Marlyn P. Langford

Purified human immune interferon has more potent anticellular activity than fibroblast or leukocyte interferon

Abstract Human immune interferon preparations have anticellular activity on human cell lines (WISH and HEp-2). This anticellular activity copurified with the human immune interferon and appears to be a function of the immune interferon molecule. On the basis of a unit of antiviral activity, purified human immune interferon had about 20 and 100 times more anticellular activity than purified fibroblast or leukocyte interferon, respectively. The possible implications of this finding in the treatment of human neoplasia are discussed.

Histamine-releasing activity. IV. Molecular heterogeneity of the activity from stimulated human thoracic duct lymphocytes

Previous studies with the lymphokine, histamine-releasing activity (HRA), showed that HRA consisted of a heterogeneous group of molecules. The possibility of using thoracic duct lymphocytes (TDL) as a source of large quantities of HRA has been investigated. Antigen-stimulated TDL synthesize and release HRA in quantities similar to an equivalent number of peripheral blood lymphocytes (PBL). Streptokinase (SK) antigen routinely caused TDL to produce HRA approximately 15,000 Da. In contrast, staphylococcus enterotoxin B (SEB) induced the formation of a heterogeneous mixture of HRAs with apparent molecular weights of 50,000 and 15,000. Two peaks of activity (HRA I and II) were recovered when the supernatant from SK-stimulated TDL was subjected to ion-exchange chromatography. Interestingly, basophil chemotactic activity (BCA) was also eluted in these two peaks. Although interferon (IFN) is also released by antigen-stimulated TDL, the nonidentity of IFN and HRA was established by fundamental differences in chromatographic properties and specific antisera to IFN. In contrast, these studies suggest that HRA and BCA may be present on the same molecular entity.

Nonsensitized lymphocytes produce leukocyte interferon when cultured with foreign cells.

Abstract Nonsensitized human lymphocytes produce interferon when cultured with either transformed or normal heterologous cells. De novo RNA and protein synthesis was not required in a foreign cell for it to act as the inducer. The interferon produced has been characterized as being leukocyte type rather than immune or fibroblast type.

Interferon-induced transfer of viral resistance by human B and T lymphocytes

Enriched human B lymphocytes cocultivated with mouse L cells produced human leukocyte interferon (IFN-alpha) and shortly thereafter transferred antiviral activity to the recipient cells (99% inhibition of expected virus yield). In contrast, cocultivation of enriched T-cell populations with mouse L cells resulted in no IFN production or transfer of antiviral activity. In addition, both T and B lymphocytes pretreated with exogenous IFN or stimulated in vitro by mitogens could transfer antiviral activity to human WISH cells. The transfer of antiviral activity was not blocked by antibodies to IFN. The data indicate that both T and B cells can be recruited by IFN to transfer antiviral activity. Thus, once cells are recruited by IFN they can transfer antiviral activity in the absence of IFN and protect cells locally or distally from the site of infection.

Serum Interferon in Navajo Children with Severe Combined Immunodeficiency Disease Inhibits Lymphoblastogenesis

Two Navajo Indian children with severe combined immunodeficiency disease (SCID) lost reconstituted immune function after virus infections. A serum factor which inhibited normal lymphocyte response to mitogens was found in one of them and led to the examination of sera from five other Navajos with SCID. Mean inhibition by six Navajo sera was 67%; no inhibitor was found in sera from normal adults and children. The inhibitor activity was nondialyzable and heat stable, yet partially sensitive to pH 2.0, suggesting that interferon(s) was present. Interferon (IFN) activity in patient sera ranged from 10 to 300 U/ml. Normal children had peak serum IFN levels of 100 and 30 U/ml in the acute and convalescent periods, respectively, of virus infections. IFNα, IFNβ, and IFNγ were identified in SCID sera by specific antisera. Both inhibitor and IFN activities in three Navajo sera were 88–95 and 89–100%, respectively, removed with anti-IFN antisera. Similar patterns of inhibition of lymphoblastogenesis were seen with IFN standards. IFN levels in the SCID patients did not correlate with documented infections; elevated levels were present when no infections could be documented. The immunologic imbalances in some forms of SCID may be related to circulating inhibitors, possibly interferon.

Antibodies to a synthetic peptide corresponding to the N-terminal end of mouse gamma interferon (IFNγ)

Antibodies to an N-terminal synthetic peptide of mouse gamma interferon (MoIFN gamma) neutralized the antiviral activity of MoIFN gamma but not MoIFN alpha/beta, human IFN alpha (HuIFN alpha), HuIFN beta or cynomologus monkey IFN gamma (CynIFN gamma). Comparatively, antibodies to mouse N-terminal synthetic peptide showed only 10% reciprocal cross-reactivity in neutralization tests against heterologous HuIFN gamma and 13% cross-reactivity in the ELISA test against Hu N-terminal peptide. The predetermined specificity of these antibodies make them powerful tools for studying antigenic relatedness and biological properties of IFN gamma s.

Inhibition of RNA synthesis in human lymphoid cells induces interferon production.

Abstract Human lymphoid cell cultures produced an interferon-like activity in the absence of inducers. Using actinomycin D, cycloheximide, and other metabolic inhibitors, we have shown that the cellular requirement for de novo RNA synthesis is not a requisite for interferon induction. We show here that the production of an interferon-like protein may be triggered in cultured lymphoid cells by substances capable of suppressing DNA-dependent RNA synthesis. Our data suggest that a rapidly turning over regulatory mechanism controls the production of an interferon-like molecule in lymphoid cells. In fact, the induction by inhibitors of RNA synthesis and the requirement for protein synthesis for production, but not for induction, suggests a preformed messenger RNA for an interferon-like molecule whose translation is normally prevented by a rapidly turning over mechanism which requires ongoing RNA synthesis. Experiments with neutralizing antibody for interferon suggest a new antigenic type of immune interferon or a slightly different molecule with lowered affinity for antibody. The very existence, however, of such a rapidly activated regulation of interferon production infers an important role in lymphocyte response and immune regulation.

Evaluation of immune-enhancing effects of ibuprofen in an immunodeficiency model

Abstract: Three children and one adult with chronic mucocutaneous candidosis with documented deficient cellular immunity to Candida antigen were evaluated as a model to study the specific cellular immune‐enhancing potential of the prostaglandin synthetase inhibitor ibuprofen. Oral ibuprofen failed to have any consistent effect during sequential 4‐week on and off cycles on the following parameters: delayed hypersensitivity skin testing; lymphocyte transformation to Candida antigen; T‐cell subsets as determined by monoclonal antibody techniques; production of human immune interferon in response to staphylococcal enterotoxin A (SEA). Two patients showed a trend toward enhanced lymphocyte transformation to PHA while taking ibuprofen. In two patients who were studied 8–10 weeks after discontinuation of oral ketoconazole therapy, clinical recurrence of CMC was not prevented by oral ibuproten therapy.