Peter Parham

Stanford University, Stanford, California, United States

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Publications (317)2962.92 Total impact

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    ABSTRACT: MHC haplotypes of humans and the African great ape species have one copy of the MHC-A, -B, and -C genes. In contrast, MHC haplotypes of orangutans, the Asian great ape species, exhibit variation in the number of gene copies. An in-depth analysis of the MHC class I gene repertoire in the two orangutan species, Pongo abelii and Pongo pygmaeus, is presented in this article. This analysis involved Sanger and next-generation sequencing methodologies, revealing diverse and complicated transcription profiles for orangutan MHC-A, -B, and -C. Thirty-five previously unreported MHC class I alleles are described. The data demonstrate that each orangutan MHC haplotype has one copy of the MHC-A gene, and that the MHC-B region has been subject to duplication, giving rise to at least three MHC-B genes. The MHC-B*03 and -B*08 lineages of alleles each account for a separate MHC-B gene. All MHC-B*08 allotypes have the C1-epitope motif recognized by killer cell Ig-like receptor. At least one other MHC-B gene is present, pointing to MHC-B alleles that are not B*03 or B*08. The MHC-C gene is present only on some haplotypes, and each MHC-C allotype has the C1-epitope. The transcription profiles demonstrate that MHC-A alleles are highly transcribed, whereas MHC-C alleles, when present, are transcribed at very low levels. The MHC-B alleles are transcribed to a variable extent and over a wide range. For those orangutan MHC class I allotypes that are detected by human monoclonal anti-HLA class I Abs, the level of cell-surface expression of proteins correlates with the level of transcription of the allele.
    No preview · Article · Dec 2015 · The Journal of Immunology
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    ABSTRACT: Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV-negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation.
    No preview · Article · Sep 2015 · The Journal of Immunology
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    ABSTRACT: Chimpanzees have orthologs of the six fixed, functional human MHC class I genes. But, in addition, the chimpanzee has a seventh functional gene, Patr-AL, which is not polymorphic but contributes substantially to population diversity by its presence on only 50% of MHC haplotypes. The ancestral AL gene emerged long before the separation of human and chimpanzee ancestors and then subsequently and specifically lost function during human evolution, but was maintained in chimpanzees. Patr-AL is an alloantigen that participates in negative and positive selection of the T cell repertoire. The three-dimensional structure and the peptide-binding repertoire of Patr-AL and HLA-A*02 are surprisingly similar. In contrast, the expression of these two molecules is very different, as shown using specific mAbs and polyclonal Abs made against Patr-AL. Peripheral blood cells and B cell lines express low levels of Patr-AL at the cell surface. Higher levels are seen for 221-cell transfectants expressing Patr-AL, but in these cells a large majority of Patr-AL molecules are retained in the early compartments of the secretory pathway: mainly the endoplasmic reticulum, but also cis-Golgi. Replacing the cytoplasmic tail of Patr-AL with that of HLA-A*02 increased the cell-surface expression of Patr-AL substantially. Four substitutions distinguish the Patr-AL and HLA-A*02 cytoplasmic tails. Systematic mutagenesis showed that each substitution contributes changes in cell-surface expression. The combination of residues present in Patr-AL appears unique, but each individual residue is present in other primate MHC class I molecules, notably MHC-E, the most ancient of the functional human MHC class I molecules.
    No preview · Article · Sep 2015 · The Journal of Immunology
  • Peter Parham

    No preview · Article · Sep 2015 · Immunological Reviews
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    ABSTRACT: Shaping natural killer (NK) cell functions in human immunity and reproduction are diverse killer cell immunoglobulin-like receptors (KIRs) that recognize polymorphic MHC class I determinants. A survey of placental mammals suggests that KIRs serve as variable NK cell receptors only in certain primates and artiodactyls. Divergence of the functional and variable KIRs in primates and artiodactyls predates placental reproduction. Among artiodactyls, cattle but not pigs have diverse KIRs. Catarrhine (humans, apes, and Old World monkeys) and platyrrhine (New World monkeys) primates, but not prosimians, have diverse KIRs. Platyrrhine and catarrhine systems of KIR and MHC class I are highly diverged, but within the catarrhines, a stepwise co-evolution of MHC class I and KIR is discerned. In Old World monkeys, diversification focuses on MHC-A and MHC-B and their cognate lineage II KIR. With evolution of C1-bearing MHC-C from MHC-B, as informed by orangutan, the focus changes to MHC-C and its cognate lineage III KIR. Evolution of C2 from C1 and fixation of MHC-C drove further elaboration of MHC-C-specific KIR, as exemplified by chimpanzee. In humans, the evolutionary trajectory changes again. Emerging from reorganization of the KIR locus and selective attenuation of KIR avidity for MHC class I are the functionally distinctive KIR A and KIR B haplotypes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    No preview · Article · Sep 2015 · Immunological Reviews
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    ABSTRACT: The human killer cell Ig-like receptor (KIR) locus comprises two groups of KIR haplotypes, termed A and B. These are present in all human populations but with different relative frequencies, suggesting they have different functional properties that underlie their balancing selection. We studied the genomic organization and functional properties of the alleles of the inhibitory and activating HLA-C receptors encoded by KIR haplotypes. Because every HLA-C allotype functions as a ligand for KIR, the interactions between KIR and HLA-C dominate the HLA class I-mediated regulation of human NK cells. The C2 epitope is recognized by inhibitory KIR2DL1 and activating KIR2DS1, whereas the C1 epitope is recognized by inhibitory KIR2DL2 and KIR2DL3. This study shows that the KIR2DL1, KIR2DS1, and KIR2DL2/3 alleles form distinctive phylogenetic clades that associate with specific KIR haplotypes. KIR A haplotypes are characterized by KIR2DL1 alleles that encode strong inhibitory C2 receptors and KIR2DL3 alleles encoding weak inhibitory C1 receptors. In striking contrast, KIR B haplotypes are characterized by KIR2DL1 alleles that encode weak inhibitory C2 receptors and KIR2DL2 alleles encoding strong inhibitory C1 receptors. The wide-ranging properties of KIR allotypes arise from substitutions throughout the KIR molecule. Such substitutions can influence cell surface expression, as well as the avidity and specificity for HLA-C ligands. Consistent with the crucial role of inhibitory HLA-C receptors in self-recognition, as well as NK cell education and response, most KIR haplotypes have both a functional C1 and C2 receptor, despite the considerable variation that occurs in ligand recognition and surface expression. Copyright © 2015 by The American Association of Immunologists, Inc.
    No preview · Article · Aug 2015 · The Journal of Immunology
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    ABSTRACT: Modulating natural killer cell functions in human immunity and reproduction are diverse interactions between the killer cell immunoglobulin-like receptors (KIR) of Natural Killer (NK) cells and HLA class I ligands on the surface of tissue cells. Dominant interactions are between KIR2DL1 and the C2 epitope of HLA-C and between KIR2DL2/3 and the C1 epitope of HLA-C. KhoeSan hunter-gatherers of Southern Africa represent the earliest population divergence known and are the most genetically diverse indigenous people, qualities reflected in their KIR and HLA genes. Of the ten KhoeSan KIR2DL1 alleles, KIR2DL1*022 and KIR2DL1*026 likely originated in the KhoeSan, and later were transmitted at low frequency to the neighboring Zulus through gene flow. These alleles arose by point mutation from other KhoeSan KIR2DL1 alleles that are more widespread globally. Mutation of KIR2DL1*001 gave rise to KIR2DL1*022, causing loss of C2 recognition and gain of C1 recognition. This makes KIR2DL1*022 a more avid and specific C1 receptor than any KIR2DL2/3 allotype. Mutation of KIR2DL1*012 gave rise to KIR2DL1*026, causing premature termination of translation at the end of the transmembrane domain. This makes KIR2DL1*026 a membrane-associated receptor that lacks both a cytoplasmic tail and signaling function. At higher frequencies than their parental allotypes, the combined effect of the KhoeSan-specific KIR2DL1*022 and KIR2DL1*026 is to reduce the frequency of strong inhibitory C2 receptors and increase the frequency of strong inhibitory C1 receptors. Because interaction of KIR2DL1 with C2 is associated with risk of pregnancy disorder, these functional changes are potentially advantageous. Whereas all other KhoeSan KIR2DL1 alleles are present on a wide diversity of centromeric KIR haplotypes, KIR2DL1*026 is present on a single KIR haplotype and KIR2DL1*022 is present on two very similar haplotypes. The high linkage disequilibrium across their haplotypes is consistent with a recent emergence for these KIR2DL1 alleles that have distinctive functions
    Full-text · Article · Aug 2015 · PLoS Genetics
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    ABSTRACT: We conducted a nationwide study comparing self-identification to genetic ancestry classifications in a large cohort (n = 1752) from the National Marrow Donor Program. We sought to determine how various measures of self-identification intersect with genetic ancestry, with the aim of improving matching algorithms for unrelated bone marrow transplant. Multiple dimensions of self-identification, including race/ethnicity and geographic ancestry were compared to classifications based on ancestry informative markers (AIMs), and the human leukocyte antigen (HLA) genes, which are required for transplant matching. Nearly 20% of responses were inconsistent between reporting race/ethnicity versus geographic ancestry. Despite strong concordance between AIMs and HLA, no measure of self-identification shows complete correspondence with genetic ancestry. In certain cases geographic ancestry reporting matches genetic ancestry not reflected in race/ethnicity identification, but in other cases geographic ancestries show little correspondence to genetic measures, with important differences by gender. However, when respondents assign ancestry to grandparents, we observe sub-groups of individuals with well- defined genetic ancestries, including important differences in HLA frequencies, with implications for transplant matching. While we advocate for tailored questioning to improve accuracy of ancestry ascertainment, collection of donor grandparents' information will improve the chances of finding matches for many patients, particularly for mixed-ancestry individuals.
    Full-text · Article · Aug 2015 · PLoS ONE
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    Full-text · Dataset · Aug 2015
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    ABSTRACT: Infection of humans and chimpanzees with Hepatitis C virus (HCV) results in either the resolution of the acute infection or its progression to a persistent infection associated with chronic liver disease. In cohorts of human patients, resolution of HCV infection has been associated with homozygosity for both C1+HLA-C and its cognate inhibitory receptor, KIR2DL3. Compared here are the killer cell immunoglobulin-like receptors (KIR) and major histocompatibility complex (MHC) class I factors of chimpanzees who resolve, or resist, HCV infection with those chimpanzees who progress to chronic infection. Analysis of Pt-KIR gene content diversity associated two of the 12 Pt-KIR with clinical outcome. Activating Pt-KIR3DS2 and inhibitory Pt-KIR2DL9 are strong receptors specific for the C2 epitope. They are encoded by neighboring genes within the Pt-KIR locus that are in strong linkage disequilibrium. HCV-infected chimpanzees with KIR genotypes containing Pt-KIR3DS2 and KIR2DL9 are significantly more likely to progress to chronic infection than infected chimpanzees lacking the genes (p = 0.0123 and p = 0.0045, respectively), whereas human HLA-B allotypes having the C1 epitope are unusual, such allotypes comprise about one quarter of the chimpanzee Patr-B allotypes. Homozygous C1 + Patr-B are enriched in chimpanzees with chronic HCV infection, and the compound genotype of homozygous C1 + Patr-B combined with either Pt-KIR3DS2 or Pt-KIR2DL9 is more strongly associated with disease progression than either factor alone (p = 0.0031 and p = 0.0013, respectively). Thus, despite similarities suggesting a common basis in disease resistance, there are substantial differences in the KIR and MHC class I correlations observed for HCV-infected humans and chimpanzees, consistent with the divergence of their KIR and MHC class I systems.
    No preview · Article · Aug 2015 · Immunogenetics
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    DESCRIPTION: How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we find that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (KYA), and after no more than 8,000-year isolation period in Beringia. Following their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 KYA, one that is now dispersed across North and South America and the other is restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative ‘Paleoamerican’ relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
    Full-text · Research · Jul 2015
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    ABSTRACT: The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5 Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons, this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show that this panel represents a significant proportion of European HLA allelic and haplotype diversity (60-95 %). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21 Mbp. Within HLA, the mean haplotype length is 4.3 Mbp, and 65 % of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250 kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls.
    No preview · Article · Jul 2015 · Immunogenetics
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    ABSTRACT: How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative “Paleoamerican” relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
    Full-text · Article · Jul 2015 · Science
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    ABSTRACT: Soluble recombinant proteins that comprise the extracellular part of a surface expressed receptor attached to the Fc region of an IgG antibody have facilitated the determination of ligand specificity for an array of immune system receptors. Among such receptors is the family of killer cell immunoglobulin-like receptors (KIR) that recognize HLA class I ligands. These receptors, expressed on natural killer (NK) cells and T cells, play important roles in both immune defense and placental development in early pregnancy. Here we describe a method for the production of two domain KIR-Fc fusion proteins using baculovirus infected insect cells. This method is more scalable than traditional mammalian cell expression systems and produces efficiently folded proteins that carry posttranslational modifications found in native KIR. We also describe a multiplex binding assay using the Luminex platform that determines the avidity and specificity of two domain KIR-Fc for a panel of microbeads, each coated with one of 97 HLA class I allotypes. This assay is simple to perform, and represents a major improvement over the assays used previously, which were limited in the number of KIR and HLA class I combinations that could be assayed at any one time. The results obtained from this assay can be used to predict the response of NK cell and T cells when their KIR recognize HLA class I. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Journal of immunological methods
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    ABSTRACT: Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display 'adaptive' or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an 'adaptive' phenotype (NKG2C(+)CD57(+)). Compared to CMV seronegative recipients, those who reactivated CMV (React(+)) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low-frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces.
    Full-text · Article · May 2015 · PLoS Biology

  • No preview · Conference Paper · May 2015
  • Jill Hollenbach · Peter Parham · Paul Norman

    No preview · Conference Paper · May 2015
  • Article: LBP10

    No preview · Article · Apr 2015
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    ABSTRACT: In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.
    Full-text · Article · Jan 2015 · Proceedings of the National Academy of Sciences

Publication Stats

24k Citations
2,962.92 Total Impact Points


  • 1981-2015
    • Stanford University
      • • Department of Structural Biology
      • • Department of Microbiology and Immunology
      • • Department of Medicine
      Stanford, California, United States
    • University of Wisconsin–Madison
      • Laboratory of Genetics
      Madison, Wisconsin, United States
  • 1982-2014
    • Stanford Medicine
      • • Department of Structural Biology
      • • Department of Medicine
      • • Department of Microbiology and Immunology
      Stanford, California, United States
  • 1980-2006
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2003-2005
    • Anthony Nolan Research Institute
      Londinium, England, United Kingdom
  • 2002
    • University of Alberta
      • Department of Biological Sciences
      Edmonton, Alberta, Canada
    • Hospital Universitario Puerta de Hierro-Majadahonda
      • Servicio de Inmunología
      Махадаонда, Madrid, Spain
    • Fondation Jean Dausset (CEPH)
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1979-1998
    • Harvard Medical School
      • Department of Microbiology and Immunobiology
      Boston, Massachusetts, United States
  • 1983
    • Duke University Medical Center
      • Department of Immunology
      Durham, North Carolina, United States
  • 1979-1980
    • University of Oxford
      • • Nuffield Department of Clinical Medicine
      • • Sir William Dunn School of Pathology
      Oxford, England, United Kingdom