with double therapy to 72% with triple therapy. 21. Triple therapy improved the 3-year cadaveric graft survival rate of kidneys requiring dialysis from 51% with double therapy to 67% for triple therapy. There was a similar improvement for living donors needing dialysis from 37% to 61% at 3 years.

Adolescent↗
PubMed2001

Sensitization 2001.

1. The rate of transfusion decreased from 64% in 1992 to 36% in 2000. This need for transfusions continued despite the introduction of erythropoetin. Females were transfused more frequently than males. SLE patients were transfused more often than those with other diseases. 2. Transfusions no longer had a beneficial effect on the outcome of transplantation, but rather with more transfusions, the graft outcome became lower, as might be expected. 3. Rejection of a kidney transplant had the strongest effect on sensitization, followed by transfusion and then pregnancies. Females were more susceptible to sensitization than males. Although non-transfused males should not have been sensitized, as many as 13% were reported to have antibodies. As many as 20% of nulliparous females without transfusions also were reported to have antibodies. 4. SLE patients were most often sensitized among patients with various diseases. Females of all diseases were more sensitized than males. 5. Unsensitized regraft patients had a 3% lower 3-year graft survival than unsensitized first graft patients. Among sensitized patients, regraft patients had a 4% lower graft survival than sensitized first graft patients. 6. Patients with polycystic kidney disease had the highest 3-year graft survival in both the sensitized and non-sensitized patients. Sensitization to a PRA level of less than 50% was not detrimental to patients with all the various diseases. 7. For cadaver donor regraft patients, HLA-DR mismatch had a greater effect than AB mismatch. There was a 10 percentage point lower 3-year graft survival in cadaver donor regraft patients mismatched for 2 DR antigens than mismatched for 0 DR antigens. 8. For living donor transplants, regrafts from 0 AB or 0 DR mismatched transplants had the same graft survival as first transplants.

Blood Transfusion↗
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↗
PubMed2000

Longmire lecture: my 50 years at the University of California, Los Angeles.

The main concept driving my work has been the humoral theory of immunity to allografts. It led to the development of the microlymphocytotoxicity test, which is used to look for the relevant transplant antigens using alloantisera. Using alloantibodies produced by pregnancies, the HLA system was defined through a series of international histocompatibility workshops. It was then shown that the HLA system was important for matching donors and recipients for bone marrow transplants and organ transplants. More than 6000 HLA-matched kidney transplants from cadaver donors have now been shared in the United States. HLA antigens were found to be of importance in anthropologic and disease susceptibility studies. Currently HLA antibodies are being studied intensively to determine their role in chronic rejection. If it is proven that these antibodies trigger intimal proliferation, occluding arterioles, HLA antibodies will become essential to the monitoring of chronic rejection.

Academic Medical Centers↗
PubMed2000

Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles.

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.

Animals↗
PubMed2000

HLA-B*4012: a new allele with unique serological features.

We have defined the new allele HLA-B*4012, which had been isolated from a black individual. It was initially recognized as a serologically unique allele when typing her father for renal transplantation. The HLA class I phenotype was A*0201,*6602; B*4001,*4012; Bw6; Cw*0304,*1505. Sequencing from exon 1 through intron 3 of B*4012 was performed. B*4012 is identical to B*4001 and B*4010 in exon 3, and in the 3' part of exon 2, but it is unique in that exon 1 and the 5' part of exon 2 are identical to B*1503, B*1509, B*1510, B*1518, B*1523, and B*1529. The generation of this allele is best explained by a recombination event in exon 2 (break point between nucleotides 205 and 222 from the beginning of the coding region) of B*4001 or B*4010 with one of these B*15 variants as a donor allele. Its unique serological feature (B48, B60, B70, and B72 reactivity) is consistent with the sequence data of its donor alleles.

Alleles↗