Pearson, Gary R.

Abstract Eleven males with XLP were evaluated for EBV-specific antibodies during periods of 2 to 7 yr. Variable responses to EBV-specific antigens were found. All 11 patients had subnormal anti-EBNA titers, which probably reflected a T cell deficiency. The patients showed four different patterns in their anti-VCA response: 1) two boys who had experienced malignant lymphoma mounted no antibodies at all; 2) two patients showed intermittent anti-VCA titers; 3) four males had persistently elevated anti-VCA titers; and 4) three patients showed normal anti-VCA titers. ADCC against EBV-infected cells was abnormally low in six patients and was elevated in two patients given gamma-globulin. ADCC titers did not correlate with anti-VCA titers. However, most patients with XLP failed to effect regression of autologous EBV-infected lymphoblastoid cell lines, indicating a deficiency in long-lived T cell-mediated immunity to EBV.

Abstract Inhibitory factors were detected in the supernatant fluids of two herpesvirus-transformed lymphoid cell lines, one a B cell line established from a cotton-topped marmoset with EBV-induced lymphoma (1605L) and the other a HVS-transformed marmoset T cell line (C-1 Ax). The factors produced by both cell lines inhibited the uptake of 125I-iododeoxyuridine (125I-IUDR) by lymphocytes stimulated by both phytohemagglutinin and pokeweed mitogen. Both factors also suppressed the uptake of 125I-IUDR by cells of lymphoid cell lines of both B and T cell origin, indicating that neither factor was specific for lymphoid subpopulations. Furthermore, the factor produced by the 1605L cell line did not exhibit tissue specificity in the target cells that it affected, since it also suppressed 125I-IUDR uptake by the HEp-2 cell line, which is epithelial. Antibody-dependent cellular cytotoxicity, an assay that has been reported to require effector cells capable of protein synthesis but not DNA synthesis, was not suppressed by either factor, indicating that these inhibitors acted at the level of DNA synthesis. Experiments investigating the kinetics of the inhibition of PHA blastogenesis by the 1605L factor suggested that this inhibitor blocked an early stage in the DNA synthetic cycle, since maximum inhibition was observed only when the factor was present early in the culture period.

Abstract An inhibitory factor, which has been shown to suppress the uptake of 125I-iododeoxyuridine by both lymphoid and nonlymphoid cells, was isolated from the supernatant of an Epstein-Barr virus- (EBV) transformed B cell line (1605L) established from a cotton-topped marmoset. Purification of the inhibitor, which was produced in serum-free medium by crowded cultures of the 1605L cells, was achieved by DEAE-cellulose chromatography followed by preparative polyacrylamide gel electrophoresis. The apparent m.w. of the 1605L factor was determined to be 65,000 to 70,000 by SDS-polyacrylamide gel electrophoresis. The inhibitor was sensitive to digestion by trypsin and chymotrypsin but not RNase or DNase, indicating that it was protein in nature. Exposure of the 1605L factor to 56 degrees C for 1/2 hr or pH 2 for 48 hr at 4 degrees C destroyed its inhibitory activity. The biochemical characteristics and activity of the 1605L inhibitor distinguish it from Type I interferon and several other soluble immunologic mediators known to be produced by lymphoid cell lines.

Natural killing (NK) may play an important role in immunosurveillance against virus‐infected and malignant cells. This study has demonstrated that the NK susceptibility of Epstein‐Barr virus (EBV)‐related cell lines increases with increased viral expression within the cells. This finding has implications for surveillance against, and treatment of, EBV‐related disease. Additionally, preliminary studies of the NK status of head and neck cancer patients reveal a distinct clustering of the patients into either groups of high or low NK reactivity. This clustering phenomenon may have a correlation with patient prognosis.

Because antibody titers against Epstein‐Barr virus (EBV) antigens often are elevated in patients with active undifferentiated and nonkeratinizing nasopharyngeal carcinoma, anti‐EBV serologic tests have been applied as a diagnostic aid in patients who have metastatic lymphadenopathy in the neck without an obvious source. In this study of 44 patients, the serologic testing procedure proved useful in identifying six patients with nasopharyngeal carcinoma that was initially occult but was eventually confirmed by biopsy.

The Epstein‐Barr virus (EBV) is closely associated with nasopharyngeal carcinoma, suggesting an etiologic relationship. We have undertaken studies (1) to quantitate the relationship between antibody titers to EBV‐associated antigens and nasopharyngeal carcinoma in American patients since most of the patients in previous studies were of either Asian or African descent and (2) to determine the relationship between antibody titers and the clinical course of disease. Sera from patients with primary or recurrent nasopharyngeal carcinoma and from patients in remission, from patients with various other head and neck tumors (including occult primary lesions and lymphomas), and from normal controls were titrated for IgG antibodies to viral capsid antigen (VCA) and early antigen and IgA antibodies to VCA, using indirect immunofluorescence procedures previously detailed. High titers of antibodies to EBV‐induced early antigen and VCA in the IgG fraction and VCA in the IgA fraction were frequently found in the sera of patients with nasopharyngeal carcinoma. A significant reduction in these titers was observed with clinical remission of the disease in treated patients. Preliminary findings suggest that EBV serology may be useful in the evaluation and treatment of patients with nasopharyngeal carcinoma and also in patients with cervical metastases from clinically occult primary sites in order to identify those with occult nasopharyngeal carcinoma.

IgA immunoglobulin fractions containing antibodies to Epstein‐Barr virus (EBV)‐induced membrane antigens were isolated from the sera of two patients with nasopharyngeal carcinoma (NPC), from one non‐NPC patient, and from three persons with sera negative for IgA antibodies. IgA antibodies were not cytotoxic against cells expressing EBV‐induced membrane antigens in the antibody‐dependent cellular cytotoxicity (ADCC) assay. However, IgA antibodies blocked IgG‐mediated ADCC, which indicated that these antibodies could serve as a blocking “factor” in patients with disease and, therefore, were potentially detrimental to the host.

From 1978 to 1981, 151 patients with nasopharyngeal carcinoma (NPC) were enrolled in a prospective, collaborative study of North American patients, most of them white. Thirty‐seven had World Health Organization (WHO) type 1 tumors, and 114 had WHO types 2 and 3 tumors. The anti‐Epstein‐Barr virus (EBV) profile of elevated antibody titers directed against viral capsid antigen and early antigen was seen in 85% of the patients with WHO types 2 and 3 tumors but in only 16% of the patients with WHO type 1 tumors. Geometric mean titers tended to be higher in higher stages of the disease in several staging systems. Low antibody‐dependent cellular cytotoxicity at diagnosis appears to reflect a poorer prognosis, and the determination of antibody titers by this assay may prove to be useful for identifying persons in whom recurrent disease is likely to develop after conventional therapy. Anti‐EBV titers can aid in diagnosis and treatment planning in patients with NPC, particularly those with occult primary NPC.