Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28

The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.     

Controversy of treatment for advanced colorectal cancer--intermedisine

Until recently, few chemotherapy options were available to treat metastatic colorectalcancer. For years, the standard chemotherapy has been a Fluorouracil (5-FU) alone of 5-FU with leucovorin (LV) modulation. The newer cytotoxic drugs irinotecan (CPT-11) and oxaliplatin (L-OHP) has generated further improvement in survival. Additionally, improvement in convenience of drug administration has been achieved with the development of oral fluoropynmidines. In randomized trials, oral fluoropyrimidines were equally effective to bolus 5-FU and LV. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new generation of drug development such as angiogenesis inhibitors and epidermal growth factor inhibitors. Randomized trials will determine the impact of these newer agents on survival and quality of life.     

Quantitative assessment of contaminating tumor cells in autologous peripheral blood stem cells of B-cell non-Hodgkin lymphomas using immunoglobulin heavy chain gene allele-specific oligonucleotide real-time quantitative-polymerase chain reaction

A real-time quantitative-polymerase chain reaction (RQ-PCR) targeting the immunoglobulin heavy chain (IgH) gene has been used for the quantification of minimal residual disease (MRD) in B-cell hematological malignancies. In non-Hodgkin lymphoma (NHL), experimental costs are increased, as a large number of primer-probe sets are required because of diversity, due to somatic and ongoing mutations of the IgH gene. We developed an allele-specific oligonucleotide (ASO) combined with a germline consensus probe-based RQ-PCR assay and examined MRD in peripheral blood stem cells (PBSC). The IgH consensus probes were adapted in seven (50%) of 14 amplifiable cases. Patients with heavily contaminating tumor cells in PBSC relapsed after PBSC transplantation. Our strategy will contribute to the development of a cost-efficient, precisely quantitative and systemic detection assay for MRD in NHL.     

Expression of inflammatory chemokines combined with local tumor destruction enhances tumor regression and long-term immunity

Expression of chemokines within tumors can be used to recruit immature dendritic cells (DCs) for the initiation of antitumor T-cell responses. Here, we describe the chemokine receptor expression on murine bone marrow-derived immature DCs. On the basis of these receptor studies, we chose to express the chemokines CCL3 (Mip-1alpha) or CCL20 (Mip-3alpha) in tumors. We show that expression of these chemokines in the colorectal tumor model CMT93 significantly decreases tumorigenesis. This decrease is associated with an increase in CD8 T cells, natural killer cells, and Class II DCs in the tumor within the first 24 h. Furthermore, studies in immunodeficient mice show that both natural killer cells and T cells are required for this decrease in immunogenicity. CCL3 and CCL20 expression alone did not significantly inhibit the development of the B16 melanoma tumor. However, coexpression of the Herpes Simplex Virus thymidine kinase gene (HSVtk) and CCL20, cured large established tumors where HSVtk expression alone was not sufficient. Finally, coexpression of HSVtk with either CCL3 or CCL20 was able to significantly increase protection against subsequent tumor rechallenge.     

Selection of surrogate marker genes in primary central nervous system lymphomas for radio-chemotherapy by DNA array analysis of gene expression profiles

Primary central nervous system lymphomas (PCNSLs) are extra nodal B-cell non-Hodgkin's lymphomas with primary manifestation in the brain, and their incidence has been increasing among both immunocompetent and immunocompromised populations. Samples of oligodendroglioma (n=5), glioblastoma (n=7), PCNSL (n=6), and normal brain (n=3) were studied (total of 21 samples) using cDNA array technology. The hierarchical clustering algorithm was used to obtain a phylogenetic tree, and it revealed a striking feature: PCNSL was clearly separated. The genes encoding laminin receptor 2, thioredoxin peroxidase, and elongation factor-1 were selected as specific genes in PCNSL by principal component analysis (PCA). When Mann-Whitney tests were performed to identify genes responsible for the differences between responders and non-responders to the treatment schedule for PCNSL, 76 known genes were found to show significantly different expression patterns between the two groups at the P<0.01 level. The two groups were clearly separated by the re-clustering method using the selected genes related to response to chemo-radiotherapy. This is the first report describing the gene expression profiles of PCNSL. In conclusion, accumulation of data with respect to the expression profiles of PCNSL specimens, clinicopathological data, susceptibility to treatment, and outcome will provide information for identifying optimal therapeutic modalities for individual patients and novel therapeutic targets.     

Identifying occupational therapists' referral priorities in community health

Occupational therapists in British community mental health teams have been debating how the most effective services can be targeted at the most needy clients. This paper presents the results of a quantitative study that examined 40 British occupational therapists' referral prioritization policies. Results showed half of the participants felt their generic responsibilities, which involved having care co-ordination responsibilities, were too large. Only 25% of participants co-ordinated care for clients whose needs were related to occupational dysfunction. Judgement analysis, that involved regressing the 40 individuals' prioritization decisions onto the 90 respective referral scenarios, was used to statistically model how referral information had been weighted. Group agreement of prioritization was moderate with the reason for referral, history of violence and diagnosis being given the most weighting. Consistency in policy application, as measured by examining prioritization decisions on identical referrals, showed wide variability. Further research is required to identify the optimal and most stable policies within this group.     

Inhibitory effects of ursodeoxycholic acid on the induction of nitric oxide synthase in vascular smooth muscle cells

The expression of inducible nitric oxide synthase (iNOS) and the resultant increased nitric oxide production are associated with endotoxemia and atherosclerotic lesions observed in transplant hearts or balloon-injured artery. Ursodeoxycholic acid has been shown to have cardiovascular protective effects, such as inhibition of the development of transplant arteriosclerosis, but its mechanism remains unclear. Here, we investigated the effects of ursodeoxycholic acid on nitric oxide production and the expression of iNOS in vascular smooth muscle cells isolated from adult rat aorta and rabbit coronary artery. Nitrite released from cells in the culture medium was measured with the Griess reaction. iNOS mRNA and protein were measured by Northern and Western blot analyses. Treatment with ursodeoxycholic acid (30-1000 microM) significantly inhibited lipopolysaccharide plus interferon-gamma-induced nitric oxide production in a concentration-dependent manner, but ursodeoxycholic acid showed only small inhibitory effects on nitric oxide production that had already been induced by lipopolysaccharide plus interferon-gamma. Ursodeoxycholic acid by itself did not affect basal nitric oxide production. Ursodeoxycholic acid also suppressed lipopolysaccharide plus interferon-gamma-induced expression of iNOS mRNA and protein. Ursodeoxycholic acid had the most potent inhibitory effect among various kinds of bile acids examined, i.e. chenodeoxycholic acid, deoxycholic acid, cholic acid and conjugated bile acids such as tauroursodeoxycholic acid. These results suggest that ursodeoxycholic acid inhibits the induction of iNOS and then nitric oxide production in aortic and coronary artery smooth muscle cells, suggesting a possible mechanism for the cardiovascular protective effect of ursodeoxycholic acid under various pathophysiological conditions such as endotoxemia and atherosclerosis.     

Usefulness of urinary NMP22 to detect tumor recurrence of superficial bladder cancer after transurethral resection

Background In a prospective study we compared the usefulness of urinary nuclear matrix protein 22 (NMP22) with that of urine cytology and other urinary markers in the monitoring of superficial bladder cancer after transurethral resection (TURBT).Methods The subjects were 156 patients, comprising 99 patients with superficial bladder cancer in whom TURBT was planned (untreated group) and 57 patients without tumors in the bladder who had been followed up after TURBT (follow-up group).Results Among the 156 patients, who were monitored for 11–26 months (median, 21 months), recurrence was observed in 51 patients (33.0%). At the time of recurrence, the sensitivities of NMP22, basic fetoprotein (BFP), and bladder tumor antigen (BTA) tests, and urine cytology were 18.6%, 23.3%, 9.3%, and 7.0%, respectively. The factors affecting the sensitivity of NMP22 were tumor size and urinary WBC. The size of recurrent tumors was significantly smaller (P 0.05) than that of the initial tumors. Based on receiver operating characteristic (ROC) curves calculated from the data of patients with recurrence, the ideal cutoff values at recurrence were recommended to be 5.0U/ml for NMP22 and 6.0ng/ml for BFP. Using these cutoff values, the sensitivities of NMP22 and BFP were 48.8% and 44.2%, respectively.Conclusions Because the size of recurrent bladder tumors is usually smaller than that of the initial tumors, the cutoff values of urinary markers should be reduced to detect these tumors. We recommend 5.0U/ml as a cutoff value of NMP22 for detection of recurrence of bladder tumor.