Shun-Zi Jin

Role of CD28/B7 costimulation and IL-12/IL-10 interaction in the radiation-induced immune changes

BackgroundThe present paper aims at studying the role of B7/CD28 interaction and related cytokine production in the immunological changes after exposure to different doses of ionizing radiation.ResultsThe stimulatory effect of low dose radiation (LDR) on the proliferative response of lymphocytes to Con A was found to require the presence of APCs. The addition of APCs obtained from both low- and high-dose-irradiated mice to splenic lymphocytes separated from low-dose-irradiated mice caused stimulation of lymphocyte proliferation. B7-1/2 expression on APCs was up-regulated after both low and high doses of radiation. There was up-regulation of CD28 expression on splenic and thymic lymphocytes after LDR and its suppression after high dose radiation (HDR), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression showed changes in the opposite direction. IL-12 secretion by macrophages was stimulated after both low and high doses of radiation, but IL-10 synthesis by splenocytes was suppressed by low dose radiation and up-regulated by high dose radiation.ConclusionThe status of CD28/CTLA-4 expression on T lymphocytes in the presence of up-regulated B7 expression on APCs determined the outcome of the immune changes in response to radiation, i.e., up-regulation of CD28 after LDR resulted in immunoenhancement, and up-regulation of CTLA-4 associated with down-regulation of CD28 after HDR led to immunosuppression. Both low and high doses of radiation up-regulated B7-1/2 expression on APCs. After LDR, the stimulated proliferative effect of increased IL-12 secretion by APCs, reinforced by the suppressed secretion of IL-10, further strengthened the intracellular signaling induced by B7-CD28 interaction.

A Study of Circulating Gliadin Antibodies in Schizophrenia Among a Chinese Population

The present work measured circulating antibodies against native gliadins, deamidated gliadin-derived epitopes, and transglutaminase 2 (TGM2) in 473 patients with schizophrenia and 478 control subjects among a Chinese population. The results showed that 27.1% of patients with schizophrenia were positive for the IgA antibody against native gliadins compared with 17.8% of control subjects (χ(2) = 11.52, P = .0007, OR = 1.72, 95% CI 1.25-2.35), although this significant difference appeared to be due mainly to low IgA gliadin antibody levels in female controls. A total of 27.6% of female patients were positive for IgA gliadin antibodies compared with 13.9% of female controls (χ(2) = 10.46, P = .0012, OR = 2.36, 95% CI 1.39-4.01), and 26.4% of male patients were positive for IgA antibodies compared with 19.8% of male controls (χ(2) = 3.26, P = .071, OR = 1.46, 95% CI 0.97-2.19). Of 128 patients who were positive for the IgA antibody against native gliadins, 8 were positive for the IgA antibody against deamidated gliadin epitopes and 1 was positive for IgA anti-TGM2 antibody. However, quantitative analysis demonstrated that the mean levels of IgA antibodies against deamidated gliadin epitopes and TGM2 were significantly lower in patients with schizophrenia than the control subjects (P < .001 and P = .008, respectively). The prevalence of IgG antibodies against native gliadins was not significantly different between the patient group and the control group (χ(2) = 2.25, P = .134, OR = 1.32, 95% CI 0.92-1.88). This study suggests that specific gliadin-derived epitopes may be involved in schizophrenia.

A family-based study of the IL3RA gene on susceptibility to schizophrenia in a Chinese Han population

Schizophrenia has been observed to be associated with various abnormalities in cytokines and cytokine receptors that have been one of the recent focal points of immunological research in schizophrenia. Recent reports have showed that IL-3 gene, colony stimulating factor 2 receptor alpha (CSF2RA) and IL-3 receptor alpha (IL3RA) are associated with schizophrenia. The aim of this study was to investigate IL3RA gene variants in schizophrenia among a Chinese population by using a family-based association approach. Our sample included 101 Chinese parent-offspring trios of Han descent. All subjects were genotype for IL3RA-rs6603272 and -rs6645249 using PCR techniques. Single marker analysis showed a significant association for rs6603272 (X(2)=5.15, df=1, P=0.023), but not for the rs6645249. However, there was a significant genotypic association of both the polymorphisms with schizophrenia (for rs6603272, X(2)=6.15, df=2, P=0.046; for rs6645249, X(2)=21.79, df=2, P=1.85e-005). Haplotype TDT was statistically significant (X(2)=5.14, df=1, P=0.023), with the rs6603272(T)-rs6645249(G) haplotype significantly associated with schizophrenia (OR=1.66; 95% CI=1.08-2.55). In conclusion, our family-based association study also revealed a small but significant contribution of the IL3RA variants to susceptibility to schizophrenia in a Chinese population.

Whole-Body Low Dose Irradiation Promotes the Efficacy of Conventional Radiotherapy for Cancer and Possible Mechanisms

The purpose of the present study was to explore the possibility of establishing cancer radiotherapy protocols that could promote treatment efficacy at a reduced radiation dose. Mouse models of melanoma (B16) and Lewis lung carcinoma (LLC) were used in the experiments. Conventional local radiotherapy was combined with low dose whole-body irradiation (LDWBI) in the presence or absence of gene therapy by intratumor injection of a recombinant plasmid Egr-mIL-18-B7.1 (E18B). After a number of trials with different combinations it was found that a protocol of 2-week treatment with 2 × (E18B + 2 Gy + 0.075 Gy × 2) was found to be able to promote treatment efficacy at a reduced radiation dose. In this protocol local irradiation with 2Gy was administered 24h after intratumor injection of 10 μg of the plasmid E18B followed by LDWBI with 0.075 Gy every other day for 2 sessions in 1 week, and the procedure was repeated for another week. When this combined treatment was compared with conventional radiotherapy, i.e., 2Gy every other day 3 times in one week repeated for 2 weeks, the treatment efficacy was improved, as judged by increased average survival rate, reduced mean tumor weight, reduced pulmonary metastasis and suppressed intratumor capillary growth with a 2/3 reduction of radiation dose. Immunologic studies showed stimulated natural killer (NK) and cytotoxic T lymphocyte (CTL) activity as well as increased interferon-γ (IFN-γ) secretion in this combined treatment group as compared with the group receiving local treatment alone. It is suggested that up-regulation of host anticancer immunity by LDWBI and the initiation of expression of immune genes by both the local large dose and LDWBI are important factors in the realization of improved cancer control.

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect.

Antiangiogenic therapy could destroy tumor vasculature and inhibit tumor growth. It might inhibit tumor growth significantly when used as a single treatment modality and its therapeutic benefit may even be greater when used in combination with established treatment modalities such as radiation therapy (RT). In the present report, we investigated the effect of recombinant human plasminogen kringle 5 domain (rhK5) in combination with ionizing radiation on angiogenesis, tumor growth and survival in a murine Lewis lung carcinoma (LLC) tumor model. Combined treatment using rhK5 and radiotherapy displayed obvious suppressive effect on LLC tumor growth as compared with single treatment with either modality (p < 0.05), and resulted in a more additive effect on tumor growth delay in this model. In addition, combined treatment significantly enhanced the survival of mice and no toxic effect, such as weight loss, was observed. The significant antitumor effect of rhK5 plus radiation was associated with a direct suppression effect on early neoangiogenesis and tumor cell apoptosis. Furthermore, the expression of VEGF and HIF‐1α in tumor tissue correlated well with decreased vessel density. The results suggest that rhK5 significantly enhances the antitumor activity of RT and could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for lung cancer.

Increase in efficacy of cancer radiotherapy by combination with whole-body low dose irradiation

Purpose:Design of cancer radiotherapy protocol to reduce radiation dose and increase treatment efficacy in Lewis lung cancer (LLC) model. Methods: C57BL/6J mice subcutaneously implanted with LLC were treated by conventional radiotherapy (2Gy × 6) combined with LDWBI (low dose whole-body irradiation; the second, third, fifth and sixth local doses of 2Gy each substituted by LDWBI with 0.075Gy) and/or gene therapy (intratumor injection of pEgr-IL-18-B7.1 plasmid 24 h before the first and fourth local doses). Immunologic mechanisms were explored. Results: Cancer control was most significantly improved in the group receiving local radiotherapy combined with LDWBI and gene therapy as shown by prolongation of mean survival time by 60.4%, reduction in average tumor weight by 70.8%, decrease in pulmonary metastasis by 66.9% and decrease in intratumor angiogenesis by 64.8% as compared to local radiotherapy alone (p < 0.05). These changes in tumor growth and progression were accompanied with up-regulation of host immunity manifested by stimulated NK (natural killer) and CTL (cytotoxic T lymphocyte) activity, IFN (interferon)-gamma and TNF (tumor necrosis factor)-alpha secretion, PKC (protein kinase C)-theta activation and LAMP (lysosomal associated membrane protein)-1 expression. Conclusion: Combination of conventional radiotherapy with LDWBI and gene transfer could reduce total radiation dose by 2/3 and at the same time improve treatment efficacy of cancer accompanied with up-regulated host anticancer immunity.

Lack of genetic association of the HLA-DQA1⁎0501 variant with schizophrenia in a Chinese population

A genome-wide association (GWA) study recently revealed that the human leucocyte antigen (HLA) DQA10501 variant was strongly associated with protective effects on susceptibility to schizophrenia in a Caucasian population as its relative risk (odds ratio, OR) was 0.798 (The International Schizophrenia Consortium, 2009). Another GWA study also showed strong association of the DQA1 gene with a low risk (ORo1) of the illness (Shi et al., 2009). Schizophrenia has a lifetime prevalence of about 1% in the population worldwide. An estimated heritability of over 80% has driven the search for a causative gene involved in the common pathway of developing the illness (Sullivan et al., 2003). The present work was designed to examine the DQA10501 association with schizophrenia in a Chinese population. A total of 521 individuals with schizophrenia (221 males and 300 females, aged 38.56712.66 years) and 662 healthy control subjects (390 males and 272 females, aged 38.03713.06 years) were recruited for genetic analysis. All the subjects were of Chinese Han origin from the northeast of China. These 521 patients were diagnosed as having schizophrenia using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Their diagnosis was made independently by at least two consultant psychiatrists. The control subjects were recruited from local communities. Written informed consent was given by every participant to donate their blood samples for genetic analysis. This study was approved by the Ethics Committee of Jilin University, Changchun, China. Genotyping of the DQA10501 variant was performed with two HLA-tagging single nucleotide polymorphisms (SNPs), rs4639334 and rs6908943, as reported by de Bakker and co-workers (2006). The rs4639334(G)–rs6908943(T) haplotype is in complete linkage disequilibrium with the DQA10501 variant in the Chinese population (de Bakker et al., 2006). These two SNPs were genotyped by polymerase chain reaction (PCR)-based restriction fragment length polymorphism analysis. The primers used to genotype rs4639334 (Xba I site) were 50-CCTCAACTTCCCATCCAAGA-30 (forward) and 50-GGTCCCATTTGAGATGTGCT-30 (reverse); the primers used to genotype rs6908943 were 50-GTACATGATTCTTCATTACGCAAG-30 (forward) and 50-CTTTGCTGATATCAGATGCACCTATTTCATGGTCCA-30 (reverse), of which a T to C base change was made at the third 30position of the reverse primer to create a BstNI site. The UNPHASED program was used to estimate the frequency of the rs4639334(G)– rs6908943(T) haplotype that represents the frequency of the DQA10501 variant in this study population (Dudbridge, 2008). The 2 2 chi-squared (w) test was performed to detect a difference in frequency of the rs4639334(G)–rs6908943(T) haplotype between the

Genetic and functional study of the IPO5 gene in schizophrenia

The present work reported on a weak association of the importin 5 (IPO5) gene with schizophrenia in combined family and case-control samples and also investigated a possible mechanism by which the IPO5 gene may contribute to the development of the disease in a Chinese population. Our results suggest that abnormal expression and alternative splicing of the IPO5 gene may be involved in the pathophysiology of schizophrenia.

A family-based study of genetic association of the PTGDS gene with schizophrenia in a Chinese population.

Several lines of evidence suggest that niacin-induced dermal flush may be a biomarker for schizophrenia (Ward et al., 1998; Puri et al., 2001; Liu et al., 2007). Up to 80% of schizophrenic patients show diminished niacin flush as compared with 20% of healthy individuals (Ward et al., 1998; Puri et al., 2001). As the niacin flush is highly inheritable (Waldo, 1999; Lin et al., 2007), the niacin skin test can be used as endophenotypes to track down a gene for schizophrenia. Many genes, however, are involved in the niacin flush pathway, including those for niacin receptors, phospholipase A2, prostaglandin synthases and receptors. The genes involved in the prostaglandin D2 (PGD2) pathway may be particularly important as niacin flush mainly reflects the PGD2-induced vasodilatation. In a recent study, Ruano et al., 2007 detected the PGD2 synthase (PTGDS) gene for genetic association with schizophrenia in Portuguese and Brazilian populations, but they failed to observe disease association. We have also recently tested the PTGDS gene for its association with the illness in a Chinese population. A total of 282 Chinese parent-offspring trios of Han descent were recruited for the genetic analysis. The patients (181 males and 101 females), aged 25.3 ± 6.7 years, were admitted to a psychiatric hospital in Northeast China during the period between 2000 and 2005. They were diagnosed as having schizophrenia using the ICD-10 (International Statistical Classification of Diseases and Related Health Problems: Tenth Revision) criteria. All the participants gave written informed consent for the genetic analysis as approved by the ethics committee of the Jilin University.

P03-151 - A study of the genetic association between the MYO9B locus and schizophrenia in a Chinese population

Objectives An increasing number of studies have described the relationship between celiac disease and schizophrenia. Based on the reported correlations and the overlapping linkage regions on 19p13, the myosin IXB gene (MYO9B) can be considered a highly relevant positional and functional candidate gene for schizophrenia. The present work was undertaken to investigate the association of the MYO9B gene with schizophrenia in a Chinese population. Methods A total of 329 patients with schizophrenia and 350 healthy control subjects in a Chinese population were recruited. A PCR-based RFLP protocol was applied to genotype 7 single nucleotide polymorphisms (SNPs), including rs7249490, rs7256689, rs2279007, rs8113494, rs2305767, rs1545620 and rs2305764, in the MYO9B gene to investigate their association with schizophrenia. Results The X 2 goodness-of-fit test showed that the genotypic distributions of all 7 SNPs were in Hardy-Weinberg equilibrium in both the patient group and the control group. Disease association was shown for rs8113494 (X 2 =12.77, P =0.0003, OR=1.89, 95% CI 1.33-2.68) and rs1545620 (X 2 =15.44, P =8.379e-5, OR=1.65, 95% CI 1.29-2.12), while rs2279007 was associated with schizophrenia in the female subjects (X 2 =4.637, P =0.031, OR=0.69, 95% CI 0.49-0.97) but not in the male subjects (X 2 =1.082, P =0.299, OR=0.85, 95% CI 0.63-1.15). Conclusions The present work shows that the polymorphisms of the MYO9B gene are likely to confer susceptibility to schizophrenia. Because the MYO9B gene has been found to be highly expressed in the tight junction gate, it could be considered as a meeting point for the interaction between environmental and genetic factors in the pathogenesis of schizophrenia.