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PubMed1976

Evidence for separate subpopulations of B cells responding to T-independent and T-dependent immunogens.

BALB/c spleen cell cultures were double-challenged with optimal doses of TNP-T independent and TNP-T-dependent immunogens. The anti-hapten response was additive or synergistic in double challenged cultures compared to the response in cultures challenged with either immunogen alone. A high, suppressive dose of either immunogen did not prevent the response to an optimal dose of the second immunogen in the same culture. Spleen cell cultures were also double challenged with combinations of two T-dependent or two T-independent immunogens. Addition or synergy in the anti-hapten response only occurred when the double challenge consisted of a mixutre of T-dependent and T-independent immunogens. These results are consistent with the proposed B1B2 classification of B cell subpopulations.

Animals↗
PubMedDate not supplied

[Introduction of biologically active fragments of interferon-alpha2 and insulin into the artificial protein albebetin affects immunogenicity of the final construct].

The immunogenicity of the artificial protein albebetin and its derivatives with active peptide fragments was investigated. We also studied the influence of the peptides on the immunogenicity of the whole construct and contribution of each component to the immunogenicity. Two of three studied proteins contained active peptides from human IFN-alpha and insulin. Three continuous antigenic sites with different immunogenic potential were recognized in the chimerical proteins. The interferon fragment was the immunodominant site in the albeferon and albeferon-insulin molecules, while the insulin fragment displayed low immunogenic activity. All continuous B-epitopes are located at the boundaries of the secondary structure elements and at the predicted surface-located sites of albebetin molecule. Thus, peptide fragments attached to the artificial protein carrier can influence immunogenicity of the resulting construct.

Amino Acid Sequence↗
PubMed2003

Animal models as indicators of immunogenicity of therapeutic proteins in humans.

Animal models have not been able to predict the immunogenicity of therapeutic proteins in humans reliably. The main issue is that administration of a human protein in an animal species is likely to be immunogenic. In non-human primate studies, we have seen a variety of responses; from little to no antibody response, to a strong neutralizing response, or even a cross-reactive antibody response. These have generally not correlated well with the immune response seen in humans. The route of administration, duration and schedule of dosing, the cumulative dosage of the protein, the pharmacological (i.e., immune altering) properties of the protein, as well as the purity of the clinical material can influence the immunogenicity. The animal studies should mimic these factors to the best extent possible for the animal model to be at all relevant to humans. Models do exist which provide valuable information to compare the immunogenicity of various compounds or routes of administration. Presumably, this 'relative' immunogenicity would be similar in humans. Additional characterization of transgenic mice, or use of homologous proteins, may help to establish better models to predict immunogenicity.

Animals↗
PubMed1992

Enhancing the immunogenicity of a permissive binding T cell epitope derived from the simian immunodeficiency virus-encoded negative regulatory factor.

Using the murine system we have analyzed an immunogenic T cell peptide epitope corresponding to amino acids 96-112 of the simian immunodeficiency virus-negative regulatory protein sequence. This epitope was unusual in that it was strongly immunogenic in mice of five of the six H-2 haplotypes tested. We generated a T cell hybridoma (SVNF) specific for this peptide in order to determine how manipulating the peptide might alter its immunogenicity. Substitution analysis showed that His 103, Pro 104, Val 106, and Pro 107 were important amino acids for stimulating SVNF because substitutions at these positions diminished the reactivity of SVNF. However, we also found that substituting an Ala for a Val at position 100 or a Val for an Ala at position 110 enhanced reactivity of SVNF. We were able to further enhance the immunogenicity of this epitope by extending the carboxyl terminus two amino acids and making the resulting carboxyl-terminal Lys an amide and by adding a Glu to the amino terminus. These modifications shifted the in vitro activity of SVNF at least two orders of magnitude. We also compared the ability of this modified peptide and the wild-type SIV nef 96-112 to prime a T cell response in vivo. We primed mice with various doses of either the wild-type or the modified peptide and looked at the ability of the draining lymph node cells to proliferate to wild-type peptide. We found that the modified peptide was 10- to 100-fold better at priming a T cell response than the wild-type peptide. Therefore, we were able to create a peptide that was more immunogenic than the wild-type peptide in vivo as well as in vitro. Manipulations such as these that enhance the immunogenicity of T cell epitopes must be considered in developing peptide vaccines against HIV or other infectious agents.

Amino Acid Sequence↗
PubMed2004

Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans.

Despite advances at the level of gene sequence (eg, humanized versus murine antibodies), expression systems (eg, mammalian versus prokaryotic) and post-expression modification (eg, 'PEGylation'), clinical immunogenicity of therapeutic proteins remains a concern. Although animals are routinely and effectively used to evaluate pharmacological activity and to support a claim of safety for recombinant proteins, their usefulness for predicting clinical immunogenicity is more questionable. This review argues that recombinant proteins can be grouped into immunogenic classes; for some of these classes, for example, bacterial proteins, immunogenicity in animals is often predictive for humans, but for others, for example, fully human proteins, even data from non-human primates can have little predictive value. We will attempt to make the case that for a variety of immunological and practical constraints, animal studies, even those conducted in non-human primates, have limited predictive power for immunogenicity in humans, and tend to over-predict clinical immunogenicity.

Animals↗
PubMed1990

[The risk of recurrence following the thyrostatic treatment of immunogenic and nonimmunogenic hyperthyroidism].

Data of 196 patients treated for hyperthyroidism exclusively with antithyroid drugs were analyzed retrospectively concerning the relapse rate within a follow-up period of four years. Patients were subdivided for primary or recurrent disease, and for immunogenic or non-immunogenic hyperthyroidism, respectively. In immunogenic as well as in non-immunogenic hyperthyroidism, the relapse rate was significantly lower for patients with primary disease (35% and 52%, respectively) compared to those with recurrent hyperthyroidism (82%, p less than 0.001 and 83%, p less than 0.001, respectively). In patients with primary disease, clinical, biochemical and scintigraphic parameters were tested with respect to their capability of predicting a relapse. For immunogenic hyperthyroidism the highest relapse rates were observed in young patients and in those with large goitres, whereas for non-immunogenic hyperthyroidism they were highest in old patients, in those with nodular goitres and in those without an increased urinary iodine excretion at the time of diagnosing hyperthyroidism.

Adolescent↗
PubMed1989

The immunogenicity of soluble haptenated polymers is determined by molecular mass and hapten valence.

T cell-independent Ag are believed to stimulate antibody formation in the relative absence of Ag processing and T cell help. Previous studies on the type 2 T cell independent (TI-2) Ag DNP-polyacrylamide, have shown that when one systematically varies the molecular mass and hapten valence, the immunogenic potential of this type of molecule depends on definable molecular characteristics. It was found that to be immunogenic, these molecules had to exceed a threshold molecular mass of 100,000 Da and a threshold hapten valence of 20. The present study was undertaken to determine whether such findings could be generalized to other molecules belonging to the TI-2 class of Ag. The molecular characteristics of five chemically different fluoresceinated (FL)-polymers were systematically varied, and their ability to stimulate an IgM antihapten immune response was measured. The polymers used as carriers were carefully size-fractionated and consisted of one natural polymer (dextran), one modified natural polymer (carboxymethyl cellulose), and three synthetic polymers (Ficoll, polyvinyl alcohol, and polyacrylamide). The carriers varied in physical structure from the highly cross-linked Ficoll, to the somewhat branched dextran, to the linear polyacrylamide, carboxymethyl cellulose, and polyvinyl alcohol. Polymers were haptenated with FL and size-fractionated so as to yield a panel of molecules with varying molecular mass, hapten valence, and hapten density. Anti-FL IgM response to these haptenated polymers was measured in vivo after i.p. injection of the FL-polymer in saline, and measured in vitro after culture with unfractionated spleen cells from naive mice. In agreement with the previous studies on DNP-polyacrylamide, it was found that to be immunogenic, each of the FL-polymers had to exceed a comparable threshold value of molecular mass and of hapten valence. Optimal immunogenicity occurred when the FL-polymers had values of mass and hapten density lying within a predictable range. Immunogenicity decreased when these optimal parameters were substantially increased or decreased. We conclude that the immunogenicity of soluble haptenated polymers depends on predictable physical molecular characteristics, and is relatively independent of the chemical composition and conformation of the carrier polymer.

Animals↗
PubMed1988

Induction in a murine tumor of immunogenic tumor variants by transfection with a foreign gene.

Transfection of the undifferentiated murine colon carcinoma line CT-26 with the gene coding for the hemagglutination antigen (HA) of influenza virus resulted in the generation of highly immunogenic tumor cells. CT-26 cells transfected with HA not only failed to grow in syngeneic mice but also protected normal animals against a challenge with otherwise lethal doses of parental nontransfected cells. The immunogenicity of HA-transfected cells appeared to correlate with surface HA expression in that tumorigenic clones of HA-transfected CT-26 cells expressed little HA, while immunogenic clones were high expressers of HA. Irradiation of immunogenic HA clones did not abrogate their immunogenicity. These observations demonstrate that immune recognition of a poorly immunogenic tumor can be produced by immunization with tumor cells expressing a defined, foreign cell surface antigen.

Animals↗
PubMed1987

Immunogenic variants of a murine fibrosarcoma induced by mutagenesis: requirement of viable cells for antigen-specific cross-protection.

The purpose of the study was to investigate the immunological and biological consequences of neoantigen expression by immunogenic tumor variants (Imm+) following in vitro treatment with the mutagen 1-methyl-3-nitro-1-nitrosoguanidine. The weakly immunogenic murine fibrosarcoma MCA-F was used because we have previously characterized the tumor-specific transplantation antigen expressed by this tumor. Immunogenic variant clones were obtained at high frequency following four treatments with 1-methyl-3-nitro-1-nitrosoguanidine. The immunogenicity of the Imm+ clones was confirmed by their progressive growth in immunosuppressed C3H/HeN mice and their lack of growth in normal syngeneic (C3H/HeN mice. The immune response engendered in immunocompetent mice after a single immunization with viable Imm+ cells was tumor specific, completely protecting hosts against challenge with 10,000-fold the minimum tumorigenic dose of parental MCA-F cells, but not against 10 minimum tumorigenic doses of the non-cross-reactive tumor MCA-D. The strong cross-protection elicited by Imm+ neoantigens against the parental tumor-specific transplantation antigen was not observed when soluble extracts or isolated plasma membranes of Imm+ cells were used for immunization. Immunogenic variant cells inactivated using either mitomycin C or gamma-irradiation also demonstrated a significantly diminished immunoprotective activity against challenge with the parent tumor. However, inactivated Imm+ cells and their isolated plasma membranes still expressed sufficient neoantigen to completely protect mice against homotypic Imm+, but not parental challenge. These results suggest that (a) the MCA-F Imm+ variants express neoantigens capable of engendering a strong specific as well as cross-protective immunity against challenge with either the parent or the variant and (b) the associative recognition of neoantigen and TSTA that results in strong cross-protection against challenge with the parent tumor requires immunization with viable Imm+ cells for full expression of the immunogenic phenotype.

Animals↗
PubMed1987

Approaches to augmenting the immunogenicity of the ganglioside GM2 in mice: purified GM2 is superior to whole cells.

The gangliosides GM2, GD2, and GD3 are differentiation antigens largely restricted to cells of neuroectodermal origin. They are expressed on most melanomas, astrocytomas, and neuroblastomas and have been shown to function as effective targets for monoclonal antibodies. In previous studies, we have immunized melanoma patients and mice with a series of melanoma cell vaccines containing these antigens, but have observed only occasional antibody responses. We report here the results of experiments in which an irradiated whole cell vaccine shown previously to be optimal was compared with a series of vaccines containing purified GM2. Mice were pretreated with low dose cyclophosphamide (Cy), or not, and were immunized twice with syngeneic melanoma cells (JB-RH) known to contain 60 micrograms of GM2 or with vaccines containing 50 micrograms of purified GM2. Serum was obtained at regular intervals and was tested by immune adherence, complement dependent cytotoxicity, and protein A assays on the JB-RH cell line. The whole cell vaccine, GM2 alone, GM2 incorporated into complete Freund's adjuvant, and GM2 attached to E. coli were all minimally immunogenic. GM2 attached to Salmonella minnesota or BCG, and GM2 attached to certain liposome preparations containing monophosphoryl lipid A, were found to be moderately immunogenic. GM2 attached to the R595 mutant of Salmonella minnesota was found to be significantly more immunogenic. Pretreatment with Cy significantly increased the immunogenicity of this vaccine. The specificities of selected sera were tested in inhibition assays and were limited to GM2. Antibodies produced after immunization were generally exclusively IgM and mediated potent complement-dependent cytotoxicity on JB-RH cells. These results identify R595 as the most effective adjuvant tested for augmenting the immunogenicity of GM2 and show that with regard to antibody production, purified tumor antigen presented optimally can be more immunogenic than optimally presented whole tumor cells containing the same amount of antigen.

Adjuvants, Immunologic↗
PubMed1983

Nephritogenicity and differential distribution of glomerular immune complexes related to immunogen charge.

Nephritogenicity and the differential distribution of glomerular deposits as a function of immunogen charge were examined in a murine model of chronic active serum sickness. A range of differentially charged immunogens was used, i.e., chemically modified highly cationic or anionic bovine gamma-globulin (BGG), native unmodified isoelectrically focused slightly cationic or anionic BGG, and heterogeneous native BGG. The amounts and distribution of immune complexes in glomeruli were compared by immunofluorescence and electron microscopy 3 to 10 weeks after the initiation of 15 intravenous injections of the five immunogens and 13 days after intraperitoneal continuous release of the native unmodified BGGs by osmotic pumps. The results demonstrate that the more cationic the immunogen, the more nephritogenic and the greater the tendency to form subepithelial deposits in the glomerular basement membrane. The observed differences in nephritogenicity and localization induced by focused unmodified cationic and anionic fractions of BGG particularly emphasize immunogen charge as a major factor influencing glomerular distribution of immune complexes in this model. The findings indicate that several degrees of nephritogenicity and the differential distribution of immune complexes can be related to immunogen charge and strongly suggest that charge interactions may be of fundamental importance in the pathogenesis of immune complex glomerulonephritis.

Animals↗
PubMed1982

Effect of lipid A incorporation on characterization of liposomal model membranes as thymus-independent type 1 or type 2 immunogens.

We used the following criteria to determine whether liposomal model membranes are thymus-independent type 1 (TI-1) or type 2 (TI-2) immunogens: a) in vivo response of (CBA/N X BALB/c)F1 male and female mice; b) in vitro response of spleen cells from these mice; c) ontogeny of the response in cultures of (C57BL/6 X DBA/2)F1 male cells obtained from mice of different ages; d) ability of a monoclonal anti-delta antibody to block the in vitro response of C57BL/6 spleen cells. The liposomes were sensitized with N(2,4,6-trinitrophenyl-6-N-aminocaproyl)-dipalmitoylphosphatidylethanolamine (TNP-Cap-DPPE) and were prepared without and with incorporation of the B cell mitogen, lipid A. On the basis of the above criteria, liposomes prepared without lipid A can be characterized as a TI-2 immunogen and resemble TNP-Ficoll. In contrast, liposomes prepared with lipid A behave like a TI-1 immunogen such as TNP-BA (trinitrophenylated Brucella abortus). Conversion of liposomes from a TI-2 to a TI-1 immunogen by inclusion of lipid A in the bilayers was achieved under conditions of constant TNP-Cap-DPPE epitope density. Increasing the epitope density in liposomes made without lipid A does not result in transformation of immunogen type. These results, which bear on the features that may distinguish TI-1 from TI-2 immunogens, are discussed with regard to the involvement of macrophages and T cells in the response.

Animals↗
PubMed1981

Immunogenicity and characterization of supernatant DNA released by murine spleen cells.

The cellfree supernatant from cultured splenocytes contains an immunogenic molecule capable of inducing anti-DNA antibodies in vitro and in vivo in young preautoimmune NZB/W and some normal mouse strains. The response to this supernatant material does not reflect polyclonal activation, and the molecule responsible for its immunogenic activity appears to be a relatively small (approximately 150 base pairs) DNA molecule, predominantly (75 to 80%) double stranded with tail-end single-strand regions. It does not appear to contain any unusual secondary structure. This immunogenic DNA molecule can be recovered from cultures of some normal as well as young B/W mice. It contains no observable protein moiety, and after phenol-chloroform extraction, the immunogenic DNA migrates on polyacrylamide and agarose gels as a relatively narrow homogeneous band. The anti-DNA antibody response detected in the serum of mice after injection of this DNA molecule appears to have its greatest affinity for the homologous DNA and for undenatured calf thymus DNA. Unique base sequences do not appear to be responsible for its immunogenic effects. Rather, this may depend on its relatively small size, since calf thymus DNA sheared to a similar size and also found incapable of digestion with restriction endonucleases had a similar immunogenic effect.

Animals↗
PubMed1995

Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides.

Human papillomavirus type 16 (HPV16) is strongly associated with cervical carcinogenesis. The HPV16 E6 and E7 oncoproteins are constitutively expressed in the majority of cervical tumor cells and are, therefore, attractive targets for CTL-mediated immunotherapy. In mice, the outgrowth of a lethal dose of HPV16-induced tumor cells has been prevented by vaccination with a CTL epitope encoded by HPV16 E7, indicating the feasibility of peptide immunization to obtain antitumor CTL responses. In the present study, the immunogenicity of 9 HLA-A*0201-binding peptides encoded by HPV16 E6 and E7 was analyzed in vivo in HLA-A*0201Kb transgenic mice and in vitro in CTL cultures induced from PBMC of HLA-A*0201+ healthy donors. Four peptides with a good binding affinity were immunogenic in HLA-A*0201Kb transgenic mice, and three of them were also highly immunogenic in CTL induction experiments with PBMC of HLA-A*0201+ healthy donors. Human CTL clones specific for these three peptides were capable of lysing the HPV16 E7-containing HLA-A*0201+ cervical carcinoma cell line CaSki. These E7-derived peptides (11-20, YMLDLQPETT; 82-90, LLMGTLGIV; 86-93, TLGIVCPI), therefore, are likely to represent naturally processed human CTL epitopes of HPV16. Additionally, these three HPV16-encoded peptides have the highest affinity of binding to the HLA-A*0201 molecule. In this study, peptides with a lower binding affinity were less immunogenic. Therefore, our data illustrate that the HLA-binding affinity of a peptide has a major impact on its immunogenicity. In conclusion, we have identified immunogenic peptides encoded by HPV16 E6 and E7 that could be used in vaccines for the prevention and treatment of cervical carcinoma.

Amino Acid Sequence↗
PubMed1994

Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70.

Stress-induced proteins (or heat shock proteins (HSPs)) of 96 kDa size (gp96) have been shown previously to elicit specific immunity to tumors from which they are isolated. In this report, we show that in contrast to Meth A-derived gp96, gp96 preparations derived from normal tissues did not elicit immunity to Meth A sarcoma at any dose tested. Further, in light of recent studies showing that other major cellular HSPs hsp90 and hsp70 also elicit tumor-specific immunity, we have compared the relative immunogenicities of gp96, hsp90, and hsp70 derived from the Meth A sarcoma. The proteins gp96 and hsp70 were observed to be highly and equally immunogenic, whereas the immunogenicity of hsp90 was approximately 10% of that of gp96 or hsp70. It is suggested that the poor immunogenicity of hsp90 results from its lack of a measurable ATPase activity, which has been implicated in the ability of HSPs to transfer peptide to acceptor molecules. This is the first study that documents the lack of immunogenicity of gp96 preparations derived from normal tissues and compares the immunogenicity of each of the three major cellular HSPs in one tumor system.

Animals↗
PubMed1997

Dacarbazine-induced immunogenicity of a murine leukemia is attenuated in cells transfected with mutated K-ras gene.

Strong immunogenicity is induced by antitumor triazene compounds in tumor cells through a mutagenic mechanism. A highly immunogenic < > clone, isolated from a dacarbazine-treated L5178Y leukemia of DBA/2 mice, was transfected with K-ras mutated at codon 12 (i.e. ras(m12)). This transfected clone presents at least 2 mutations, one concerning K-ras gene, and the other affecting an unrelated gene, responsible for the generation of a highly immunogenic, MHC class I restricted non-self peptide. The results indicate that cells of < > clone transfected with ras(m12) were less immunogenic than cells of the same origin transfected with the vector alone. Moreover, ras(m12)-transfected cells showed lower levels of H-2K(d) gene expression with respect to those detectable in control cells. In addition, in vivo and in vitro sensitization against < > clone carrying mutated ras did not result in a strong cytotoxic T lymphocyte response against ras(m12)-transfected non immunogenic L5178y target cells. These preliminary results suggest that K-ras mutation could down-regulate the level of tumor immunogenicity, possibly acquired through a mutagenic process affecting other unrelated genes.

Animals↗
PubMed1998

Cytokine gene transduction into non-immunogeneic murine tumor cells.

The effect of cytokine transduction on the tumorigenicity and immunogenicity of murine non-immunogeneic mammary carcinoma (4T1), acute myeloid leukemia (mAML) and partially immunogenic B-cell leukemia (BCL1) has been evaluated in syngeneic strains of mice. Transduction by retroviral vectors containing the genes for GM-CSF, IL-2 or IFN-gamma did not lead to a marked antitumor effect in 4T1 mammary tumor or BCL1. A reduced local tumor size was observed in mice inoculated with 4T1 cells transduced with both GM-CSF and IL-2 genes followed by an in vitro exposure to recombinant IFN-gamma, but survival was not prolonged. Tumorigenicity of mAML cells transduced with the gene coding for IFN-gamma was significantly reduced as manifested by prolonged survival of mice in comparison with animals inoculated with non-transduced mAML cells. Transduction by each of the aforementioned cytokines did not affect the immunogenicity of these tumor model cells. The results suggest that genetic modification of spontaneous and non-immunogenic experimental tumor models does not necessarily support direct utilization of cytokine gene therapy for clinical application. More effective methods have yet to be established in order to achieve an antitumor effect in spontaneous non-immunogenic malignancies.

Animals↗
PubMed1999

Terminal modifications inhibit proteolytic degradation of an immunogenic MART-1(27-35) peptide: implications for peptide vaccines.

Peptide epitopes for tumor-reactive cytotoxic T-lymphocytes (CTL) have been identified on human cancers and are being used in tumor vaccine trials. However, the pharmacokinetics and pharmacodynamics of such peptides have been inadequately studied. It is predicted that immunogenic tumor peptides would have short half-lives in vivo. The goal of the present work was to evaluate the stability of the immunogenic peptide MART-1(27-35) in fresh normal human plasma (NHP) and to identify modifications that convey protection against enzymatic destruction without loss of immunogenicity. We evaluated the stability of the MART-1(27-35) peptide (AAGIGILTV) and modified forms of that peptide for stability and immune recognition in an in vitro model. The peptides were incubated in plasma for varied time intervals and evaluated for their ability to reconstitute the epitope for MART-1(27-35)-reactive CTL. Loss of CTL reactivity signaled loss of immunoreactive peptide. When 1 microM MART-1(27-35) peptide was incubated in plasma prior to pulsing on target cells, CTL reactivity was lost within 3 hr, and the calculated half-life of this peptide was 22 sec. This degradation was mediated by peptidases. The stability of MART-1(27-35) was markedly prolonged by C-terminal amidation and/or N-terminal acetylation (peptide capping), or by polyethylene-glycol modification (PEGylation) of the C-terminus. These modified peptides were recognized by CTL. The MART-1(27-35) peptide is very unstable in plasma. It is probable that it and other immunogenic peptides will be similarly unstable in vivo. Immunogenicity of these peptides might be enhanced by creating modifications that enhance stability.

Antigens, Neoplasm↗