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PubMed1997

Synergistic antitumor effects of human interferon-beta and interferon-gamma on human gastric adenocarcinoma cells.

The combined effects of different classes of interferon (IFN) on human gastric adenocarcinoma cell line HPE-GAC-2 (GAC-2) were investigated in vitro. Synergistic effects of IFN-beta and -gamma, causing cell death, were observed in a dose-dependent manner. IFN-gamma modulated the sensitivity of GAC-2 cells to the cytocidal effect of IFN-gamma. The modulatory effect was independent of the cytostatic or cytocidal activity of IFN-beta since brief contact with IFN-beta did not influence the growth kinetics of the cells and was effective in modulate the cellular sensitivity to IFN-gamma. A brief pretreatment of the cells with IFN-alpha or-beta resulted in a variable level of modulation, whereas coculture of the cells with IFN-beta or -alpha and IFN-gamma had a similar cytotoxic effect indicating a different level of activity induced by IFN-alpha and -beta with the common type I receptor. These results suggest that IFN-beta-induced modulation was receptor-mediated. Phase contrast microscopy showed evidence of apoptotic cell death induced by one or more IFN agents. The morphological changes included chromatin condensation and nuclear fragmentation which were apparent at as early as 6 hr of culture with a high concentration of IFN(s). Our results indicate that IFN-beta and IFN-alpha enhance the in vitro apoptotic effects of IFN-gamma against GAC-2 tumor cells.

Adenocarcinoma↗

PubMed1997

Soluble interferon-gamma receptor and interferon-gamma in patients undergoing allogeneic bone marrow transplantation for hematological malignancies.

Interferon-gamma (IFN-gamma) is known to be involved in graft rejection of solid organs and acute graft-versus-host disease (GVHD). Its role, and especially that of soluble IFN-gamma receptor (sIFN-gamma R), in bone marrow transplantation (BMT) has not been established. We evaluated the sera of 27 patients following BMT. Fourteen of them underwent uneventful BMT, whereas 13 developed transplant-related complications, including acute GVHD (n = 5), early rejection (n = 4), or relapse of basic disease (n = 4). Soluble IFN-gamma R and IFN levels were evaluated at day -10 (preconditioning), day 0 (day of BMT), day of engraftment, and during BMT-related complications using sIFN-gamma R-specific monoclonal antibodies (McAB) followed by double-sandwich ELISA, and a sensitive radioimmunoassay respectively. In normal controls (n = 80) sIFN-gamma R and IFN-gamma levels in the sera were 0.5 +/- 0.05 and 0.3 +/- 0.04 ng/ml respectively. Soluble IFN-gamma R levels increased in direct correlation with engraftment (0.63 +/- 0.11 ng/ml at the day of BMT to 1.43 +/- 0.16 ng/ml at the day of engraftment; n = 14; P < 0.001). IFN-gamma levels increased in direct correlation with engraftment (0.37 +/- 0.03 ng/ml at the day of BMT to 5.69 +/- 1.64 ng/ml at the day of engraftment; n = 14; P < 0.001). In five patients with GVHD sIFN-gamma R levels increased from 0.43 +/- 0.19 ng/ml at the day of BMT to 1.73 +/- 0.17 ng/ml (P < 0.004) at the time of GVHD. Similarly, IFN-gamma levels increased from 0.43 +/- 0.08 ng/ml at the day of BMT to 3.03 +/- 0.5 ng/ml at the time of GVHD (P < 0.05). Both graft rejection and early relapse were associated with an elevation of IFN-gamma levels. In short, both s-IFN-gamma R and IFN-gamma were found to be significantly elevated during engraftment and GVHD. Hence these cytokines may be used as a tool for assessing engraftment and AGVHD.

Adolescent↗

PubMed1998

A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons.

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-gamma but not by IFN-beta in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-beta and IFN-gamma. M1 leukemic cells stably expressing JAB were also resistant to IFN-gamma and IFN-beta-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-gamma did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-gamma-induced activation of JAK1 and JAK2 and IFN-beta-induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.

3T3 Cells↗

PubMed1996

Natural leukocyte interferon-alpha therapy in patients with chronic granulocytic leukemia who have antibody-mediated resistance to treatment with recombinant interferon-alpha.

Two patients with chronic-phase chronic granulocytic leukemia initially responded to recombinant interferon alpha-2a (rIFN-alpha-2a) but relapsed as a result of development of hightiter neutralizing antibodies to rIFN-alpha-2a. Both patients were subsequently treated with natural leukocyte IFN-alpha (IFN-alpha-n3), and one of the two patients achieved a durable second hematologic and cytogenetic remission. IFN-alpha-n3 may be considered for patients in whom antibody-mediated resistance to rIFN-alpha-2a develops.

Aged↗

PubMed2000

Intermediate dose recombinant interferon-alpha as second-line treatment for patients with recurrent cutaneous melanoma who were pretreated with low dose interferon.

BACKGROUND: Interferon (IFN) is widely considered the most effective agent in the adjuvant therapy of patients with cutaneous melanoma (CM). However, little is known about the effect of IFN on pretreated CM patients who experience disease recurrence. The authors conducted a Phase II study to determine whether intermediate doses of IFN could be beneficial for these patients. METHODS: A series of 24 consecutive CM patients who had undergone surgery for local, in-transit, or lymph node disease recurrence during adjuvant therapy with low dose IFN (IFNalpha-2b, 3 million units [MU] per day, three times per week) were enrolled for second-line therapy with intermediate dose IFN (IFNalpha-2b, 10 MU per day) for one year. RESULTS: IFN was discontinued in 7 patients (29.2%) because of toxicity. Several patients complained of impairment in their daily activities. Progression of disease was registered in 17 patients (70. 8%), with a median disease free survival of 5.5 months (95% confidence interval, 3.4-14.2). The median follow-up for the 7 patients who did not experience disease recurrence was 15 months (range, 13-22 months). CONCLUSIONS: An increased dose of IFN as second-line adjuvant treatment was poorly tolerated and produced negative clinical outcomes in patients with CM. However, these patients probably were unresponsive to IFN regardless of the dosage level. In fact, the first adjuvant IFN treatment was ineffective in all patients. Thus, the key factor in the treatment of CM seems to be patient responsiveness to IFN rather than the total dosage achieved.

Adult↗

PubMed1989

Cytokines in chronic inflammatory arthritis. III. Rheumatoid arthritis monocytes are not unusually sensitive to gamma-interferon, but have defective gamma-interferon-mediated HLA-DQ and HLA-DR induction.

Macrophages present in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) express large amounts of HLA-DR molecules on their surface, despite low levels of gamma-interferon (gamma-IFN) in the joint. To determine whether this apparent paradox is the result of increased sensitivity to gamma-IFN in RA, we compared concentrations of gamma-IFN that induced HLA-DR and DQ on peripheral blood monocytes of RA patients and normal donors, using fluorescence-activated cell sorter analysis. Among normal donors, highly variable sensitivity to gamma-IFN was observed. Higher amounts of gamma-IFN were required to induce class II major histocompatibility complex molecules on RA monocytes versus normal monocytes. The maximum amount of HLA-DR that could be induced on RA and normal monocytes was similar; however, peak levels of HLA-DQ were significantly less in RA. Monocytes from patients with other forms of chronic inflammatory arthritis had intermediate HLA-DQ expression after gamma-IFN treatment. These data suggest that an increased sensitivity to gamma-IFN in RA does not account for the high level of HLA-DR expression in the joint. Also, a defect in HLA-DQ and HLA-DR induction by gamma-IFN was observed.

Arthritis, Rheumatoid↗

PubMed1987

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. II. Low levels of synovial fluid and synovial tissue interferon suggest that gamma-interferon is not the primary macrophage activating factor.

Because synovial fluid monocytes (SFM) in patients with inflammatory arthritis bear an activated phenotype (i.e., high expression of HLA-DR and low expression of the monocyte differentiation antigen Mo2), we assessed the role of gamma-interferon (gamma-IFN) in the activation of these cells. Sensitive and specific radioimmunoassays detected only 0.40 +/- 0.20 units/ml of gamma-IFN in the SF of patients with rheumatoid arthritis (RA) and 0.61 +/- 0.67 units/ml of gamma-IFN in the SF of patients with other forms of chronic inflammatory arthritis. There was no detectable alpha-IFN in any SF studied by radioimmunoassay. Bioassays failed to detect nonimmunoreactive IFN. Synovial tissue (ST) explants produced very little gamma-IFN (0.14 +/- 0.091 units/ml), and production was not increased by the presence of indomethacin in the cultures or by removal of adherent cells. However, gamma-IFN was produced if ST was cultivated in the presence of phytohemagglutinin. In SF and ST supernatants, gamma-IFN-mediated induction of HLA-DR on monocytes was inhibited, even though the amount of immunoreactive IFN was not affected. Prostaglandin E2 was shown to be one possible inhibitor. We demonstrated that a factor that induces HLA-DR on some individuals' peripheral blood monocytes, and cannot be neutralized by monoclonal anti-gamma-IFN antibody, is present in SF and ST supernatants. These data suggest that activation of SFM may occur by mechanisms other than gamma-IFN.

Absorption↗

PubMed1990

Serum activity that confers acid lability to alpha-interferon in systemic lupus erythematosus: its association with disease activity and its independence from circulating alpha-interferon.

We conducted a longitudinal evaluation of a patient with systemic lupus erythematosus who constitutively exhibited elevated levels of circulating alpha-interferon (alpha-IFN). This study demonstrated that the serum levels of an activity that renders the endogenous alpha-IFN acid labile are positively correlated with disease activity. This IFN acid lability-inducing activity can also be found in the sera of systemic lupus erythematosus patients who have active disease but who do not have circulating alpha-IFN.

Acids↗

PubMed2006

Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNalpha treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. METHODS: Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNalpha4, IFNbeta, the type I IFN-inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor alpha were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. RESULTS: Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti-Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNalpha/beta (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. CONCLUSION: Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Adolescent↗

PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗

PubMed2002

Subcutaneous interleukin-2 and interferon alpha in the treatment of patients with metastatic renal cell carcinoma-Less efficacy compared with intravenous interleukin-2 and interferon alpha. Results of a multicenter Phase II trial from the Groupe Français d'Immunothérapie.

BACKGROUND: The main objective of this trial was to evaluate the combination of subcutaneous (SC) interleukin-2 (IL-2) with interferon alpha-2a (IFN-alpha) in the treatment of patients with metastatic renal cell carcinoma (MRCC) compared with a previous trial that used continuous-infusion IL-2 and IFN-alpha with identical schedules and dosages. METHODS: Between April, 1997 and January, 1998, 66 patients with MRCC received SC IL-2 at a dose of 9 x 10(6) IU/m(2) twice daily for 5 days during 2 induction cycles and during 4 additional cycles, with a 3-week rest between cycles. Each induction cycle consisted of two 5-day courses of IL-2 separated by a 9-day break. IFN-alpha at a dose of 6 x 10(6) IU per day three times per week was given during induction cycles and additional cycles. RESULTS: All patients were assessable for response and toxicity. The median follow-up was 43 months. Thirty-five patients (51%) and 43 patients (63%) received >or= 80% of the planned induction doses of IL-2 and IFN-alpha, respectively. Five patients achieved objective responses (7.6%; 95% confidence interval [95%CI], 2.5-16.8%), with two complete responses. The median survival was 14 months (95%CI, 11.3-16.7 months). Fifty-three patients (80%) had at least one episode of Grade 3 toxicity related to treatment. Twenty-two patients developed Grade 4 toxicities, which included hypotension (24% of patients), decreased performance status (6% of patients), dyspnea (3% of patients), and mucositis (3% patients) as well as fever, ventricular tachycardia, and anemia. CONCLUSIONS: The current results seem to indicate reduced efficacy and higher toxicity rates with SC IL-2 plus IFN-alpha compared with the results from a previous trial that used an identical regimen with IV IL-2 administration. Although SC IL-2 regimens are used widely, their interest remains to be determined.

Adult↗

PubMed1978

Immune interferon. II. Different cellular site for the production of murine macrophage migration inhibitory factor and interferon.

The production of macrophage migration inhibitory factor (MIF) and immune interferon (IF) by concanavalin A (Con A)-stimulated cultures of thymus, lymph node and spleen cells was investigated. It was found that all cultures produced MIF activity, whereas only spleen cells produced marked IF activity. The capacity to produce IF was found to be correlated with the macrophage content of a cell preparation as evidenced by staining for esterase-positive cells. Furthermore, column-purified spleen T cells produced MIF but no IF. Migration inhibition caused by residual mitogen could be ruled out. On the other hand, when macrophages grown from bone marrow cells were pre-exposed to supernatants of mitogen-stimulated lymphocytes, IF activity was released into freshly added medium while no significant MIF activity was found. IF was also found in supernatants of macrophage cultures after exposure to conventional inducers in vitro (polyinosinic-polycytidylic acid, Corynebacterium parvum) or in vivo (C. parvum), whereas no MIF was detected. An anti-Type I IF serum neutralized IF in supernatants from Con A-stimulated spleen cells but did not affect MIF in the same supernatants. This indicates that IF and MIF activity are associated with different molecules. It is, therefore, concluded that under the described conditions, IF and MIF are produced by different cells. T cells are the prime producers of MIF while IF is released by macrophages following induction by lymphokines.

Animals↗

PubMed1985

Regulation of Epstein-Barr virus infection by recombinant interferons. Selected sensitivity to interferon-gamma.

Interferons (IFN) are antiviral proteins that may be important in mediating cellular defenses against Epstein-Barr virus (EBV) infection. However, the means by which IFN-alpha, -beta and -gamma modify EBV infectivity are not clear. We have evaluated the effects of purified recombinant preparations of all three classes of IFN on EBV-induced B lymphocyte proliferation and Ig secretion. When added early after EBV infection, all three recombinant IFN reduced B cell outgrowth and Ig secretion. IFN-gamma exerted a 7-10-fold more potent antiviral effect than IFN-alpha or -beta. All three types of IFN act directly on B cells. Monocytes and natural killer cells are not necessary for the anti-EBV activity. Of the three recombinant IFN, only IFN-gamma reduced EBV-induced proliferation and Ig secretion when added 3-4 days after virus infection; IFN-alpha/beta were only effective up to 24 h. B lymphoblastoid lines already transformed by EBV are insensitive to the anti-proliferative actions of all three types of IFN. On the basis of these findings, we propose three phases of regulation during EBV infection. In the early phase, EBV-infected cells can be regulated by all IFN. Subsequently, there is an intermediate period where only IFN-gamma is capable of directly affecting EBV-induced B cell responses. In the third phase, B lymphocytes become insensitive to direct actions of all IFN and are now subject to regulation only by cytotoxic cells.

B-Lymphocytes↗

PubMed1986

Analysis of the role of interferon-gamma, interleukin 2 and a third factor distinct from interferon-gamma and interleukin 2 in human B cell proliferation. Evidence that they act at different times after B cell activation.

Recombinant interferon-gamma (rIFN-gamma) was able to induce proliferation of human tonsillar B cells activated with suboptimal concentrations of anti-mu antibody. The B cell growth factor (BCGF) activity of rIFN-gamma was not due to substances contaminating the IFN-gamma preparation, nor was it mediated by factors released by T cells or large granular lymphocytes following activation by rIFN-gamma. The response of B cells to rIFN-gamma peaked on day 3 of culture and rapidly declined thereafter, whereas the response of parallel anti-mu-activated B cell cultures to recombinant interleukin 2 (rIL2) appeared on day 3, but continued at least until day 5. In addition, B cells responsive to rIFN-gamma could be at least in part separated from those responsive to rIL2, the former being primarily contained in B cell fractions enriched for high-density small B lymphocytes. Finally, the addition to anti-mu-stimulated B cell cultures of very low concentrations of rIFN-gamma potentiated the B cell proliferation promoted by rIL2. The simultaneous addition of monoclonal antibodies against IFN-gamma and T cell activation antigen to anti-mu-stimulated B cell cultures strongly reduced the B cell proliferative response promoted by three different crude BCGF preparations obtained by polyclonal T cell activation in mixed lymphocyte culture. However, the supernatant from a T cell clone (DP5/11) apparently free of IL2, which manifested a BCGF activity similar to that of rIFN-gamma, still maintained its ability to promote proliferation of anti-mu-activated B cells after complete removal of IFN-gamma. Taken together, our data indicate that although some T cell clones are able to produce a BCGF distinct from both IFN-gamma and IL2, these lymphokines account for most of the BCGF activity of supernatants obtained from polyclonal T cell populations. They also suggest that IFN-gamma and the BCGF distinct from IFN-gamma and IL2 act primarily in the earlier phases of B cell activation and potentiate the proliferative response of activated B cells to IL2.

Adjuvants, Immunologic↗

PubMed1987

High-affinity binding sites for human 26-kDa protein (interleukin 6, B cell stimulatory factor-2, human hybridoma plasmacytoma growth factor, interferon-beta 2), different from those of type I interferon (alpha, beta), on lymphoblastoid cells.

The human 26-kDa glycoprotein (26K) is a cytokine produced by lymphoid as well as nonlymphoid cells. So far it is active as (a) a potent hybridoma and plasmacytoma growth factor on mouse cells, (b) a B cell differentiating factor on human cells, and (c) (for some authors) an interferon (IFN). Internally labeled recombinant human 26K, obtained by translation of mRNA in Xenopus oocytes, was used to investigate the presence of specific receptors for this new cytokine and to analyze its binding to responsive cells. The results indicate that (a) the 26K-responsive human lymphoblastoid CESS cells express about 1500 high-affinity (Kd = 30 pM) binding sites for this cytokine, (b) this binding is not competed for by interleukin (IL)1, IL2, tumor necrosis factor (TNF), IFN-alpha 2, IFN-beta or IFN-gamma, and (c) these 26K-binding sites are different from the classical type I (alpha-beta) IFN receptors by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Binding Sites↗

PubMed1989

Schwann cells co-cultured with stimulated T cells and antigen express major histocompatibility complex (MHC) class II determinants without interferon-gamma pretreatment: synergistic effects of interferon-gamma and tumor necrosis factor on MHC class II induction.

Schwann cells (SC) do not express major histocompatibility complex (MHC) class II antigens under normal culture conditions. SC can, however, be induced in vitro to express MHC class II molecules by exposure to high concentrations of interferon-gamma (IFN-gamma) and can present antigens to antigen-specific T cell lines. In the present study immunohistochemical labeling showed that most SC (greater than 90%) prepared from rat neonatal sciatic nerves expressed MHC class II molecules when cultured together with mycobacterial antigen and T cells, and as a consequence were able to function as antigen-presenting cells in lymphoproliferation assays, without requiring pretreatment with IFN-gamma. Antigen or T cells alone were ineffective in stimulating MHC class II expression and induction of class II molecules was MHC restricted, requiring the presence of syngeneic T cells. Addition of monoclonal antibody DB1, directed against IFN-gamma to co-cultures of SC and T lymphocytes stimulated with antigen, prevented the induction of MHC class II antigen on SC. When SC were incubated with recombinant (r)IFN-gamma alone, up to 50% of SC showed positive labeling for MHC class II antigen. This level of expression was enhanced to greater than 80% when recombinant tumor necrosis factor (rTNF) was also added. rTNF alone had no effect, and addition of DBI antibody inhibited the synergistic effects of rTNF on MHC class II expression. The effects of rIL 4 were also investigated but neither rIL 4 alone nor rIL 4 in combination with rIFN-gamma induced MHC class II expression by SC. These results show that in the presence of sensitized T lymphocytes and antigen, SC do not require pretreatment with exogenous rIFN-gamma to express MHC class II antigens and function as antigen-presenting cells. T cell-derived TNF and IFN-gamma appear to act as mediators of the T cell-induced expression of MHC class II by SC.

Animals↗

PubMed1996

Specific expression of surface interferon-gamma on interferon-gamma producing T cells from mouse and man.

Interferon (IFN)-gamma is a potent immunoregulatory protein secreted by CD4+ and CD8+ T cells and by natural killer cells. Here, we show that IFN-gamma is specifically displayed at a low concentration on the cell surface of those activated T cells from mouse and man which express IFN-gamma. It is transiently expressed on the cell surface with kinetics similar to those of intracellular IFN-gamma expression. Detectable surface IFN-gamma is not expressed by activated T helper (Th) cells producing other cytokines but which do not express IFN-gamma. Thus, surface IFN-gamma is the first available marker for live T lymphocytes expressing IFN-gamma, e.g. Th1 cells.

Animals↗

PubMed1996

Epitopes recognized by neutralizing therapy-induced human anti-interferon-alpha antibodies are localized within the N-terminal functional domain of recombinant interferon-alpha 2.

During prolonged recombinant interferon (rIFN)-alpha 2 therapy, a minority of patients develop high-titer neutralizing IFN-alpha antibodies. Sera from nine IFN-alpha antibody-positive patients were studied to characterize the specificity of anti-IFN-alpha neutralizing antibodies by their ability to inhibit the antiviral and antiproliferative activity of different rIFN-alpha subtypes and rIFN-alpha 1/alpha 2 hybrids. These therapy-induced antibodies (Tab) were compared with IFN-alpha-specific autoantibodies (Aab) from two patients with systemic lupus erythematosus who had never received any exogenous IFN-alpha. Although IFN-alpha subtypes are closely related in structure, Tab inhibited the antiviral activity of only recombinant (r)IFN-alpha 2 and rIFN-alpha 6, but not or slightly that of rIFN-alpha 1, -alpha 7, -alpha 8 and -alpha 14. Furthermore, of four different rIFN-alpha 1/alpha 2 hybrids tested, Tab inhibited only those which contained the N-terminal residues 17-64 of rIFN-alpha 2. Comparison of the primary sequences of neutralized and not neutralized subtypes suggests an epitope involving the residues 22-31 of IFN-alpha 2 is recognized. Thus, Tab block rIFN-alpha 2 by reacting with only one of two functional domains. In contrast, Aab possessed a broad specificity and neutralized both the antiviral and antiproliferative activity of rIFN-alpha 2, -alpha 6, -alpha 7, -alpha 8, and -alpha 14. They also neutralized all four rIFN-alpha 1/alpha 2 hybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN-alpha subtype and specifically neutralize rIFN-alpha 2 by binding to its N-terminal functional domain.

Antibodies↗