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Biomedical subjects

Mayumi Nakagawa

Publications and source records attributed to Mayumi Nakagawa.

10 recordsLinked to original sources
PubMed2006

HLA class I binding promiscuity of the CD8 T-cell epitopes of human papillomavirus type 16 E6 protein.

One of the critical steps in the progression to cervical cancer appears to be the establishment of persistent human papillomavirus (HPV) infection. We have demonstrated that the lack of cytotoxic T-lymphocyte response to HPV type 16 (HPV 16) E6 protein was associated with persistence and that the potential presence of dominant CD8 T-cell epitopes was most frequently found (n = 4 of 23) in the E6 16-40 region by examining the pattern of CD8 T-cell epitopes within the E6 protein in women who had cleared their HPV 16 infections. The goal of this study was to define the minimal/optimal amino acid sequences and the HLA restricting molecules of these dominant CD8 T-cell epitopes as well as those of subdominant ones if present. Three dominant epitopes, E6 29-38 (TIHDIILECV; restricted by the HLA-A0201 molecule), E6 29-37 (TIHDIILEC; restricted by B48), and E6 31-38 (HDIILECV; restricted by B4002), and one subdominant epitope, E6 52-61 (FAFRDLCIVY; restricted by B35) were characterized. Taken together with a previously described dominant epitope, E6 52-61 (FAFRDLCIVY; restricted by B57), the CD8 T-cell epitopes demonstrated striking HLA class I binding promiscuity. All of these epitopes were endogenously processed, but the presence of only two of the five epitopes could have been predicted based on the known binding motifs. The HLA class I promiscuity which has been described for human immunodeficiency virus may be more common than previously recognized.

Binding, Competitive↗
PubMed2006

Recognition of a cervical cancer derived tumor cell line by a human papillomavirus type 16 E6 52-61-specific CD8 T cell clone.

The E6 and E7 proteins of high-risk human papillomavirus (HPV) types are thought to be the ideal sources of antigens for immunotherapy for cervical cancer since they are expressed by the tumors and not by normal cells. We recently described new HPV 16 epitopes, including the E6 52-61 peptide restricted by HLA class I molecule B57. Primary tumor cell lines were established from three HLA-B57 positive, HPV 16 positive cervical cancer patients, and their recognition by a E6 52-61 specific CD8+ T cell clone was determined using a chromium release assay and an IFN-gamma enzyme-linked immunospot (ELISPOT) assay. The recognition of homologous epitopes contained in other high-risk HPV types (18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73) was also examined at the peptide level. A low level of killing of two of the tumor cell lines derived from the three patients was demonstrated using a chromium release assay. The level of killing of one of these tumor cell lines was enhanced upon treatment with IFN-gamma and/or the addition of antigen. This tumor cell line also induced measurable IFN-gamma secretion. The recognition of homologous epitopes from HPV 35, 39, 45, 51, and 73 was detected in an ELISPOT assay. Therefore, the HPV 16 E6 52-61 epitope appears to be at least weakly expressed by tumor cell lines derived from cervical cancer, and the HPV 16 E6 52-61-specific T cell clone can recognize homologous peptides derived from other high risk HPV sequences.

Cell Line, Tumor↗
PubMed2005

Patterns of CD8 T-cell epitopes within the human papillomavirus type 16 (HPV 16) E6 protein among young women whose HPV 16 infection has become undetectable.

The patterns of CD8 T-cell epitopes recognized within the E6 protein in women who had cleared their human papillomavirus 16 infection were examined. T-cell lines were established using autologous dendritic cells infected with a recombinant vaccinia virus. Evidence of potential antigenic epitopes was shown in 8 of 23 (34.8%) women.

Adolescent↗
PubMed2005

Inhibition of human papillomavirus type 16 E7 phosphorylation by the S100 MRP-8/14 protein complex.

The human papillomavirus type 16 (HPV16) E7 is a major viral oncoprotein that is phosphorylated by casein kinase II (CKII). Two S100 family calcium-binding proteins, macrophage inhibitory-related factor protein 8 (MRP-8) and MRP-14, form a protein complex, MRP-8/14, that inactivates CKII. The MRP-8/14 protein complex may inhibit CKII-mediated E7 phosphorylation and therefore may alter its interaction with cellular ligands and reduce E7 oncogenic activity. We examined the inhibitory effect of the MRP-8/14 complex on CKII activity and HPV16 E7 phosphorylation. We have shown that CKII activity and HPV16 E7 phosphorylation were inhibited by uptake of exogenous MRP-8/14 and activation of endogenous MRP-8/14. MRP-8/14-mediated inhibition of E7 phosphorylation occurred at the G1 phase of the cell cycle. Analysis of MRP expression in primary keratinocytes and in HPV16- and 18-transformed cervical and foreskin epithelial cell lines showed that expression of MRP-8, MRP-14, and the MRP-8/14 complex was detected only in primary untransformed keratinocytes and not in the HPV-infected immortalized epithelial cells. CKII activity in HPV-immortalized keratinocytes was approximately fourfold higher than in HPV-negative primary keratinocytes. Treatment of HPV-positive immortalized epithelial cells with exogenous MRP-8/14 resulted in E7 hypophosphorylation and complete inhibition of cell growth within 2 weeks, compared with HPV-negative primary and immortalized HPV-negative cervical epithelial cells, which showed 25 and 40% growth inhibition, respectively. Together these results suggests that the MRP-8/14 protein complex in HPV-infected epithelial cells may play an important role in regulation of CKII-mediated E7 phosphorylation and inhibition of its oncogenic activity.

Calgranulin A↗
PubMed2004

Recipients of blood from a donor with multiple HLA antibodies: a lookback study of transfusion-related acute lung injury.

BACKGROUND: The effects of transfusion of HLA antibodies to patients with corresponding antigens are not well known. STUDY DESIGN AND METHODS: Records of patients who received blood from previous donations of a donor implicated in a case of transfusion-related acute lung injury (TRALI) were examined. The donor had multiple HLA antibodies reactive with 96 percent of HLA Class I antigens and 88 percent of HLA Class II antigens. RESULTS: Among 103 patients (40 with a pretransfusion white blood cell [WBC] count of >/=3.5 x 10(9)/L), 1 patient met criteria for TRALI and had clinical evidence for diffuse alveolar hemorrhage. Among the subset of 55 patients (17 with a pretransfusion WBC count of 3.5 x 10(9)/L) with known HLA types, none developed TRALI even though 54 (98%) had one to five corresponding HLA antigens. In a subgroup of patients four of 62 patients with chest radiographs, developed new or worse bilateral infiltrates with implicated but not control units (p = 0.0625). CONCLUSION: Transfusion of HLA antibodies from this donor to nonneutropenic patients did not cause TRALI, but there was a trend of an association with new or worse bilateral pulmonary infiltrates. Further research is needed to determine why transfusion of HLA antibodies to recipients with corresponding antigens causes TRALI in some cases and not in others.

Adult↗
PubMed2004

Acute and transient decrease in neutrophil count in transfusion-related acute lung injury: cases at one hospital.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare but serious complication of blood transfusion. The syndrome is characterized by new acute lung injury developing during or within 6 hours of blood transfusion. STUDY DESIGN AND METHODS: The study design was observational in nature. RESULTS: All three cases of TRALI were associated with acute but transient decrease in the white blood cell (WBC) count. Implicated donors had HLA antibodies that matched the recipients' HLA antigens. The implicated units were a plateletpheresis in one case and fresh frozen plasma units in the other two. All implicated donors were multiparous women. The implicated antibody specificities were anti-HLA Class I and Class II in one case and anti-HLA Class II in the other two cases. Interestingly, patient neutrophil counts decreased by 80 to 90 percent in all three cases, including the two cases associated with HLA Class II antibodies. CONCLUSION: An acute and transient decrease in WBC count may be a previously underrecognized feature of TRALI. A drop in the neutrophil count can occur even when the implicated antibodies have specificities to HLA Class II antigens, although they are expressed only on stimulated neutrophils. Based on the observations in these cases, it is recommended that a complete blood count and differential be obtained when TRALI is suspected. Further investigations into the mechanisms of the decrease in circulating neutrophils that is associated with infusion of HLA Class II antibody may yield new insights into the mechanism of TRALI.

Adult↗
PubMed2004

Different methods of identifying new antigenic epitopes of human papillomavirus type 16 E6 and E7 proteins.

Human papillomavirus (HPV) infection is the most common cause of sexually transmitted viral infection and is the main cause of cervical cancer. Identification of HPV T-cell epitopes would be instrumental not only in our understanding of the protective immune response but also in the development of vaccines and immunotherapies. In contrast to viruses which cause systemic infection, identification of HPV epitopes is technically challenging because HPV causes a localized mucosal infection and the frequency of pathogen-specific T lymphocytes in peripheral blood is expected to be low. Here we describe three new antigenic epitopes (E7 7-15 [TLHEYMLDL], E6 52-61 [FAFRDLCIVY], and E7 79-87 [LEDLLMGTL]) of HPV 16 E6 and E7 proteins which have oncogenic activities. E7 7-15 was identified among peptides previously shown to bind to human leukocyte antigen (HLA)-A2.1 molecule, but it was found likely to be restricted by the HLA-B48 molecule. E6 52-61 (likely to be restricted by HLA-B57) and E7 79-87 (likely to be restricted by HLA-B60) were detected, based on the magnitude of the T-cell immune responses, in another individual. In particular, T-cell clones specific for the E6 52-61 epitope were isolated effectively by magnetically selecting them based on gamma interferon secretion. This is an efficient method of identifying new epitopes of antigens for which the number of specific T lymphocytes in the circulation is expected to be small, and it should be widely applicable in identifying new T-cell epitopes.

Amino Acid Sequence↗
PubMed2002

Molecular analysis of the human esterase D gene ESD(*)Q0(yonago) responsible for incompatibility in a Japanese paternity case.

In a Japanese paternity test, an alleged father was excluded only by reverse homozygosity of esterase D (ESD) phenotypes (mother, ESD 1; child, ESD 1; alleged father, ESD 2) out of 43 classical and DNA markers investigated. To solve the aberrant inheritance of the ESD phenotypes observed between them, fragments for all eight coding exons amplified by polymerase chain reaction (PCR) were subjected to DNA analysis. The child and alleged father shared a null allele, originating from ESD(*)1. It was characterized by having TGA for the stop codon instead of TCA for serine at codon 63. Thus, the sharing of a rare null gene, ESD(*)Q0(yonago), increased the probability of paternity.

Alleles↗
PubMed2002

Time course of humoral and cell-mediated immune responses to human papillomavirus type 16 in infected women.

The time course of cell-mediated and humoral immune responses was elucidated in eight women with human papillomavirus type 16 (HPV-16) infection by performing serial HPV-16 E6 and E7 cytotoxic T-lymphocyte (CTL) assays and HPV-16 virus-like particle (VLP) antibody analyses. Four subjects had a single incident of HPV-16 DNA detection, and four subjects had two periods of HPV-16 DNA detection. In two of the women in the latter group, the second episode of HPV-16 detection occurred in the presence of high titers of HPV-16 VLP antibody, bringing into question the protective role of humoral immunity in preventing repeated infection. However, all four subjects rapidly became HPV-16 DNA negative following the second detection of HPV-16 DNA, suggesting the presence of immunological memory. In addition, one subject rapidly became negative for HPV-16 DNA despite having no evidence of CTL or VLP antibody response prior to the second HPV-16 DNA detection, suggesting the presence of immunological responses at an undetectable level. Overall, seven of eight subjects (88%) had detectable HPV-16 E6 and/or E7 CTL responses and seven of eight women (88%) had detectable HPV-16 VLP antibody responses.

Adult↗