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Results for “Antigenic Modulation”

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PubMed1984

Therapy of chronic lymphocytic leukemia and cutaneous T-cell lymphoma with T101 monoclonal antibody.

The findings accompanying the administration of 50 intravenous courses of monoclonal antibody to human T-cell (T101) in eight patients, four with chronic lymphocytic leukemia and four with cutaneous T-cell lymphoma are reported. Infusion rates of 0.7 to 1 mg/min were associated with unacceptable toxicity in the presence of circulating target cells, but slower rates were well-tolerated. Immunofluorescence techniques confirmed that circulating cells did bind the antibody in vivo and were subsequently removed from the circulation. Modulation of the antigen on target cells in the bone marrow and skin has important implications for the schedule of administration of such antibodies, and points out the possible limitation of effector cell-mediated cytotoxicity at the tissue level. Production of anti-mouse antibodies resulted in neutralization of therapy in two patients with cutaneous T-cell lymphoma, and suggests that whether such an anti-mouse response is produced may be secondary to the underlying immune status of the patient or the amount of mouse protein to which immunocompetent cells are exposed. The relative specificity and efficacy of monoclonal antibody therapy is encouraging, but the limited clinical benefit and problems of modulation and anti-mouse antibody production underscore the need for continued research into passive therapy and suggest that cytotoxic conjugates may be of more clinical value.

Adult↗

PubMed1983

Purification and characterization of fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA).

Fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA) were purified from both fetal liver and fetal bone marrow by immune rosetting with sheep erythrocytes coated with rabbit anti-mouse immunoglobulin and by fluorescence-activated cell sorting. Dual fluorescence techniques disclosed that these cells were heterogenous with respect to the expression of a series of differentiation and activation antigens defined by monoclonal antibodies. Thus, whereas all CALLA+ cells were Ia+ and expressed two activation antigens, J2 and T10, only 30-50% expressed B1 antigen. Furthermore, using methanol-fixed cells, it could be shown that approximately 20% contained intracytoplasmic mu chains (cyto-mu) and that approximately 15% were positive for the terminal transferase enzyme (TdT) marker. The CALLA+ fetal cells thus closely resemble the childhood acute lymphoblastic leukemia cell with respect to surface marker phenotype. A population of CALLA- cells devoid of mature erythroid and myeloid surface markers was found to contain higher numbers of TdT+ cells but lower numbers of cyto-mu, B1, and Ia+ cells than the CALLA+ subset. In vitro analysis of normal, purified CALLA+ cells demonstrated that incubation at 37 degrees C with J5 monoclonal antibody specific for CALLA resulted in the specific modulation of surface antigen. Similar results have previously been obtained with CALLA+ tumor cells. Although phenotypic analysis of CALLA+ cells suggests that these cells are relatively immature lymphoid cells, CALLA+ cells do not appear to contain either myeloid precursor cells (CFU-G/M) or the earliest lymphoid stem cells.

Antibodies, Monoclonal↗

PubMed2000

A functional hot spot for antigen recognition in a superagonist TCR/MHC complex.

A longstanding question in T cell receptor signaling is how structurally similar ligands, with similar affinities, can have substantially different biological activity. The crystal structure of the 2C TCR complex of H-2Kb with superagonist peptide SIYR at 2.8 A elucidates a structural basis for TCR discrimination of altered peptide ligands. The difference in antigen potency is modulated by two cavities in the TCR combining site, formed mainly by CDRs 3alpha, 3beta, and 1beta, that complement centrally located peptide residues. This "functional hot spot" allows the TCR to finely discriminate amongst energetically similar interactions within different ligands for those in which the peptide appropriately stabilizes the TCR/pMHC complex and provides a new structural perspective for understanding differential signaling resulting from T cell cross-reactivity.

Animals↗

PubMed1978

Human lung tissue and anaphylaxis: the effects of histamine on the immunologic release of mediators.

The IgE-mediated, antigen-induced release of histamine from human lung tissue causes profound changes in lung cyclic adenosine monophosphate and cyclic guanosine monophosphate. Exogenous histamine similarly induces increases in both cyclic nucleotides; pretreatment with H-1 antihistamines prevents the increase in cyclic guanosine monophosphate, whereas H-2 antihistamines prevent the increase in cyclic adenosine monophosphate. Anaphylaxis of human lung in vitro is unaffected by the presence of 1-100 micron histamine, H-1 antihistamines, H-2 antihistamines, or combinations of these agents despite the production of selective increases in total lung cyclic nucleotides. Futhermore, selective histamine agonists (2-methylhistamine [H-1 agonist] or dimaprit [H-2 agonist]) also fail to significantly influence the immunologic release of mediators. Histamine examined in the presence of ethylenediaminetetra-acetate was no more capable of modulating mediator release than when in the presence of calcium, in contrast to previous studies involving the human basophilic leukocyte. Therefore, the human lung mast cell is unresponsive to histamine with regard to modulating the antigen-induced, IgE-dependent, generation of mediators.

Antigens↗

PubMed2000

Melanoma antigen recognition by tumour-infiltrating T lymphocytes (TIL): effect of differential expression of melan-A/MART-1.

We have isolated, from an individual patient with metastatic melanoma, a series of eight TIL clones capable of lysing autologous melanoma cell targets. Six of the eight clones expressed TCRAV2S1 and lysed targets expressing HLA-A2 and the Melan-A/MART-1 peptide: AAGIGILTV. Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) analysis showed that the Melan-A/MART-1-specific clones were predominant in the bulk culture prior to cloning. However, the tumour progressed in vivo even in the presence of these tumour cell-lytic clones. Using the anti-Melan-A/MART-1 MoAb (A-103), we noted that Melan-A/MART-1 expression on three melanoma cell lines varied considerably during in vitro culture, in the absence of T cell immunoselection, relative to cell density. Tumour cells which spontaneously decreased Melan-A/MART-1 expression were less susceptible to specific TIL lysis. Melan-A/MART-1 expression and susceptibility to lysis increased in cells cultured at lower density. These data suggest that modulation of tumour antigen may account for tumour progression in the presence of tumour cell-lytic T lymphocytes. The observations suggest a possible explanation for the common finding of Melan-A/MART-1-specific lytic TIL in clinically progressing melanomas, as well as a possible pathway for therapeutic intervention.

Amino Acid Sequence↗

PubMed1992

Non-additive effects of multiple amino acid substitutions on antigen-antibody recognition.

Synthetic peptides have been used to mimic the main antigenic site of foot-and-mouth disease virus (FMDV) of serotype C and of several variant isolates. This region includes multiple continuous B cell epitopes. The effect of single amino acid replacements, individually or in combination, on antigen specificity has been evaluated using monoclonal antibodies. Quantitative enzyme immunodot assays have shown that both additive and non-additive effects of multiple replacements occur in continuous B cell epitopes, with regard to antibody recognition. Antigenically critical single replacements may be compensated by other, non-critical replacements. Thus, the role of a single amino acid on antibody recognition depends on the sequence context in the antigenic domain. The non-additive effects of multiple replacements may modulate the extent of antigenic diversification of highly variable RNA viruses, and keep viruses confined within antigenic groups by precluding linear antigenic divergence.

Amino Acid Sequence↗

PubMed1999

Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence.

The immune response to viral antigens is thought to be responsible for viral clearance and disease pathogenesis during hepatitis C virus (HCV) infection. In chronically infected patients, the T-cell response to the HCV is polyclonal and multispecific, although it is not as strong as the response in acutely infected patients who display a more vigorous T-cell response. Importantly, viral clearance in acutely infected patients is associated with a strong CD4(+) helper T-cell response. Thus, the dominant cause of viral persistence during HCV infection may be the development of a weak antiviral immune response to the viral antigens, with corresponding inability to eradicate infected cells. Alternatively, if clearance of HCV from the liver results from the antiviral effect of T-cell-derived cytokines, as has been demonstrated recently for the hepatitis B virus, chronic HCV infection could occur if HCV is not sensitive to such cytokines or if insufficient quantities of cytokines are produced. Liver cell damage may extend from virally infected to uninfected cells via soluble cytotoxic mediators and recruitment and activation of inflammatory cells forming the necroinflammatory response. Additional factors that could contribute to viral persistence are viral inhibition of antigen processing or presentation, modulation of the response to cytotoxic mediators, immunological tolerance to HCV antigens, mutational inactivation of cytotoxic T lymphocyte (CTL) epitopes, mutational conversion of CTL epitopes into CTL antagonists, and infection of immunologically privileged tissues. Analysis of the basis for viral persistence is hampered because the necessary cell culture system and animal model to study this question do not yet exist.

CD4-Positive T-Lymphocytes↗

PubMed2002

Immunology of hepatitis B infection.

The immune response initiated by the T-cell response to viral antigens is thought to be fundamental for viral clearance and disease pathogenesis in hepatitis B virus (HBV) infection. The T-cell response during acute self-limited hepatitis B in people is characterised by a vigorous, polyclonal, and multispecific cytotoxic and helper-T-cell response. By contrast, the immune response in chronic carriers, not able to eliminate the virus, is weak or undetectable. Thus a dominant cause of viral persistence could be the existence of a weak antiviral immune response. Methodological progress in animal models allows more precise investigation of the mechanisms by which the immune system resolves viral infection or develops chronic infection. Although clearance of most virus infections is widely thought to indicate the killing of infected cells by virus-specific T cells, data suggest that non-cytolytic intracellular viral inactivation by cytokines released by virus-inactivated lymphomononuclear cells could have an important role in the clearance of this virus without killing the infected cell. Additional factors that could contribute to viral persistence, which have been partly proven in animal models, are viral inhibition of antigen processing or presentation, modulation of the response to cytotoxic mediators, immunological tolerance to viral antigens, viral mutations, and infection of immunologically privileged sites. In view of the central role of cellular immunity in disease pathogenesis, strategies have been proposed to manipulate this cellular immune response in favour of protection from disease.

Adult↗

PubMed2004

Rapid detection of human HLA transgenes in pigs by fluorescence in situ hybridization (FISH) for adjuvant study of human xenotransplantation.

OBJECTIVES: We have recently generated several lines of transgenic pigs for HLA-DP and -DQ to elucidate the role of HLA-II antigens in the modulation of cell-mediated rejection of xenotransplantation. Using fluorescence in situ hybridization (FISH) analysis, the aim of this study was to determine integration sites and to test zygosity of these transgenes in the piglets after cross mating. METHODS: Blood lymphocytes of transgenic pigs for HLA-DP and -DQ were collected and cultured. Chromosome spreads were prepared by standard methodology. Gene constructs of HLA-DP A1+B1, -DQ A1 & B1 were labeled with fluorescein isothiocyanate or Texas Red by nick-translation. Hybridization was based on a standard FISH protocol. RESULTS: FISH analysis revealed that the HLA-DP probe hybridized to porcine chromosome 6, while both HLA-DQ A1 and B1 probes hybridized to porcine chromosome 11 at the same site. There was no cross-hybridization of HLA transgenes to the swine leukocyte antigen complex. Mosaic integration of HLA-DQ transgenes in the genome of F0, but full penetrance in F1 after selective breeding was observed. Both HLA-DP and HLA-DQ lines were determined to be heterozygous at the integration site. CONCLUSION: By FISH, we have detected specific integration sites of the HLA-DP and -DQ transgenes in pig genome and determined mosaic levels and zygosity types of these transgenes. We conclude that FISH is both sensitive and labor-efficient in confirming and differentiating transgenic pigs for multiple rejection-regulatory genes by visualizing individual integration sites in chromosomes or interphase nuclei.

Animals↗

PubMed2005

Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibody-mediated injury in a model of acute motor axonal neuropathy.

Anti-GD1a ganglioside antibodies (Abs) are the serological hallmark of the acute motor axonal form of the post-infectious paralysis, Guillain-Barre syndrome. Development of a disease model in mice has been impeded by the weak immunogenicity of gangliosides and the apparent resistance of GD1a-containing neural membranes to anti-GD1a antibody-mediated injury. Here we used mice with altered ganglioside biosynthesis to generate such a model at motor nerve terminals. First, we bypassed immunological tolerance by immunizing GD1a-deficient, beta-1,4-N-acetylgalactosaminyl transferase knock-out mice with GD1a ganglioside-mimicking antigens from Campylobacter jejuni and generated high-titer anti-GD1a antisera and complement fixing monoclonal Abs (mAbs). Next, we exposed ex vivo nerve-muscle preparations from GD1a-overexpressing, GD3 synthase knock-out mice to the anti-GD1a mAbs in the presence of a source of complement and investigated morphological and electrophysiological damage. Dense antibody and complement deposits were observed only over presynaptic motor axons, accompanied by severe ultrastructural damage and electrophysiological blockade of motor nerve terminal function. Perisynaptic Schwann cells and postsynaptic membranes were unaffected. In contrast, normal mice were not only unresponsive to immunization with GD1a but also resistant to neural injury during anti-GD1a Ab exposure, demonstrating the central role of membrane antigen density in modulating both immune tolerance to GD1a and axonal susceptibility to anti-GD1a Abmediated injury. Identical paralyzing effects were observed when testing mouse and human anti-GD1a-positive sera. These data indicate that anti-GD1a Abs arise via molecular mimicry and are likely to be clinically relevant in injuring peripheral nerve axonal membranes containing sufficiently high levels of GD1a.

Animals↗

PubMed1984

Interactions between immunoglobulins and I region antigens on the B lymphocyte membrane.

Modulation and co-modulation of membrane-bound IgM and IgD and of I region-encoded antigens (I-A and I-E) were studied by immunofluorescence with the use of monoclonal antibodies. The two sets of molecules displayed different ability to be redistributed, by divalent ligands: immunoglobulins could be easily redistributed, while this was not the case for I-A and I-E molecules. After short periods of activation, however, this property was found to change drastically: I-region antigens were redistributed into polar caps, and immunoglobulins were modulated without clear polar redistribution. Cross-linking and removal of one of the molecules always resulted in the modulation of at least one other, often two membrane molecules. Concomitantly, an additional molecule was expressed in higher amount. The results are compatible with the existence of specific interactions at the level of the B cell membrane, involving the four molecules in the order I-A----IgM----I-E----IgD. Such interactions, probably reversible in the unperturbed state, are likely to change in affinity when one molecule interacts with a ligand. The possible relevance of membrane interactions between immunoglobulin and class II antigens in the regulation of the B cell is discussed.

Animals↗

PubMed2002

Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination.

The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by "danger" motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity.

Adaptation, Physiological↗

PubMed2006

Nef alleles from human immunodeficiency virus type 1-infected long-term-nonprogressor hemophiliacs with or without late disease progression are defective in enhancing virus replication and CD4 down-regulation.

Infection with human immunodeficiency virus (HIV)-encoding defective nef variants may contribute to a relatively benign course of disease in a minority of long-term nonprogressors (LTNP). We have examined the functions of nef alleles from six individuals belonging to the same cohort of hemophiliacs infected with HIV-1 prior to 1985 and classified as LTNP in 1995. Three out of six individuals have progressed to HIV disease (late progressors [LP]), whereas the three remainders have maintained their LTNP status at least up to 2003. The nef alleles were obtained from both plasma virus and peripheral blood mononuclear cells of all six individuals in 1995 and 1998. The proportion of sequences containing mutations not yielding Nef expression significantly diminished in 1998 versus that in 1995. Several previously defined functional regions of intact nef alleles were highly conserved. However, the major variant obtained in 1998 from plasma RNA of five out of six individuals significantly reduced HIV infectivity/replication and impaired Nef-mediated CD4 but not major histocompatibility complex class I antigen down-modulation from the cell surface. Thus, functional alterations of the nef gene are present in both LP and LTNP, suggesting that Nef defectiveness in vitro is not necessarily associated with the long-term maintenance of LTNP status. Of interest is the fact that isolates from three out of three LP showed a dual CCR5/CXCR4 coreceptor use (R5X4), in contrast to those from LTNP, which were exclusively R5. Thus, in vivo evolution of gp120 Env to CXCR4 use appears to be associated with HIV disease progression in individuals infected with nef-defective viruses.

Alleles↗

PubMed1991

CD22 antigen: biosynthesis, glycosylation and surface expression of a B lymphocyte protein involved in B cell activation and adhesion.

The CD22 antigen, although present in the cytoplasm of early and immature B cells, first appears on the cell surface of mature B lymphocytes. The phenotypic patterns and some functional properties of the surface-expressed CD22 antigen are well described, but little is known about its molecular structure. We have therefore investigated the relationship of the two CD22 glycoproteins (140/130 kd), and the influence of their complex N-glycosylation on surface expression and antibody recognition. Comparative peptide mapping of the 100 and 80 kd protein cores, obtained by endoglycosidase F treatment, revealed a common structure shared by both protein cores. In pulse-chase experiments the mature glycoproteins originated from two separate precursor molecules, indicating that the two proteins may be generated by different RNA processing. In cell lysates a CD22 specific polyclonal anti-serum recognized both molecules the size of the protein cores and glycosylated CD22 molecules, whereas in membrane preparations only the glycosylated forms were detected. The CD22 mAb HD39 reacted exclusively with the glycoprotein froms in either cellular preparation. The influence of glycosylation on surface expression and epitope recognition was investigated in more detail by applying various inhibitors of the glycosylation pathway. 1-Deoxymannojirimycin and Swainsonine, which block glycosylation at the high-mannose and hybrid-type stages respectively, modulated the CD22 antigen but did not alter its surface expression. Tunicamycin blocked de novo glycosylation and led to reduced surface recognition of the CD22 antigen. Together, these results suggested that comparatively simple oligosaccharide structures of high-mannose type are sufficient for surface expression of the CD22 antigen and for epitope recognition by mAb HD39. It is most likely that glycosylation is required to stabilize epitopes in the protein moiety recognized by CD22 mAb. Finally, we demonstrated the presence of glycosylated, cytoplasmic CD22 antigen in CD22 surface negative B-lineage ALL cells. This finding led us to conclude that complex glycosylation does not provide the determining signal for the switch from cytoplasmic to surface expression of the CD22 antigen.

Antibodies, Monoclonal↗

PubMed1994

Size heterogeneity among antigenically related Giardia lamblia variant-specific surface proteins is due to differences in tandem repeat copy number.

Giardia lamblia undergoes antigenic variation by modulating the expression of the different genes that comprise the trophozoite's variant-specific surface protein (VSP) repertoire. We studied an epitope that is conserved among VSPs expressed by cloned trophozoite lines derived from the independent G. lamblia isolates WB, G3M, Be-2, and CAT. The epitope recognized by monoclonal antibody 6E7 lies entirely within the region of tandemly repeated 65-amino-acid units that is characteristic of these size-variant VSPs. Northern (RNA) hybridization, cDNA cloning, and DNA sequence analysis indicate that size heterogeneity among these VSPs is due to differences in the number of repetitive units.

Amino Acid Sequence↗

PubMed1984

IgG-induced experimental immune synovitis: hormonal modulation of in vitro splenic immune responses to homologous antigens.

The effect of oestrogen or anti-oestrogen administration on gross pathology and in vitro cell-mediated immune responses to homologous IgG, native and denatured interstitial collagens and PPD was studied in an IgG-induced rabbit model of immune synovitis. During induction of synovitis, rabbits were administered oestradiol valerate (0.075 mg/kg/day) or tamoxifen, an anti-oestrogen (2.0 mg/kg/day, high dose or 0.5 mg/kg/day, low dose) or placebo injections. Low dose tamoxifen administration was associated with significant improvement P less than 0.05 in immune synovitis with regard to gross pathology, when compared to placebo and the oestradiol treatment group. High dose tamoxifen treatment was not associated with significant improvement in observed synovitis. With regard to cell-mediated immune responses, spleen cells derived from immune synovitis rabbits were observed to increase 3H-thymidine uptake on incubation with native or denatured homologous collagens. Modulation of these immune responses to antigens was observed in anti-oestrogen treated rabbits with immune synovitis. In vitro cell-mediated immune responses to denatured type I, II and III collagens, PPD, as well as native type II and III collagens were not observed in the low dose tamoxifen treatment group. However, in vitro immune responses to these antigens were observed in spleen cell cultures from immune synovitis rabbits treated with either high dose tamoxifen or oestradiol valerate. The data suggest that in vivo anti-oestrogen administration can modulate the in vitro cell-mediated immune response to connective tissue constituents observed in immune synovitis. Concomitant with reduced immune responses is a significant reduction in the observed lesions of the inflammatory response.

Animals↗

PubMed2003

Upregulation of MHC class II, interferon-alpha and interferon-gamma receptor protein expression in HIV-associated nephropathy.

BACKGROUND: Renal cellular HIV infection has been linked to the pathogenesis of HIV-associated nephropathy (HIVAN), but mediators of its development are unknown. HIV infection is associated with disordered cytokine metabolism, and chemokine receptors are coreceptors for HIV immune cellular infection. Chemokines such as interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1) and RANTES, and interferons (IFNs) have been implicated in the progression of nephropathy. Renal major histocompatibility complex (MHC) protein expression is involved in antigen presentation and modulating tissue cellular immune responses. Their relative importance in HIVAN pathogenesis is unknown. METHODS: We measured levels of chemokines, IFN-alpha, IFN-gamma receptor and non-polymorphic MHC Class II protein by high performance capillary electrophoresis, and incubation with antibodies for quantification by chemiluminesce in renal tissue of patients with HIVAN, compared with tissue without HIV infection, in the presence and absence of nephropathy. Renal biopsy tissue protein levels were correlated with the number and type of infiltrating tissue immune cells. RESULTS: Mean renal interstitial and glomerular MCP-1, RANTES and IL-8 tissue levels were higher in patients with HIV infection compared with tissue without HIV infection, regardless of the presence of renal disease. In contrast, mean renal interstitial and glomerular non-polymorphic MHC Class II, IFN-alpha and IFN-gamma receptor protein were higher in patients with HIVAN compared with all other groups. Tissue MHC Class II and IFN-gamma receptor protein levels did not correlate with immune cellular infiltration in patients with HIV infection and renal disease. CONCLUSIONS: The data suggest an upregulated renal immune microenvironment, capable of antigen presentation, exists in HIVAN. MHC Class II proteins and IFNs, and the capacity to present antigen may be crucial in HIVAN pathogenesis.

AIDS-Associated Nephropathy↗

PubMed2004

The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest.

Latently infected Kaposi's sarcoma-associated herpes-virus (KSHV)-associated tumor cells have both endothelial and lymphoid origins and express a limited set of latent viral genes. One such gene, ORF73, encodes the latency-associated nuclear antigen (LANA), a multifunctional protein that plays roles in viral DNA replication, episome maintenance, and transcriptional regulation. LANA interacts with cellular proteins involved in transcriptional regulation such as the tumor suppressors, retinoblastoma (Rb) and p53, and RING3 family members. Although several reports about specific LANA-regulated promoters exist, only limited data are available that address how LANA expression in KSHV-infected cells globally affects cellular gene expression, thereby potentially contributing to KSHV pathogenicity. To investigate this question, we generated an Epstein-Barr virus-negative Burkitts lymphoma line that expresses LANA from a tetracycline-inducible promoter (BJAB/Tet-On/LANA), and we performed microarray-based gene expression profiling. Expression profiling at different time points post-induction revealed that 186 genes were activated or repressed over 2-fold in the presence of LANA. Of these genes, 41 are regulated in the Rb/E2F pathway, whereas 7 are related to p53 signaling. To determine whether these gene expression changes translate into LANA-dependent changes in cell cycle regulation, we overexpressed p16 INK4a, a CDK4/6 inhibitor that efficiently induces cell cycle arrest in Rb-positive cells. Under these conditions, LANA expression protects lymphoid cells from p16 INK4a-induced cell cycle arrest and induces S-phase entry.

Antigens, Viral↗