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T Simonis

Publications and source records attributed to T Simonis.

13 recordsLinked to original sources
PubMed2004

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities.

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

AIDS Vaccines↗
PubMed2001

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome.

Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-AP-deficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z = 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z = 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z = 2.69). Both the presence of HLA-DR2 and the PNH clone were independent predictors of response but the size of PNH clone did not correlate with improvement in blood count. The results suggest that clonal expansion of GPI-AP-deficient cells is linked to HLA and likely related to an immune mechanism.

Alleles↗
PubMed1999

Recognition of a shared human prostate cancer-associated antigen by nonclassical MHC-restricted CD8+ T cells.

To identify prostate cancer-associated Ags, tumor-reactive T lymphocytes were generated using iterative stimulations of PBMC from a prostate cancer patient with an autologous IFN-gamma-treated carcinoma cell line in the presence of IL-2. A CD8+ T cell line and TCR alphabeta+ T cell clone were isolated that secreted IFN-gamma and TNF-alpha in response to autologous prostate cancer cells but not to autologous fibroblasts or lymphoblastoid cells. However, these T cells recognized several normal and malignant prostate epithelial cell lines without evidence of shared classical HLA molecules. The T cell line and clone also recognized colon cancers, but not melanomas, sarcomas, or lymphomas, suggesting recognition of a shared epithelium-associated Ag presented by nonclassical MHC or MHC-like molecules. Although Ag recognition by T cells was inhibited by mAb against CD8 and the TCR complex (anti-TCR alphabeta, CD3, Vbeta12), it was not inhibited by mAb directed against MHC class Ia or MHC class II molecules. Neither target expression of CD1 molecules nor HLA-G correlated with T cell recognition, but beta2-microglobulin expression was essential. Ag expression was diminished by brefeldin A, lactacystin, and cycloheximide, but not by chloroquine, consistent with an endogenous/cytosolic Ag processed through the classical class I pathway. These results suggest that prostate cancer and colon cancer cells can process and present a shared peptidic Ag to TCR alphabeta+ T cells via a nonclassical MHC I-like molecule yet to be defined.

Antigen Presentation↗
PubMed1999

Association of major histocompatibility complex determinants with the development of symptomatic and asymptomatic genital herpes simplex virus type 2 infections.

The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.

Adult↗
PubMed1998

HLA antigens in childhood onset schizophrenia.

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Adolescent↗
PubMed1998

HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies.

We studied the HLA class II associations in patients with sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) and attempted to distinguish these myopathies on the basis of HLA allele assignments. Forty-five patients, 30 with s-IBM and 15 with h-IBM, underwent HLA class II allele-specific typing using polymerase chain reaction sequence-specific primers for 71 alleles contained in the DRbeta1, DRbeta3-5, and DQbeta1 loci. In s-IBM, we found a high (up to 77%) frequency of DRbeta1*0301, DRbeta3*0101 (or DRbeta3*0202) and DQbeta1*0201 alleles. No significant association with alleles in the DR and DQ haplotypes was found among the 15 h-IBM patients. The strong association of prominent alleles with s-IBM, but not h-IBM, suggests that s-IBM is a distinct disorder with an immunogenetic background that differs from h-IBM.

Aged↗
PubMed1996

DR2/DQw1 inheritance and haplotype sharing in affected siblings from multiple sclerosis families.

Although the human leukocyte antigen DR2/DQw1 allele has been associated with multiple sclerosis, studies of DR2/DQw1 inheritance in multiple sclerosis multiplex families have yielded conflicting results. We examined this question in "high-incidence" families, defined as families with more than 50% of siblings affected. DR2/DQw1 allele frequencies were significantly increased, particularly in mothers and affected siblings (p < 0.0001). The transmission of DR2/DQw1 from both parents was more frequent in affected offspring (p = 0.005). While evidence for segregation of disease with a particular parental allele was lacking in most families, the frequency of haplotype sharing was higher in affected sib pairs (p < 0.01).

Alleles↗
PubMed1996

Novel HLA-B alleles, B*8201, B*3515 and B*5106, add to the complexity of serologic identification of HLA types.

Three class I alleles, B*8201, B*3515 and B*5106, have been described using DNA and cDNA sequencing. The B*8201 allele is most structurally related to B*5602, differing from it by 14 nucleotide substitutions resulting in 5 amino acid differences. The other two alleles, B*3515 and B*5106, differ from their most closely related HLA-B alleles by 2-3 nucleotide substitutions resulting in 1-2 amino acid substitutions, respectively. The majority of nucleotide substitutions marking these new alleles are observed in other HLA-B alleles suggesting that gene conversion and/or reciprocal recombination have created this diversity. All of the amino acid substitutions are predicted to alter the antigen binding site of the HLA-B molecule. The newly defined HLA-B allelic products were originally defined by their unusual serologic reactivity patterns. The B*8201 allelic product is serologically typed as a B "blank" or as a variant of B22 or B45. These patterns and the serologic reactivity of the other newly described allelic products are consistent with the protein sequence homology among specific HLA-B molecules. While serology remains a powerful tool for detecting HLA diversity, alleles generated by events resulting in the sharing of HLA sequence polymorphisms among alleles at a locus will continue to create complexity in the interpretation of typing results.

Alleles↗
PubMed1991

Common expression of melanoma tumor-associated antigens recognized by human tumor infiltrating lymphocytes: analysis by human lymphocyte antigen restriction.

Major histocompatibility complex (MHC) class I antigens (Ag), particularly human lymphocyte antigen (HLA)-A2, have been shown to function as restriction elements in human cytotoxic T lymphocyte recognition of tumor. This study was undertaken to determine the function of non-A2 MHC class I Ag in tumor recognition by tumor-infiltrating lymphocytes (TILs) cultured from six melanomas, and to find evidence for shared or unique tumor-associated Ag. Four predominantly CD8+ and two mixed CD4+, CD8+ population TIL cultures were tested for lysis in short-term 51Cr-release assays against a panel of targets including 29 fresh melanomas, 2 fresh sarcomas, 11 cultured melanoma lines, and 14 nonmelanoma cell lines derived from HLA-typed patients. All six melanoma TILs lysed the autologous melanoma. Two of three TILs from HLA-A2+ patients lysed allogeneic melanomas matched for HLA-A2, giving evidence for shared tumor Ag; one of these TILs also used HLA-B44 as a restriction element. The third HLA-A2+ TIL lysed autologous melanoma but not autologous Epstein-Barr virus-transformed B cells nor 14 HLA-A2 matched allogeneic melanomas, suggesting the possibility of a unique tumor Ag in this system. The three HLA-A2- TILs each lysed multiple HLA-matched melanomas, using HLA-A24, HLA-A31, and HLA-Cw7 as restriction elements. Blocking of autologous and allogeneic melanoma lysis by TILs with mAb w6/32 (anti-MHC class I) and anti-CD3, as well as cold target inhibition assays, confirmed that specific interaction of the T-cell receptor with MHC class I Ag and the relevant tumor Ag on the target cell surface is required for tumor lysis. These data provide evidence for specific recognition of shared melanoma Ag by human TILs.

Antibodies, Monoclonal↗
PubMed1988

A new specificity, SH7 (Bw75), defined by antisera produced by planned immunization.

SH7 specificity was defined by a group of antisera developed in Shanghai, China by planned immunization. SH7 antibody is cross-reactive with B5 and B15, as demonstrated by the serological reaction patterns obtained during planned immunization. Using 9th and 10th International Histocompatibility Workshop sera, we were able to confirm SH7, TS-1 and B15Kemp as identical specificities. They are equivalent to BW62S and B15Short-Thai. In view of the cross-reaction patterns obtained during planned immunization, SH7 appears to belong to the B5, B15, B35 and Bw70 cross-reactive groups.

Epitopes↗
PubMed1982

Donor-specific transfusion with diminished sensitization.

Fourteen mixed lymphocyte culture (MLC)-reactive haploidentical recipients have received donor specific transfusions (DSTs) with diminished sensitization to HLA antigens. A single unit of donor blood was obtained in CPD-A anticoagulant, packed, and transfused in three aliquots at 1-week intervals when the blood was 1, 3, and 5 weeks old. Transplantation, performed 22 to 149 days after the last DST, has been successful in all patients for 3 to 26 months except for one experiencing hyperacute rejection despite a negative crossmatch. In vitro studies suggest that blood storage results in the loss of T lymphocytes, which are presumably responsible for the sensitization, and preservation of B cells and monocytes, which remain capable of stimulating a cellular immune response in vitro throughout the 30-day storage period. Apparently this change in the cellular characteristics of blood with storage produces the salutory effects of blood transfusion without the undesirable sensitization to HLA antigens. The mechanisms remain under study.

Antilymphocyte Serum↗
PubMed1982

Fresh versus stored blood in donor specific transfusion.

Haploidentical, MLC responsive recipients were randomized to receive either fresh (less than 48 hours old) or stored donor specific transfusions (DST). In the stored DST group, one donor unit obtained with CPD-Adenine anticoagulant was split into three aliquots and administered as packed cells after 1, 3, and 5 weeks of storage. While 3/6 fresh DST recipients became sensitized to their donors, 0/12 receiving stored DSTs developed positive donor crossmatches. Eleven patients (three fresh, eight stored) have been transplanted and have had similar posttransplant courses. None of the stored DST recipients has rejected his transplant. Four recipients of stored DSTs are awaiting transplantation. Leukocyte enumeration and FACS analysis of aliquots of stored blood shown that cells bearing HLA-ABC antigens disappear with time while B cells and monocytes persist. Taken in concert, the observations suggest that favorable recipient conditioning for transplantation can take place without sensitization to HLA antigens by simply storing the blood prior to transfusion.

Adolescent↗