Humoral immune response to Epstein-Barr virus antigens and immunoglobulin allotypes in African Burkitt lymphoma patients

We examined whether any immunoglobulin allotype was associated with an elevated risk of Burkitt's lymphoma because of the association between Burkitt's lymphoma and abnormalities of the immunoglobulin-bearing chromosomes. The distribution of Gm and Km phenotypes among 56 Burkitt lymphoma cases and 25 age-matched controls was unremarkable. Burkitt's lymphoma has also been associated with the Epstein-Barr virus, and we therefore sought a relationship between immunoglobulin allotypes and antibody response to the component antigens of the Epstein-Barr virus, VCA, EA-D, EA-R and EBNA. No immunoglobulin phenotype was associated with higher antibody titers against any antigen, but there appeared to be an interactive effect in which persons homozygous at both Gm and Km loci had elevated titers against several of the component antigens of the Epstein-Barr virus. This is the first report of an interactive effect between immunoglobulin allotypes and viruses. Antibody titers against antigens of the Epstein-Barr virus were higher in cases than in controls, as expected. However, female cases had significantly higher titers than male cases, a finding similar to that previously reported in healthy persons.     

Spontaneous immune response of bovine leukemia-virusinfected cattle against five different viral proteins

The sera from cattle exposed to bovine leukemia virus (BLV) have been studied by the radioimmunoprecipitation assay (RIPA) of disrupted virus proteins. All sera of animals with the adult form of lymphosarcoma precipitated four different viral proteins: gp51, gp35, p24 and p12. In contrast, the sera of five animals with the juvenile or thymic forms of bovine lymphosarcoma were completely devoid of precipitating activity against BLV proteins, confirming the absence of relationship between these rare malignant diseases and BLV infection. The sera of non-leukemic cattle from areas of high risk of exposure to BLV were either negative or positive to a lower degree than the sera of lymphosarcomatous cows. When positive they precipitated gp51, p24 and p12. Only one serum precipitated gp35. The difference was probably quantitative, the sera of leukemic animals having higher levels of precipitating activity against all the viral proteins. The anti-gp51 reactivity was in most cases the strongest, whatever the origin of the serum. In the rare sera which were positive in the classical antigp51 radioimmunoassay (RIA) but negative in the antip24 RIA, an anti-p24 activity was, however, detected by the RIPA. These results suggest that BLV-infected cows regularly produce antibodies reacting with four different viral proteins including minor viral components. In three cases with no other special features a low level of activity was detected against a fifth component: p15. There was no apparent correlation, however, between the antibody response and an hypothetical protection against BLV-induced disease.     

Cytolytic T-cell response against Epstein-Barr virus in lung cancer patients and healthy subjects

Background

This study aimed to examine whether EBV seropositive patients with lung cancer have an altered virus-specific CTL response, as compared to age-matched healthy controls and whether any variation in this response could be attributed to senescence.

Methods

Peripheral blood mononuclear cells from lung cancer patients, age-matched and younger healthy individuals were used to measure EBV-specific CTLs after in vitro amplification with the GLCTLVAML and RYSIFFDYM peptides followed by HLA-multimer staining.

Results

Lung cancer patients and aged-matched controls had significantly lesser EBV-specific CTL than younger healthy individuals. Multimer positive populations from either group did not differ with respect to the percentage of multimer positive CTLs and the intensity of multimer binding.

Conclusions

This study provides evidence that patients with lung cancer exhibit an EBV-specific CTL response equivalent to that of age-matched healthy counterparts. These data warrant the examination of whether young individuals have a more robust anti-tumor response, as is the case with the anti-EBV response.     

异种黑色素细胞疫苗诱导小鼠抗恶性黑色素瘤免疫反应

目的：研究异种黑色素细胞疫苗对小鼠恶性黑色素瘤生长的抑制新作用。方法制轩异种黑色素细胞疫苗,皮皮预防免疫小鼠后再接种恶性黑色素瘤,并以该疫苗皮下注射治疗恶性黑色素瘤鼠,随后测量肿瘤大小,采用^51Cr释放法,体外分析小鼠脾细胞的细胞毒性T细胞（CTL）活性,以间接ELISA法检测小鼠血清抗肿瘤抗 。结果预防免疫使90％小鼠恶性黑色素瘤生长受到抑制,疫苗治疗使50％小鼠肿瘤生长受到抑制,免疫组鼠较对照组CTL杀伤活性在20：1、10：1、5：1不同效靶比时,分别增高34．0％、24．1％及13．9％（P＜0．05）,体内出现抗恶性黑色素瘤抗体。结论：异种黑色素细胞疫羁可诱导小鼠抗恶性黑色素瘤特异性免疫反,抑制肿瘤生长。     

NK cell-mediated immune response against cancer

The past fifteen years have witnessed great progress in our undestanding of how natural killer (NK) cells function, their role in innate defenses and their possible exploitation in therapy. This contribution traces the major advances in these formerly mysterious cells, from the first discovery of HLA-class I-specific inhibitory receptors to a more recent major breakgthrough that highlighted important perspectives and major expectations regarding the cure of life-threatening leukemias. The key role of "alloreactive" NK cells in eradicating acute myeloid leukemias and in preventing both graft rejection and graft-versus-host disease, led to a true revolution in bone marrow transplantation. Thus, it is now possible to search for appropriate HLA class I mismatches to set NK cells in action to cure high risk leukemias.     

Epstein-Barr virus and breast cancer: state of the evidence for viral carcinogenesis.

As the etiology and progression of breast cancer remain incompletely understood, novel routes of disease pathogenesis are important to consider. Viral pathogens have not been much explored, but recent interest has focused on Epstein-Barr virus (EBV). Studies of an association of this ubiquitous herpesvirus with breast cancer have had notably inconsistent results, marked by varying EBV presence (from 0% to 50% of tumors) and the absence of certain viral characteristics found in other EBV-related malignancies. The research has been plagued by the technical challenges of localizing EBV to tumor cells and by a tendency to overlook epidemiological cofactors, shown in all other EBV-related cancers to impact the EBV association. Breast cancer studies to date have used several viral detection methods of varying or uncertain sensitivity and specificity; most have involved small and/or poorly characterized case series and paid insufficient attention to epidemiological cofactors relevant to breast cancer and to EBV-related malignancies. Given these limitations and the established complexity of the connection of EBV with other cancers, a definitive judgment regarding the presence of this virus in breast cancer cannot yet be rendered. Recent advances in laboratory methodologies should help overcome the challenges of EBV detection in breast cancers. Further research is warranted, given the potential for an EBV association to inform not only breast cancer etiology but also early detection, treatment, and prevention.     

Difference in viral binding between two Epstein-Barr virus substrains to a spectrum of receptor-positive target cells

Radio-labelled Epstein-Barr virus (EBV) was utilized in a direct binding assay to detect the presence of EBV receptors. The sensitivity of this method was affirmed by the detection of EBV-receptors on three EV-carrying cell lines that have previously been reported as receptor negative. Two laboratory substrains of EBV, derived from the cell lines B95-8 and P3HR-I (designated B and P virus respectively), were tested in the binding assay. The main repcptor prototype adsorbed both viral strains without apparent distinction. In contrast, two lines, a Swedish EBV-negative B-cell lymphoma (U698) and a virus non-producer subline of the receptor-negative P3HR-1 line, adsorbed P virus selectively but failed to adsorb B virus.     

Epstein-Barr virus specific T-cell response in nasopharyngeal carcinoma patients

There is a substantial body of evidence suggesting an association between Epstein-Barr virus (EBV) and undifferentiated nasopharyngeal carcinoma (NPC). The present study has compared a group of NPC patients (newly diagnosed and long-term survivors) and controls for EBV-specific T-cell immunity using the regression of transformation assay. Newly diagnosed patients (17 tested) when compared with either long-term survivors (20 tested) or controls (30 tested) showed a significant impairment in virus-specific T-cell immunity (p = 0.036, p = 0.043 respectively). Furthermore, donors with IgA antibody to EBV showed a significant depression in virus-specific T-cell immunity compared with donors without IgA antibody (19 IgA-positive, 48 IgA-negative; p = 0.0025). These results may be important in explaining the postulated role of EBV in the aetiology of NPC.     

Immunoglobulin A against viral capsid antigen of Epstein-Barr virus and indirect mirror examination of the nasopharynx in the detection of asymptomatic nasopharyngeal carcinoma.

To evaluate the efficacy of population screening for early stage nasopharyngeal carcinoma (NPC) in southern China, the authors recruited 42,048 and 10,402 apparently healthy subjects residing in a high incidence and a low incidence area, respectively; all subjects were between the ages of 30 and 59 years. The subjects' serum specimens were tested for immunoglobulin (Ig) A antibody against viral capsid antigen (IgA/VCA) of Epstein-Barr virus (EBV). Of the subjects from the high incidence area, 2823 were found to be seropositive. In follow-up, they had yearly examinations of the nasopharynx by indirect mirror with or without biopsy; 41 were found to have histologically confirmed asymptomatic NPC during the first 2 years of follow-up. The tumors in most of these cases were localized and were at earlier stages than tumors of symptomatic cases of NPC seen in the same region before the screening. The yearly indirect mirror examination of the nasopharynx seems to have effectively identified most of the tumors at the stage of asymptomatic disease. The risk of harboring NPC was found to be different among the different sex and age subgroups of seropositive individuals. By limiting such screening to those who are at exceedingly high risk, the cost of the screening can be kept within the spending of the public health authority, and the effectiveness of the screening also is improved.     

Antibody-dependent lymphocyte cytotoxicity against cells expressing Epstein-Barr virus antigens.

Antibody-dependent lymphocyte cytotoxicity (ADLC) was demonstrated against Epstein-Barr virus (EBV)-infected RAJI cells with peripheral with peripheral blood lymphocytes from EBV-infected donors. No cytotoxic activity was detected against unifected RAJl cells. The results indicated that this antibody-mediated cytotoxic reaction was directed against the same EBV-induced membrane antigens (MA) previously defined by the membrane immunofluorescence (MF) assay. Antibody to EBV-associated early antigens did not participate in this in vitro reaction. Antibody titers to EBV-induced MA were significantly higher by the ADLC assay in comparison with the MF test. A preliminary study showed no relationship between high antibody titers and the presence of EBV-associated malignancies. The possible in vivo significance of this immune reaction was discussed.     

Reactive T cells in the immune repertoire: self-restricted and allo-restricted helper T-cell clones to Epstein-Barr virus

Helper T-cell clones were generated by stimulation with autologous or allogeneic lymphoblastoid B cells (B-LCL) transformed by the Epstein-Barr virus (EBV). Some of these T-cell clones were allo-reactive and others were specific to EBV-transformed B-LCL. Helper T-cell clones specific to EBV-transformed B-LCL were restricted either by class-I or by class-II HLA molecules of self. T-cell clones restricted by class-I HLA molecules were stained by OKT3 and OKT8 monoclonal antibodies (MAbs), whereas class-II-restricted clones stained with OKT3 and OKT4. Not all helper T-cell clones specific to EBV-transformed B-LCL were restricted to self: one clone restricted by allo-HLA antigen was established. This finding suggests that in humans, as in mice, some T cells in the T-cell repertoire can be allo-restricted. This allo restriction may represent cross-reactivity of T cells, whereby "self + X" equals "allo + Y." Activation of these cross-reacting T cells restricted by allogeneic HLA molecules during infectious mononucleosis will give a T-cell response which may appear unrestricted by self HLA molecules. This mechanism helps to explain, at least in part, the HLA unrestricted cytotoxicity to B-LCL observed in infectious mononucleosis.     

Antibodies against malaria and Epstein-Barr virus in childhood Burkitt lymphoma: a case-control study in Uganda

Burkitt lymphoma, a childhood tumor common in parts of sub-Saharan Africa, has been directly associated with Epstein-Barr virus (EBV) and indirectly with prevalence of malaria. We studied antibodies to both EBV and malaria in children diagnosed with this cancer in Uganda. We performed a case-control study of HIV-seronegative children (相似文献   

鼻咽癌HSP70表达与血清EB病毒IgA/VCA的关系及其临床意义

背景与目的:热休克蛋白(HSP)70在许多恶性肿瘤中均有表达,但在鼻咽癌组织中的表达与血清IgA/VCA滴度及预后的关系尚不清楚。本研究旨在检测鼻咽癌组织中HSP70的表达和含量水平,探讨HSP70表达与鼻咽癌患者血清EB病毒IgA/VCA滴度及预后的关系。方法:采用SP免疫组化法检测38例鼻咽癌组织中HSP70表达,ELISA法检测38例鼻咽癌组织中HSP70含量,免疫酶标法检测38例鼻咽癌患者血清IgA/VCA滴度。结果:HSP70在38例鼻咽癌组织中表达率为60.5%。在不同性别、年龄、T分期、N分期和临床分期鼻咽癌组织中HSP70表达率均无显著性差异(P>0.05)。HSP70表达和含量与血清EB病毒抗体IgA/VCA滴度呈正相关(P=0.001)。HSP70阳性组和阴性组患者的5年生存率分别为65.2%和80.0%,5年无瘤生存率分别为40.0%和78.6%(P=0.04)。结论:HSP70在临床Ⅱ、Ⅲ期鼻咽癌患者癌组织中的表达与患者的IgA/VCA滴度正相关,HSP70阳性患者常规治疗后预后较差。     

Elevated blood levels of soluble tumor necrosis factor receptors in nasopharyngeal carcinoma: correlation with humoral immune response to lytic replication of Epstein-Barr virus.

Nasopharyngeal carcinoma (NPC) is tightly associated with Epstein-Barr virus (EBV) infection and a heavy infiltration of lymphoid cells in the tumor tissue. Although various lines of evidence have shown that the immune systems of NPC patients have the potential to attack the tumor cells, it is not yet understood how this potential is blocked. In this study we determined the circulatory soluble tumor necrosis factor receptors (sTNFRI and sTNFRII), which are proven to be inhibitory to the anti-tumor effects of tumor necrosis factor-alpha (TNF-alpha), in NPC patients. The serum concentration of both sTNFRI and sTNFRII was determined with an ELISA method, and shown to be significantly higher in 28 NPC patients than in matched healthy controls. This elevation was found to be positively correlated with the serum titers of IgA against EBV early antigens and viral capsid antigens in NPC patients, suggesting that the increased serum concentration of sTNFRI and sTNFRII is possibly due to the EBV infection in NPC tumor cells. This is partly supported by FACS analysis of the circulatory T cells. Phenotypical expression of activation markers such as CD25, CD38, CD69 and CD71 in blood T cells was not significantly different between the NPC and control individuals, indicating the elevation of the sTNFRs is indeed derived from the local immune response in the tumor area. Based on these results, it seems that the increased sTNFRs may act as an inhibitor to decrease the host immune response towards tumor cells in NPC patients.     

Photodynamic therapy-mediated immune response against subcutaneous mouse tumors

The curative ability of photodynamic therapy (PDT) is severely compromised if treated tumors are growing in immunodeficient hosts. Reconstitution of severe combined immunodeficient (scid) mice with splenocytes from naive immunologically intact BALB/c mice did not improve the response to Photofrin-based PDT of EMT6 tumors growing in these animals. In contrast, adoptive transfer of BALB/c splenocytes containing EMT6 tumor-sensitized immune cells had a dramatic effect on tumor regrowth after PDT. For instance, full restoration of the curative effect of PDT was achieved with scid mice that received splenocytes from BALB/c donors that were cured of EMT6 tumors by PDT 5 weeks before adoptive transfer. Splenocytes obtained from donors cured of EMT6 tumors using X-rays were much less effective. Selective in vitro depletion of specific T-cell populations from engrafting splenocytes indicated that CTLs are the main immune effector cells responsible for conferring the curative outcome to PDT in this experimental model, whereas helper T lymphocytes play a supportive role. The immune specificity of these T-cell populations was demonstrated by the absence of cross-reactivity between the EMT6 and Meth-A tumor models (mismatch between tumors growing in splenocyte donors and recipients). The immunocompetent BALB/c mice that received adoptively transferred splenocytes containing PDT-generated, tumor-sensitized immune cells also benefited from the improved outcome of PDT of tumors they were bearing. This was demonstrated not only with the fairly immunogenic EMT6 tumor model but also with weakly immunogenic Line 1 carcinomas. The results of this study indicate that PDT is a highly effective means of generating tumor-sensitized immune cells that can be recovered from lymphoid sites distant to the treated tumor at protracted time intervals after PDT, which asserts their immune memory character. It is also shown that the treatment of tumors by PDT creates the conditions necessary for converting the inactive adoptively transferred pre-effector, tumor-sensitized immune cells into fully functional antitumor effector cells. An additional finding of this study is the evidence of NK cell activation in PDT-treated Meth-A sarcomas.     

EB病毒及EB病毒感染相关淋巴瘤发病机制的研究进展

EB病毒（Epstein-Barr virus,EBV）是一个已知与人类肿瘤相关的病毒。在多种上皮、间叶和淋巴造血肿瘤中可检测到EBV的存在,与淋巴瘤关系尤为密切,特别是与Burkitt淋巴瘤（Burkitt’s lymphoma,BL）、霍奇金淋巴瘤（Hodgkin's lymphoma,HL）、弥漫性大Ｂ细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）、移植后淋巴组织增殖性疾病（post-transplant lymphoproliferative disorders,PTLD）及NK/T细胞淋巴瘤等疾病的发生、发展、预后相关。大量的研究报道以及临床数据表明,EBV及其编码的蛋白、微小RNA在诱导淋巴细胞恶性转化的过程中发挥极其重要又复杂的作用,包括促进其增殖、抑制凋亡在内的多种信号通路中的蛋白。本文就近些年来EBV及EBV感染密切相关淋巴瘤发病机制的研究进展进行综述,旨在为进一步了解EBV感染与其导致淋巴瘤的机制提供一定的理论基础。      

Cytotoxic antibodies to cultured lymphoblasts unrelated to Epstein-Barr virus

A micro-⁵¹chromium-release assay was used to examine the possible relationship between antibodies cytotoxic to lymphoid cells and EBV infections of the donors. No correlation was found between sera capable of killing lymphoid cells pre-labelled with⁵¹ chromium and the presence or absence of antibodies to the viral capsid antigen (anti-VCA). Sera obtained from patients with infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma and Hodgkin's disease known to have elevated titers to anti-VCA showed cytotoxicity similar to control values. There appeared to be both heat-stable and heat-labile complement-dependent cytotoxic antibodies.