Departments of Surgery and Immunology
Departments of Surgery and Immunology
Research efforts in Dr. Ward's laboratory are focused on elucidating genetic and evolutionary mechanisms that contribute to the generation and maintenance of the extraordinary allelic polymorphism that occurs in the human major histocompatibility complex (MHC). Genes within the MHC are able to present both foreign and self antigens to the immune system and consequently have significant implications for tumor surveillance, autoimmunity, resistance to infectious diseases, and immune responses to tissue and organ transplants. Our current research efforts use molecular, cellular, and serologic methods to characterize new histocompatibility (HLA) alleles in African-American and Native American populations and to assess the significance of these polymorphisms for kidney graft survival; to investigate the evolution of genes that are homologous to HLA in several nonhuman primate species; to determine the effect of upregulating the expression of histocompatibility antigens on the rejection of melanoma; and to investigate the genetic and immunologic basis of resistance to herpes simplex virus (HSV-1) in a murine model system.
In the past, HLA alleles that shared serologic crossreactive patterns were assumed to share similar DNA sequences and a common allelic ancestor. However, we described 2 serologic groups of HLA-B alleles for which this is not the case. Allele HLA-B45, predominantly found in African and African-American populations, is serologically similar to HLA-B44 but molecularly divergent from it and is most similar in DNA sequence to serologically unrelated HLA-B50. In Native Americans, we found that the HLA-B*4005 allele is serologically similar to HLA-B50 but molecularly similar to HLA-B40. The molecular differences between these 2 B locus alleles and their most similar serologic alleles are predicted to alter peptide presentation and elicit strong alloreactive T-cell responses. Currently we are investigating the prevalence and significance of such serologic and molecular discrepancies, since they may account in part for shorter allograft survival rates in minority populations.
We have assessed other immunogenetic factors that may contribute to ethnic differences in allograft survival by examining the distribution of ABO blood groups, HLA antigens and haplotypes, percent reactive antibody (PRA), age, and gender in our local patient population. Significantly more unique HLA haplotypes were observed among local African-American families than among Caucasian families. Our data provide evidence for greater HLA linkage disequilibrium in Caucasians than in African Americans. HLA antigen and haplotype polymorphisms are likely, therefore, to be immunogenetic factors contributing to ethnic differences in renal allograft survival.
It has been shown recently that certain tumor-specific peptides, particularly those found in melanomas, are presented to the immune system by HLA class I genes. Using a model system in which the HLA restricting allele is downregulated, we are now examining T-cell recognition of autologous melanoma using melanoma cell lines in which the gamma IFN gene has been transduced. Although we previously reported that autologous tumor-specific cytotoxic T cells from HLA-A2 melanoma patients demonstrate HLA-A2 restricted recognition of shared melanoma tumor antigens, our recent studies indicate that HLA-A2 is not always a dominant restricting allele and that tumor vaccine strategies should include antigens appropriate for tumor recognition in the context of all HLA alleles expressed by the patient.
We have examined a murine model for herpes simplex viral encephalitis in 2 inbred strains of mice, C57BL/6 and A/J. The C57BL/6 mouse is resistant to infection with HSV-1, while the A/J mouse develops a lethal herpes simplex encephalitis (HSE) by day 1-. Our studies of this differential immune response have shown that IL 12 confers resistance to HSE by promoting the generation of a Th1 response.
Markert ML, Finkel BD, McLaughlin TM, Watson TJ, Collard HR, McMahon CP, Andrews LG, Barrett MJ, Ward FE. Mutations in purine nucleoside phosphorylase deficiency. Hum Mutat 1996;9:118-21.
Ward FE, MacQueen JM. Immunogenetic factors that may contribute to ethnic differences in renal allograft survival. Clin Transplant 1996;10:620-4.
Ruiz RE, Hall BL, Doyle C, Ward FE. Baboon and cotton-top tamarin B2M cDNA sequences and the evolution of primate b2-microglobulin. Hum Immunol 1994;39:188-94.
Buckley RH, Schiff SE, Schiff RI, Roberts JL, Markert ML, Peters W, Williams LW, Ward FE. Haploidentical bone marrow stem-cell transplantation in human severe combined immunodeficiency. Semin in Hematol 1993;30(4 Suppl 4):92-104.
Kostyu DD, Pfohl J, Ward FE, Lee J, Murray A, Amos DB. Rapid HLA-DR oligotyping by an enzyme linked immunosorbant assay (ELISA) performed in microtiter trays. Hum Immunol 1993;38:148-58.
Madrigal JA, Hildebrand WH, Belich MP, Benjamin RJ, Little AM, Zemmour J, Ennis PD, Ward FE, Petzl-Erler ML, du Toit ED, and others. Structural diversity in the HLA-A10 family of alleles: correlations with serology. Tissue Antigens 1993;41:72-80.
Carrington M, White MB, Dean M, Mann D, Ward FE. The use of DNA heteroduplex patterns to map recombination within the HLA class II region. Hum Immunol 1992;33:114-21.
Hildebrand WH, Madrigal JA, Belich MP, Zemmour J, Ward FE, Williams RC, Parham P. Serologic cross-reactivities poorly reflect allelic relationships in the HLA-B12 and HLA-B21 groups. Dominant epitopes of the a2 helix. J Immunol 1992;149:3563-8.
Kato N, Ward FE, Kano K, Takiguchi M. Conservation of the genes encoding HLA-B5 cross reactive group antigens in various races. Hum Immunol 1992;35:253-5.
Madrigal JA, Belich MP, Hildebrand WH, Benjamin RJ, Little AM, Zemmour J, Ennis PD, Ward FE, Petzl-Erler ML, du Toit ED, and others. Distinctive HLA-A,B antigens of Black populations formed by interallelic conversion. J Immunol 1992;149:3411-15.
Storkus WJ, Salter RD, Alexander J, Ward FE, Ruiz RE, Cresswell P, Dawson JR. Class I-induced resistance to natural killing: identification of non-permissive residues in HLA-A2. Proc Natl Acad Sci USA 1991;88:5989-92.