Biomedical subjects

Mary S Leffell

Publications and source records attributed to Mary S Leffell.

9 recordsLinked to original sources

PubMed2006

HLA-DR4 in families with autism.

Autoimmune disorders are observed with increased frequency among parents of individuals with autism, particularly mothers. Because there is evidence supporting an association between autoimmune disorders and specific alleles of the human leukocyte antigen (HLA) system, we examined HLA types and subtypes in families with autism. Two groups were studied: 16 families selected from a geographically defined area in eastern Tennessee have males with a diagnosis of autism; and 33 families selected across all regions in the United States have multiple males having autism diagnosis. The HLA-DR4 frequencies of mothers, fathers, and children in these two groups were compared with a reference series of 475 normal, unrelated Caucasians. Results of HLA typing indicated that mothers and their sons in the geographically defined group had a significantly higher frequency of DR4 than normal control subjects (odds ratio = 5.54, 95% confidence interval = 1.74-18.67 and odds ratio = 4.20, 95% confidence interval = 1.37-13.27, respectively). No significant difference in the distribution of HLA alleles was evident between the United States-all region group and control subjects. Findings of this study are consistent with a hypothesis that prenatal maternal-fetal immune interaction can affect fetal brain development in a population residing in a geographically defined region. Such immune interactions may involve HLA and related genes in both genetic and epigenetic mechanisms during pregnancy.

Adult↗

PubMed2005

Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation.

CONTEXT: First proposed 2 decades ago, live kidney paired donation (KPD) was considered a promising new approach to addressing the shortage of organs for transplantation. Ethical, administrative, and logistical barriers initially proved formidable and prevented the implementation of KPD programs in the United States. OBJECTIVE: To determine the feasibility and effectiveness of KPD for the management of patients with incompatible donors. DESIGN, SETTING, AND PATIENTS: Prospective series of paired donations matched and transplanted from a pool of blood type or crossmatch incompatible donors and recipients with end-stage renal disease (6 conventional and 4 unconventional KPD transplants) at a US tertiary referral center (between June 2001 and November 2004) with expertise in performing transplants in patients with high immunologic risk. INTERVENTION: Kidney paired donation and live donor renal transplantation. MAIN OUTCOME MEASURES: Patient survival, graft survival, serum creatinine levels, rejection episodes. RESULTS: A total of 22 patients received transplants through 10 paired donations including 2 triple exchanges at Johns Hopkins Hospital. At a median follow-up of 13 months (range, 1-42 months), the patient survival rate was 100% and the graft survival rate was 95.5%. Twenty-one of the 22 patients have functioning grafts with a median 6-month serum creatinine level of 1.2 mg/dL (range, 0.8-1.8 mg/dL) (106.1 micromol/L [range, 70.7-159.1 micromol/L]). There were no instances of antibody-mediated rejection despite the inclusion of 5 patients who were highly sensitized to HLA antigens due to previous exposure to foreign tissue. Four patients developed acute cellular rejection (18%). CONCLUSIONS: This series of patients who received transplants from a single-center KPD pool provides evidence that recipients with incompatible live donors, even those with rare blood type combinations or high degrees of HLA antigen sensitization, can receive transplants through KPD with graft survival rates that appear to be equivalent to directed, compatible live donor transplants. If these results can be generalized, broader availability of KPD to the estimated 6000 patients with incompatible donors could result in a large expansion of the donor pool.

Adolescent↗

PubMed2005

Factors associated with and predictive of persistence of donor-specific antibody after treatment with plasmapheresis and intravenous immunoglobulin.

Antibody to donor HLA antigens is a significant barrier to both access to and outcome of allogeneic transplants. Many attempts have been made to desensitize patients with HLA-specific antibody, but the most effective and durable have been treatment with high-dose pooled human intravenous immunoglobulin (IVIg) and a combination of plasmapheresis and low-dose IVIg. Despite the success of these treatments, low levels of donor-specific antibody (DSA) persist in some patients. We examined factors that may be related to and used to predict the elimination of DSA. The most significant associations have been strength of antibody at initiation of treatment and antibody specificity, although other factors revealed a trend toward association. We demonstrate how the types of data generated here can be used to predict elimination or persistence of DSA.

Antibody Specificity↗

PubMed2005

A computer match program for paired and unconventional kidney exchanges.

The number of renal transplants can be increased by implementing an exchange program involving donor-recipient pairs for whom the donors are each incompatible with their original patient but compatible with each other's patient. The number can be further increased if the exchanges are not limited to ABO incompatible pairs or combinations of two donor-recipient pairs. However, as the number of donor-recipient pairs willing to participate in such a program increases, there is a substantial increase in both the time taken to identify such matches and the potential for error. We have developed a computer program that accounts for ABO and HLA compatibility and is not limited to two-way exchanges. With our database of 60 patients and 83 donors, we have been able to identify 122 two-way and 1230 three-way exchanges with an average run time of 30 s.

ABO Blood-Group System↗

PubMed2004

HLA alleles and haplotypes among the Lakota Sioux: report of the ASHI minority workshops, part III.

Human leukocyte antigen (HLA) class I and II alleles were defined for 302 Lakota Sioux American Indians as part of the American Society for Histocompatibility and Immunogenetics coordinated studies on minority populations. The study group was comprised of adult volunteers from the Cheyenne River and Ogala Sioux tribes residing, respectively, on the Cheyenne River and Pine Ridge Reservations in South Dakota. Of the participants, 263 (87%) claimed full American Indian ancestry through both maternal and paternal grandparents. The study group included 25 nuclear families that were informative for genotyping. HLA phenotypes from 202 adults with no other known first-degree relative included in the study were used for calculation of allele and haplotype frequencies by maximum likelihood estimation. HLA-A, -B, and -Cw alleles were found to be in Hardy Weinberg equilibrium. Deviation from equilibrium was observed for DRB1 alleles (p=0.01), but could be attributed to the sample size and the occurrence of some genotypes with low expected frequencies. Polymorphism among the Sioux was limited with four to seven alleles comprising >80% of those observed at each locus. Several alleles were found at high frequency (0.05-0.30) among the Sioux that are also prevalent in other Native Americans and Alaska Natives, including: A*2402, *3101, and *0206; B*3501,*3901, *5101, and *2705; Cw*0702, *0404, and *03041; DRB1*0407, *0404, *1402, and *16021; and DQB1*0301, *0302, and *0402. DRB1*0811, which has been only previously described in Navajo and Tlingit Indians, was found to occur at a frequency of 0.119 among the Sioux. Two new alleles were defined among the Sioux: Cw*0204 and DRB1*040703, which were found in two and four individuals, respectively. In the haplotype analyses, significant linkage disequilibrium (p<0.00001) was seen in all pairwise comparisons of loci and numerous two and three locus haplotypes were found to have strong, positive linkage disequilibrium values. The two most common extended haplotypes among the Sioux, determined by maximum likelihood estimation and genotyping were: A*31012, B*3501, Cw*0404, DRB1*0407; and A*24021, B*3501, Cw*0404, DRB1*0404.

Adult↗

PubMed2004

TNF-alpha, TGF-beta, IL-10, IL-6, and INF-gamma alleles among African Americans and Cuban Americans. Report of the ASHI Minority Workshops: Part IV.

Point mutations or single nucleotide substitutions in the regulatory regions of cytokine genes may affect levels of cytokine expression and have been associated with acute and chronic rejection in organ transplantation, severity of graft-versus-host disease in hematopoietic stem cell transplants, and predisposition to autoimmune disorders. Because these cytokine variants have been studied primarily among Caucasians, we defined the alleles and frequencies of five cytokines among 691 unrelated, adult African Americans and 296 Cuban Americans in the American Society for Histocompatibility/National Institutes of Health Minority HLA Workshops. The genotypes of all cytokines, except for transforming growth factor (TGF)-beta among African Americans, were found to be in Hardy-Weinberg's equilibrium. Genotype frequencies among African American and Cuban American participants were compared with those of 75 North American Caucasian bone marrow donors and with published frequencies. Significant differences were observed in all comparisons except between Cuban and Caucasian Americans for alleles of interferon (IFN)-gamma, interleukin (IL)-6, and IL-10. The most notable differences were in genotype frequencies of African Americans compared with those of the two other populations. The frequency of the IFN-gamma genotype A/A, which is associated with low expression, was significantly higher in African Americans than in Caucasian or Cuban Americans (0.66 vs 0.37 and 0.26, respectively; p < 0.0001 for both comparisons). The high-expression G/G genotype for IL-6 was more than twice as prevalent among African Americans as among Caucasians and 1.5 times more frequent than among Cuban Americans (respective frequencies: 0.85 vs 0.38 and 0.49; p < 0.0001 for both comparisons). In African Americans, the frequency of the high-expression genotype for IL-10, GCC/GCC, was approximately half that of the frequency in Cuban and Caucasian Americans (0.10 vs 0.19 and 0.23, respectively; p < 0.0001, p = 0.004). Because levels of expression can affect inflammation and immune regulation, differences in cytokine allele frequencies between racial or ethnic groups may contribute to different incidences of autoimmunity and allograft rejection.

Adult↗

PubMed2004

Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers.

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor-specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post-transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.

ABO Blood-Group System↗

PubMed2003

Specific and durable elimination of antibody to donor HLA antigens in renal-transplant patients.

BACKGROUND: Donor-specific antibody (DSA) is the major barrier to success of kidney transplants. Attempts to deal with this problem have used plasmapheresis to remove antibodies or high-dose pooled immunoglobulin (IVIg) to down-regulate DSA. However, elimination of antibodies by these methods has been limited in duration or scope. METHODS: We have confirmed the presence of immunoglobulin (Ig)G antibody to one or more donor HLA antigens in 49 patients treated with alternate-day, single-volume plasmapheresis followed by low-dose cytomegalovirus (CMV) hyperimmune globulin (CMV-Ig) combined with quadruple immunosuppression. We examined the effect of the treatment protocol on antibodies to donor HLA, third-party HLA, and nominal antigens. RESULTS: At the end of treatment, 63% of patients had lost antibody to donor HLA, whereas only 27% had lost antibody to third-party HLA (P<0.001). More strikingly, loss of antibody to donor and third-party HLA antigens occurred in 89% and 19%, respectively, of patients followed for 2 or more months after end of treatment (P<0.0001). No elimination of antiviral antibodies tested was seen. With one exception, elimination of DSA appeared to be independent of antibody titer or specificity, the number of different antibody specificities, or whether or not the target antigen was a repeat mismatch. The effect appears to be long lasting, with no return of DSA observed in patients followed for an average of 13 months. CONCLUSIONS: Plasmapheresis and low-dose CMV-Ig combined with traditional immunosuppression is effective in producing a specific and durable elimination of antibody to donor HLA.

Antibody Formation↗

PubMed2002

HLA antigens, alleles and haplotypes among the Yup'ik Alaska natives: report of the ASHI Minority Workshops, Part II.

As part of the American Society for Histocompatibility and Immunogenetics coordinated studies among minority populations, human leukocyte antigen (HLA) alleles were defined for 460 volunteer Yup'ik Eskimos from the Yukon Kuskokwim delta region of southwestern Alaska. The study group included 252 adults with no other first-degree relatives and 48 informative nuclear families. Full Yupik ancestry through both maternal and paternal grandparents was claimed by 81.1% of participants. HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles were determined by SBT, SSOP, reverse SSOP, and/or RSCA according to the protocols of five participating laboratories. Polymorphism was limited with 3-6 alleles comprising > 80% of the alleles observed at each locus. Homozygosity was high, particularly at the HLA-A and -DQB1 loci, with 36.6% and 44% of individuals having a single allele defined at these respective loci. HLA-A, -B, and -DRB1 alleles were in Hardy-Weinberg equilibrium, whereas HLA-Cw and -DQB1 alleles gave significant deviation (p = 0.002; 0.005). Significant linkage disequilibrium (p < or = 0.00001) was observed in all pairwise evaluations. A new Cw*0806 allele was observed in high linkage disequilibrium with B*4801(Delta = 0.099; Delta(rel) = 1.0). Three extended haplotypes were found to have frequencies > 5%, the most prevalent being A*2402; B*4801; DRB1*0401; DQB1*0301 (0.0933). Comparison of available class I data indicate that the Yup'ik share several common alleles with other Native American populations, including: A*2402, *0206, *6801; B*1501, *2705, *3501, *4002, *4801, *5101; and Cw*0202, *0304, *0401. Comparisons of class II data also confirm a close relationship of the Yup'ik to two other Eskimo populations, Siberian and East Greenland Eskimos. DRB1*0401 and *1101, which occur in high frequency among these Eskimo populations, but not in other Native Americans, were also prevalent among the Yup'ik, with respective frequencies of 0.232 and 0.107.

Alaska↗