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R Herberman

Publications and source records attributed to R Herberman.

At least 19 recordsLinked to original sources
PubMed1994

Divergent effects of H-2K and H-2D genes on sensitivity of BL6 melanoma cells to NK cells or TNF-mediated cytotoxicity.

Transfection of BL6-8 (H-2Kb-,H-2Db+) and BL6-2 (H-2Kb-,H-2Db-) melanoma clones with H-2Kb or H-2Kd gene resulted in a stable augmentation of their sensitivity to lysis by NK cells or TNF-alpha that was associated with alterations of various phenotypic properties such as loss of endogenous A- and C-type retrovirus production and expression of melanoma-associated antigen and appearance of cell surface carbohydrates reacting with soybean agglutinin (SBA) and Grifonia simplicifolia 1-B4 (GS1B4) lectins. In contrast, transfection of the same clones with H-2Dd or H-2Ld gene did not reverse their resistance to NK cell- and TNF-mediated cytotoxicity and did not affect the phenotype of melanoma cells. These data suggest that the effect of H-2K gene on NK/TNF sensitivity of BL6 cells is indirect and it is closely associated with H-2K-induced phenotypic changes in these cells. To examine the possible role of the observed alterations of cell surface carbohydrates in augmentation of sensitivity of BL6 melanoma cells to lysis by NK cells or TNF, BL6-8 melanoma cells were transfected with cDNA encoding alpha 1,3-galactosyltransferase (alpha 1,3GT). Although the alpha 1,3GT gene-transfected cells expressed alpha-galactosyl epitopes reacting with GS1B4 lectin and reduced sialylation of cell membrane with unmasking SBA lectin-binding carbohydrates, they did not show an increase in tumor cell sensitivity to lysis by NK cells or TNF, indicating that H-2K gene-induced alterations in cell surface carbohydrate expression are not accountable for the observed increase in NK/TNF sensitivity of BL6 melanoma cells. It is possible that the H-2K gene-induced elimination of the endogenous retroviruses might be responsible for the observed increased sensitivity of BL6 melanoma cells to NK cell- and TNF-mediated cytotoxicity.

Animals↗
PubMed1993

Increased sensitivity to TNF-mediated cytotoxicity of BL6 melanoma cells after H-2Kb gene transfection.

Transfection of the H-2Kb and neor genes into BL6-8 (H-2Kb-, H-2Db+) melanoma clone resulted in various phenotypic changes with appearance of soybean agglutinin (SBA) and Grifonia Simplicifolia 1-B4 (GS1B4) lectin binding carbohydrates and loss of melanoma-associated antigen (MAA). In parallel H-2Kb gene-transfected melanoma cells showed increased sensitivity to TNF lysis. To further delineate the ability of H-2Kb gene to induce the phenotypic changes and TNF sensitivity, BL6-8 melanoma clone was transfected with the H-2Kb gene alone without cotransfection with neor gene and transfected cells were selected for adherence to SBA lectin-conjugated agarose beads. Analysis of isolated clones revealed that 38 of 47 tested clones have been found to be expressing the H-2Kb Ag, SBA, and GS1B4 lectin binding carbohydrates but lost MAA, e.g., H-2Kb+, lectin+, MAA-, and in parallel these cells became sensitive to TNF lysis. Although all clones with high expression of H-2Kb Ag were sensitive to TNF lysis, it seems unlikely that H-2K molecules are directly required for or involved in TNF-induced melanoma cell lysis. This conclusion is based on findings that four H-2Kb-transfected clones selected on SBA-agarose beads did not expressed H-2Kb Ag but manifested increase in SBA and GS1B4 lectin binding and loss of MAA and also became sensitive to TNF lysis. It seems that increase in TNF sensitivity is a part of the broad phenotypic changes induced by the H-2K gene that remained stable even in the clones in which the transfected H-2Kb gene was lost or down-regulated. We believe that the effects of the H-2Kb gene on melanoma cell phenotype and TNF sensitivity are indirect and are probably mediated via its inhibition of the melanoma-associated ecotropic retrovirus production and activation of some repressed cellular genes. Study of the mechanisms responsible for TNF sensitivity of BL6 melanoma cells revealed that the H-2Kb gene transfection resulted in an increase in p55 TNF receptor expression. TNF-induced activation of phospholipase A2 and release of arachidonic acid metabolites was observed only in the H-2Kb transfected, but not in BL6-8 melanoma cells transfected with neor or class II H-21Ak genes. TNF resistance of BL6 melanoma cells appeared to be due to a block in transduction of the lytic signal that was reversed after transfection with H-2Kb gene.

Animals↗
PubMed1992

Modulation of human natural killer cell activity by exposure to uncontrollable stress.

Changes in natural killer cell (NK) activity and proportions of circulating T and NK lymphocyte subsets were assessed in adult males immediately after exposure to controllable or uncontrollable stress (noise) as well as 24 and 72 h later, in order to track the time course of the effects of stress. The role of control-relevant personality variables as moderators of the stress-immunosuppression relationship was considered. Subjects who perceived they had control over the noise as well as no-noise "control" subjects showed no reduction in NK activity. By contrast, subjects who perceived that they had no control over the stressor showed reduced NK activity immediately after the conclusion of the first 20-min stress session, and the reduced NK activity was found as long as 72 h later. Optimism and one's desire to be in control enhanced the negative impact of uncontrollable noise on NK activity. No differences between conditions were found on number of NK cells or a variety of T cell subsets. The results suggest the importance of perceived control in moderating the short- and long-term effects of stress on NK activity.

Adolescent↗
PubMed1992

Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma.

Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1991

Increase in immunogenicity and sensitivity to natural cell-mediated cytotoxicity following in vitro exposure of MCA105 tumor cells to ultraviolet radiation.

The effect of short wave length ultraviolet C (UVC) light irradiation on tumor cell immunogenicity and sensitivity to natural cell-mediated cytotoxicity was studied. Two consecutive courses of UVC irradiation of 3LL Lewis lung carcinoma and MCA105 fibrosarcoma increased their immunogenicity and sensitivity to lysis by normal spleen cells. Analysis of the effector cells involved in lysis of the parental MCA105 and UV-treated MCA105UV tumor cells was performed by comparing the cytotoxic activity of normal spleen cells containing both natural killer (NK) and natural cytotoxicity (NC) cell activity (NK+, NC+) with: (a) normal spleen cells in which NC activity was neutralized by anti-tumor necrosis factor (TNF) antibodies (NK+, NC-); (b) NK-depleted or NK-deficient spleen cells (NK-, NC+); and (c) NK-depleted or -deficient spleen cells with NC activity blocked by anti-TNF antibodies (NK-, NC-). In addition, the ability of polyinosinic-polycytidylic acid or interleukin 2-stimulated spleen cells to lyse UV-treated and untreated tumor cells in the presence or absence of anti-TNF antibodies was also investigated. Lysis of MCA105 cells was shown to be mediated mostly by NC cells, since it was inhibited in the presence of anti-TNF antibodies and was not significantly affected by depletion or stimulation of NK cells. UV irradiation of MCA105 tumor cells substantially increased their sensitivity to both NK and NC effector cells. Augmentation of NK sensitivity of MCA105UV cells was associated with an increase in their lysability by large granular lymphocyte-derived cytolytic granules. UVC treatment of tumor cells also increased their sensitivity to lysis by recombinant TNF-alpha, pointing to the possible mechanism responsible for the increase in their sensitivity to NC cell-mediated cytotoxicity. Indeed, selection of MCA105UV cells for resistance to TNF led to resistance to spleen cell-mediated NC cytotoxicity. UVC irradiation did not affect internalization and degradation of TNF by MCA105UV cells but substantially increased sensitivity to TNF-induced DNA fragmentation. The results of this study indicate that UV irradiation can be a potent and stable modulator of the immunobiological properties of tumor cells.

Animals↗
PubMed1987

Microencapsulated tumor assay: new short-term assay for in vivo evaluation of the effects of anticancer drugs on human tumor cell lines.

A new in vivo has been developed for evaluating the antitumor activity of chemotherapeutic drugs. The assay is based on a microencapsulation technology developed by Damon Biotech, Inc., Boston, MA, which makes it possible to encapsulate human tumor cells in small (about 1 mm in diameter) microcapsules with semipermeable membranes. Microcapsules containing human tumor cells were injected i.p. into nude or C57BL/6 mice and drugs were administered i.v. The microcapsules were recovered at various intervals following treatment and determinations of drug effects were made based on the differences in the number of tumor cells recovered from the treated and nontreated animals. Using this assay we found that (a) encapsulated tumor cells grew better in the in vivo system than in vitro under the conditions tested; (b) drugs crossed the capsular membrane and killed or inhibited the proliferation of tumor cells; and (c) the antitumor effect was consistent with the relative therapeutic efficacy of drugs or level of resistance of tumor cells detected by other in vitro or in vivo tests. The tumor microencapsulation assay offers several properties which make it attractive for use in new drug development: (a) the antitumor activity of drugs can be tested against human tumor cells under conditions which provide for three-dimensional growth and in vivo supply of nutrients; (b) the sensitivity of tumor cells can be assessed following exposure to drugs at concentrations which are achievable in vivo; (c) compounds requiring in vivo metabolic activation can be tested; (d) the effect of each drug injection can be quickly evaluated; (e) inhibition of tumor cell proliferation versus cytoreductive effects of drugs can be discriminated; (f) the test is applicable to virtually all histological types of human tumor cells; and (g) the tumor microencapsulation assay is a short-term, simple, and relatively inexpensive assay.

Animals↗
PubMed1987

Correlation of stress factors with sustained depression of natural killer cell activity and predicted prognosis in patients with breast cancer.

Natural killer (NK) cell activity and psychological status were measured at baseline and at 3 months into treatment, as part of the National Cancer Institute (NCI) Protocol 79-C-111, randomizing breast cancer patients to lumpectomy/radiation v mastectomy. Patients who were found to have positive axillary lymph nodes also received combination chemotherapy (Adriamycin [Adria Laboratories, Columbus, OH], plus Cytoxan [Mead Johnson Pharmaceuticals, Evansville, IN] or methotrexate, plus 5-fluorouracil [5-FU]). Seventy-five patients were entered onto this behavioral immunology protocol at the time of data analysis. We reported in an earlier publication that NK activity was an important predictor of patient baseline prognosis relevant to nodal status. In that study, by using multiple regression analyses, 51% of the baseline NK activity variance could be accounted for by entering three distress indicators into the equation (patient "adjustment," lack of social support, and fatigue/depression symptoms). On reassessment of NK activity after 3 months, it was found that NK activity was not affected by the interim administration of chemotherapy and/or radiotherapy. However, consistent with our earlier findings, NK activity levels remained markedly lower in patients with positive nodes than in patients with negative nodes (at 60 to 1 effector to target cell [E:T] ratio, mean of 18% lytic activity v mean of 31% lytic activity [t = 1.87, P less than .05]). Even though average levels of NK activity were lower for patients with more tumor burden, there was still a substantial range of NK activity levels within the node positive patient group, as well as within the patient group as a whole. We hypothesized that differences in levels of NK activity could be predicted on the basis of baseline distress factors found to be significant in our earlier report. In fact, we found that we could account for 30% of NK activity level variance at 3 months follow-up on the basis of baseline NK activity, fatigue/depression, and lack of social support. Therefore, although neither radiation nor chemotherapy appeared to affect NK activity, tumor burden was again clearly associated with NK activity levels, and a significant amount of baseline and 3-month NK activity could be predicted on the basis of CNS-mediated effects. At the least, such factors provide a psychological marker of host biological status.

Adult↗
PubMed1983

A system for obtaining large numbers of cryopreserved human monocytes purified by leukapheresis and counter-current centrifugation elutriation (CCE).

A system has been developed for the isolation of large numbers of unfractionated mononuclear cells from single, well characterized normal individuals and for the separation by elutriation of these cells into populations of greater than 90% pure monocytes and greater than 99% pure lymphocytes. The total number of monocytes obtained from a single donor averaged about 550 million. After cryopreservation and thawing of these cells, the viability remained greater than 90%, 80% of original cells were recovered, and the ability to ingest antibody-coated targets was comparable to that of fresh monocytes. The cells remained sterile without the use of antibiotics and were suitable for long-term culture. The monocytes that were isolated and cryopreserved by these procedures functioned reproducibly as inhibitors of tumor cell growth and in an assay of responsiveness to monocyte migration inhibitory factor (MIF).

Blood Preservation↗
PubMed1981

In vivo anti-tumor effects of local adoptive transfer of mouse and human cultured lymphoid cells.

Mouse and human lymphoid cells were cultivated in the presence of T-cell growth factor (TCGF) and evaluated for their in vivo anti-tumor effect in mice. Cultured spleen cells of normal BALB/c mice or of mice bearing the M109 tumor had a high level of cytotoxic activity in vitro against a variety of tumor target cells and had characteristics of natural killer cells. These cultured cells were evaluated for their in vivo cytotoxic activity by a mixture with [125I]dUrd-labelled M109 tumor cells (2 x 10(5)) at a 30:1 ratio and inoculation of the mixture into the footpads of BALB/c mice. The level of radioactivity remaining in the footpad was determined at various periods following inoculation of radiolabelled tumor cells. The presence of cultured cells in the inocula caused a marked decrease in the footpad radioactivity by 24 h. However, the slope of clearance of the radiolabel then became similar to that in the control mice. The cultured cells delayed, but did not prevent, tumor appearance, and did not influence the subsequent rate of growth of the tumors. The transient effects of the cultured cells contrasted with the more prolonged in vivo effects of alloimmune lymphocytes, and this may be due to their short survival period. Ninety-nine percent of [125I]dUrd-labelled cultured mouse lymphoid cells were eliminated within 48 h of i.f.p. inoculation. Cultured human lymphoid cells, initiated from the blood of normal donors, also had a high level of cytotoxic activity in vitro and were evaluated for their in vivo effects by intra-footpad inoculation into nude mice, together with radiolabelled human tumor cell lines, G-11 or HT-29. In vivo cytotoxic activity of the human cultured lymphoid cells correlated with their cytotoxic effect in vitro. These results indicate that cultured mouse an human effector cells have appreciable in vivo cytotoxic effects against tumor cell lines. However, the transient duration of these effects may limit their immunotherapeutic potential.

Animals↗
PubMed1978

Delayed hypersensitivity reactions of cancer patients to antigens on lymphoid cell lines.

Four-hundred and fifty nine cancer patients were skin tested with extracts from five lymphoid cell lines. More than 50% of patients with lymphoma had positive skin tests with the extracts prepared from the cell line derived from Burkitt's lymphoma (BL) and more than 50% of nasopharyngeal carcinoma (NPC) patients reacted to the NPC-derived cell line extracts. Although the significant association between patient diagnosis and orgin of cell lines suggested that tumor-associated antigens were responsible for the pattern of delayed hypersensitivity, problems in standardization of antigen potency and non-specificity need to be resolved before this in vivo assay achieves its full potential.

Antigens, Neoplasm↗
PubMed1977

Sequential evaluation of cutaneous delayed hypersensitivity responses to recall and to lymphoid cell line antigens in Burkitt's lymphoma.

Delayed cutaneous hypersensitivity reactions to standard recall antigens (candidin, mumps and PPD), to crude membrane extracts of a cell line derived from Burkitt's lymphoma (Raji) and to cell line derived from normal lymphocytes (F265) were sequentially evaluated in 44 patients with Burkitt's lymphoma. Sixteen patients (36%) manifested delayed hypersensitivity responses to the standard antigens and seven (16%) to the Raji membrane extract at presentation. Following successful chemotherapy, there was prompt and significant improvement of reactivity to both the standard and Raji antigens (p greater than 0.001), suggesting that the initial impairment of delayed hypersensitivity was most likely related to tumor burden. By 9 months after treatment, all patients in sustained remission expressed reactivity to Raji and 21 of 22 to the standard antigens. None of the patients skin-tested with the F265 extract at presentation gave a positive response and only one subsequently expressed reactivity after remission was induced. On relapse, reactivity to the standard antigens was more readily lost (4 of 11) then reactivity to the Raji extract (1 of 7). Pretreatment delayed hypersensitivity to the standard antigens also correlated better with long-term survival than to pretreatment responses to Raji. It remains to be determined whether the antigens expressed in the Raji extract are indeed tumor-specific or related to Epstein-Barr virus.

Adolescent↗
PubMed1976

Secondary cell-mediated cytotoxic response to challenge of rats with syngeneic Gross virus-induced lymphoma.

Secondary cell-mediated cytotoxicity generated in vivo against a syngeneic Gross virus-induced lymphoma [(C58NT)D] in WF rats was detected by the 4-hour 51Cr release assay. At 30 days or more following primary tumor cell inoculation, after the tumors had regressed, lymphoid cells had little or no detectable direct cytotoxic reactivity. At rechallenge with tumor cells, high levels of cytotoxicity were detected in the peritoneal exudate, peripheral blood, mesenteric lymph node, and spleen cells. The secondary cellular immune response after challenge developed earlier, reached higher levels, and lasted longer than the primary immune response. The secondary cytotoxic reactivity was shown to be immunologically specific by the use of various tumor cells both as target and inhibitor cells. Treatment of immune spleen cells with specific antiserum to rat T-cells and complement abolished their cytotoxic reactivity, whereas removal of complement receptor-bearing cells or phagocytic cells did not reduct the cytotoxicity. These data demonstrated that specific-memory T-cells persisted for long periods in the lymphoid organs of immune rats and could rapidly become cytotoxic from rechallenge with the tumor.

AKR murine leukemia virus↗
PubMed1976

Burkitt's lymphoma: its clinical course in relation to immunologic reactivities to Epstein-Barr virus and tumor-related antigens.

In 141 patients with African Burkitt's lymphoma, the relationship between Epstein-Barr virus (EBV)-related antibody titers and the clinical course of this disease was presented. Antiviral capsid antigen tests gave positive results in all patients, siblings, and control neighbors; but the geometric mean antibody titers to viral capsid antigen were significantly higher in patients than in siblings or neighbors (P less than 0.001). No control neighbors or siblings had antibodies to restricted (EA-R) or diffuse (EA-D) early antigen. Mean geometric anti-EA-R titers at admssion and at last visit were significantly lower in patients with stage (I and II) than in those with stage (III and IV) disease; this most likely reflected the degree of tumor burden. Patients who relapsed after 1 year of sustained remission had significantly higher anti-EA-R titers than did those who did not. The increase in the probability of relapse was sixfold for those patients with an anti-EA-R titer of greater than 160 after 1 year of sustained remission. Survivors and nonsurvivors differed significantly in the final EA-R and Epstein-Barr virus nuclear antigen (EBNA) titers (P less than 0.05 and P less than 0.001, respectively). Anti-EA-D titers were particularly likely to be positive in patients with multiple relapses. When skin reactivity to an antigen from RAJI cells was compared to EBV-related serologic reactions in the same patient, a significant inverse correlation (P less than 0.001) between skin reactivity and EBNA titers appeared. Pretreatment sera from patients with high EBNA titers did not block skin reactivity to the RAJI antigen.

Antibodies, Viral↗
PubMed1976

Hodgkin's disease in siblings: a family study.

Hodgkin's disease may sporadically occur in more than one member of a family. A family in which two siblings were documented to have the nodular sclerosing form of the disease was studied for immunological competency, distribution of HL-A antigens, and Epstein-Barr virus (EBV) antibody titers. All family members examined, except the living individual with HD, had no significant abnormality in humoral and cellular immunity. HL-A antigens previously reported to appear in Hodgkin's disease with increased frequency were not found. Antibody titers to the viral capsid antigen of EBV were normal. Therefore, none of the genetically associated laboratory tests related to cancer (particularly Hodgkin's disease) were found in this family. The evidence from this family thus supports the probable importance of environmental factors in the etiology of Hodgkin's disease, particularly in the nodular sclerosis group.

Adolescent↗