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PubMed1996

Safety and immunogenicity of Env 2-3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine Evaluation Group.

We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MF59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 micrograms of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 micrograms), and 14 subjects participated in a study of 100 micrograms of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects. Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively. Lymphoproliferative responses to the immunogen, Env 2-3 were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 micrograms did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.

AIDS Vaccines↗
PubMed2005

Comparison of HIV Type 1 ADA gp120 monomers versus gp140 trimers as immunogens for the induction of neutralizing antibodies.

Designing an immunogen for effective neutralizing antibody induction against diverse primary isolates of human immunodeficiency virus type 1 (HIV-1) is a high priority for HIV-1 vaccine development. Soluble gp120 envelope (Env) glycoprotein subunit vaccines elicit high titers of antibodies that neutralize T cell line-adapted (TCLA) strains but the antibodies possess poor neutralizing activity against many primary isolates. Previously, we generated soluble trimeric recombinant gp140 from the HIV-1 primary isolate ADA. Here we compared monomeric ADAgp120 and trimeric ADAgp140 as immunogens for neutralizing antibody responses in guinea pigs. Both immunogens generated a neutralizing antibody response that was detectable against the vaccine strain and several heterologous strains. The magnitude of this response was significantly greater in ADAgp140-immunized animals when measured against the TCLA strain, MN, and the R5 primary isolate, Bal. Two additional isolates (SS1196 and Bx08) were neutralized equally by sera from both groups of animals whereas other isolates were neutralized weakly or not at all. Despite equal titers of V3 loop specific binding antibodies in sera from both groups of animals, neutralization of ADA by sera from gp140-immunized animals was insensitive to the presence of ADA-V3 peptide, whereas addition of this peptide to sera from gp120- immunized animals blocked all detectable neutralizing activity against ADA. These results support the idea that trimeric gp140 is an improved immunogen compared to monomeric gp120 but that additional improvements are required to afford broad protection against a spectrum of heterologous primary HIV-1 isolates. This ADAgp140 immunogen may be considered a starting point from which to engineer additional improvements for cross-reactive neutralizing antibody induction.

AIDS Vaccines↗
PubMed1990

Comparison of monoclonal antibodies to estradiol obtained from structurally different immunogens.

The immunization procedure and immunogen characteristics required to optimize the production of anti-steroid monoclonal antibodies have been studied. Five different estradiol-bovine serum albumin conjugates were tested for immunizing mice, as were two different immunization protocols (high and low dose) and the effect of varying the myeloma/spleen cell ratio for cell fusion. Antibody-producing hybridomas, obtained using the spleens of 9 high anti-steroid titre mice, were detected by RIA and EIA. The latter method was less specific than the former for higher affinity anti-estrogen antibodies. All the immunogens elicited anti-estrogen antibodies and the efficiency appeared related to the steroid density on the immunogen rather than the chemical nature of the derivative or the immunization and fusion protocols. Thirty-six anti-estrogen producing hybridomas were detected. Comparison showed that all the immunogens elicited antibodies in a wide range of affinities and specificities. None of the antibodies recognized corticosteroids or progesterone. Cross reactions with testosterone and other estrogens were not clearly related to the nature of the immunogen except that estradiol coupled to the BSA via its carbon 17 yielded antibodies specific for steroids with a non-derivatized phenolic A-ring.

Animals↗
PubMed2005

Cross-clade protection induced by human immunodeficiency virus-1 DNA immunogens expressing consensus sequences of multiple genes and epitopes from subtypes A, B, C, and FGH.

The correlate of protection in human immunodeficiency virus (HIV) infection is not known, but preclinical and clinical studies support the involvement of both antibodies and cellular immunity. In addition, the existence of multiple HIV clades makes HIV vaccine design especially challenging. We have constructed a vaccine platform with an HIV-1 subtype B DNA immunogen expressing full length consensus sequences from HIV-1 rev, nef, tat, and gag with additional cellular epitope clusters from the env and pol regions. Furthermore, this platform has been extended to three additional plasmids expressing the same immunogens but originating from subtypes A or C consensus or FGH ancestral sequences. Immunogenicity in BALB/c mice, by gene gun or intramuscular delivery, revealed strong IFN-gamma production in response to in vitro re-stimulation with a H-2d restricted gag peptide (AMQMLKETI) or even stronger toward an env epitope (RGPGRAFVTI). Weak humoral immunity was detected. Gene gun immunization with a cocktail of all four plasmids induced pre-challenge cellular immunity in C57Bl6/A2.01 mice and subsequently a robust frequency of protection (11/12 animals) after experimental challenge with subtype A or B HIV-1/Murine Leukemia Virus (HIV-1/MuLV). The cross-clade protection observed in this challenge experiment demonstrates that these multigene/multiepitope HIV DNA immunogens are likely to be potent immunogens also against the HIV-infection of human beings.

AIDS Vaccines↗
PubMed1975

Modifying the immunogenicity of cell membrane antigens. Tumors and transplants.

The immunogenicity of an antigenic cell is a distinctly different property from its antigenic composition. Two clinical problems might well be beneficially affected by modifying the immunogenicity of cell membrane antigens: Can the immunogenicity of tumor-specific antigens on malignant cells be increased so that effective immunity to the tumor will lead to its destruction? Conversely, can the immunogenicity of histocompatibility antigens on grafted organs be minimized so that they will survive a foreign host? Evidence is accumulating to indicate that under certain conditions a tumor vaccine can be developed utilizing autochthonous tumor cells, removed from the host, chemically modified in vitro, and reinjected into the original host which will effectively, augment specific immunologic defenses against residual tumor cells. Similarly, the moderately immunosuppressed host will tolerate grafts after suitable immunogenic modification in vitro. Both approaches may have ready clinical application, even before the mechanisms have been worked.

Adenocarcinoma↗
PubMed1976

Delayed hypersensitivity to fungal antigens in mice. II. Characterization of the active component in immunogenic RNA extracts.

In a mouse model, cell-mediated immunity to Coccidioides immitis, as assayed by the delayed hypersensitivity skin test, was transferred with whole immunogenic RNA extract and its greater than 33S and 6S-13S sedimentation fractions. Both fractions were cleaved by RNase, but the products retained their transfer activity. The greater than 33S fraction of immunogenic RNA extract was inactivated by pronase, whereas the 6S-13S fraction was resistant to the proteolytic enzyme; however, after RNase treatment the latter fraction was sensitive to pronase. This finding suggests a protective role for RNA. Dialysis of immunogenic RNA extract yielded a dialysate with a ratio of absorbance at 260 nm to that at 280 nm (A260:A280) of 1.02. Similarly, the dialysis product of RNase-treated RNA is active and has an A260:A280 ratio of 1.34. The data indicate that at least part of the active moiety of immunogenic RNA extracts is an RNA-associated, pronase-labile peptide or nucleopeptide. Furthermore, it is possible that the dialyzable transfer factor may be the same peptide or nucleopeptide cleaved from immunogenic RNA during preparation of the transfer factor.

Animals↗
PubMed2000

The geometry of synthetic peptide-based immunogens affects the efficiency of T cell stimulation by professional antigen-presenting cells.

In the pathway leading to antibody production there are two points at which CD4(+) T(h) cells need to be recruited. The first of these is priming of T cells by their interaction with dendritic cells (DC) bearing antigen presented on MHC class II molecules and the second is the collaborative interaction of these primed T cells with B cells presenting the same antigen. We have previously shown that the configuration of T and B cell determinants within synthetic peptide immunogens can greatly influence the amount of immunogen required to produce an antibody response. Here we investigate whether the difference in potency of different immunogens is related to their ability to be presented by either DC or B cells. We show that determinants in a branched configuration, which are the most efficient at eliciting antibody in vivo, are presented to T cell clones by splenic CD8(-) DC 10-fold more efficiently than the corresponding determinants in a tandem linear arrangement. B cells also showed preferential presentation of branched immunogens to one T cell clone but in contrast to DC, not to a second T cell clone, indicating differences between the two antigen-presenting cell types. We also show that branched immunogens have a greater stability in serum compared to linear peptides, which may further enhance the differences in their in vivo potency.

Amino Acid Sequence↗
PubMed1990

Monoclonal antibodies to immunogenic lymphoma cell variants displaying impaired neoplastic properties: characterization and applications.

Immunogenic, nontumorigenic cell variants derived from the highly tumorigenic mouse lymphoma cell line S-49 were used to raise monoclonal antibodies (MAbs) in syngeneic BALB/c mice. MAbs of the following specifications were derived: (a) MAbs that interacted preferentially with the immunogenic variants, (b) MAbs that interacted with both immunogenic variants and parental tumorigenic cells, and (c) a MAb that interacted with both immunogenic and tumorigenic S-49 cells and the normal BALB/c splenocytes. Six MAbs raised in this way were found to recognize at least five different cell-surface epitopes. Functional analysis of the different MAbs suggested their potential usefulness in passive immunization against parental tumorigenic cells as well as in enrichment of immunogenic cells from a mixed population containing a preponderance of tumorigenic cells.

Animals↗
PubMed1999

Cell-associated HIV-1 messenger RNA and DNA in T-helper cell and monocytes in asymptomatic HIV-1-infected subjects on HAART plus an inactivated HIV-1 immunogen.

OBJECTIVE: We examined the effect of an HIV-1-specific immune-based therapy on cell-associated HIV-1 DNA and RNA. DESIGN: Five HIV-1-infected subjects receiving HIV-1 immunogen plus HAART were compared with three HIV-1-infected subjects who received incomplete Freund's adjuvant (IFA) plus HAART. METHODS: Cell-associated HIV-1 RNA or DNA in lymphocytes and monocytes was determined using a dual immunophenotyping/in situ hybridization assay with or without in situ PCR amplification. RESULTS: Cell-associated HIV-1 RNA in CD4 cells correlated with plasma RNA overall. CD4, HIV-1 gag-pol messenger (m)RNA+ cells decreased in the immunogen plus HAART group compared with the IFA plus HAART group. Decreases in HIV-1 DNA+ CD4 cells were observed in the immunogen plus HAART compared with the IFA plus HAART group. Decreases in HIV-1 gag-pol mRNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group. Consistent with the findings in CD4 cells, decreases in HIV-1 DNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group. CONCLUSIONS: These preliminary observations support the rationale for examining the combination of immune-based therapies and antiretroviral drugs for effective HIV-1 control.

AIDS Vaccines↗
PubMed1998

Immunogenicity of cultured keratinocyte allografts deficient in major histocompatibility complex antigens.

BACKGROUND: Full-thickness (FT) and cultured keratinocyte (CK) allografts have been used as temporary skin replacements in patients with massive burns, but these grafts are ultimately rejected after restoration of host immunocompetence. Genetic engineering has permitted the creation of knockout (KO) mice deficient in class I or class II major histocompatibility antigens. This study examines the immunogenicity of such grafts to determine if these genetically modified keratinocytes could be used for permanent wound coverage. METHODS: Host sensitization to alloantigen was assessed by second-set rejection. CBA mice (n = 111) were primed with flank grafts consisting of FT and CK allografts from normal C57BL/6 donors, FT and CK class I KO allografts, FT and CK class II KO allografts, and CK autografts. Three weeks later, hosts were challenged with normal tail allografts and observed for second-set rejection. Median graft survival was analyzed by chi2 and Wilcoxon rank tests. In the second experiment, cytotoxic T lymphocytes (CTLs) were harvested from CBA mice (n = 28) 3 weeks after flank grafting. CTL effectors were tested on radiolabeled targets at various ratios in a 51Cr release assay. Dilution curves of CTL activity were compared by analysis of variance. RESULTS: Hosts primed with CK or FT allografts demonstrated accelerated rejection of second-set tail grafts compared with hosts covered with CBA autografts. CK knockout grafts were less immunogenic than FT knockout skin; class II KO allografts were considerably less immunogenic than class I KO allografts. CTL activity against the knockout CK allografts was negligible compared with that of hosts primed with normal allografts or FT knockout allografts. CONCLUSION: Although full-thickness knockout skin retains substantial immunogenicity, cultured keratinocytes deficient in class II antigens fail to prime for accelerated second-set rejection and do not elicit a CTL response in the graft recipient. This lack of immunogenicity may permit the indefinite survival of allogeneic knockout keratinocytes in patients requiring massive wound excision and coverage.

Animals↗
PubMed1997

Safety and immunogenicity of a novel mammalian cell-derived recombinant hepatitis B vaccine containing Pre-S1 and Pre-S2 antigens in neonates.

BACKGROUND: Most of the licensed hepatitis B vaccines produced by recombinant DNA contain the S protein component of the hepatitis B virus surface antigen particle but lack two important components, Pre-S1 and Pre-S2. These components have recently been shown to play an important immunogenic role by enhancing the hepatitis B surface antibody (anti-HBs) titers, stimulating response and circumventing genetic nonresponsiveness. OBJECTIVE: To assess safety, tolerability and immunogenicity in neonates of a novel recombinant HBV vaccine (Bio-Hep-B) containing the S, Pre-S1 and Pre-S2 components compared with a licensed recombinant vaccine (Engerix-B) containing the S component only. METHODS: Healthy neonates were randomized to receive either Bio-Hep-B (2.5 micrograms/dose) or Engerix-B (10 micrograms/dose) at ages < 24 h, 1 month and 6 months. Blood was obtained at ages 0, 1, 7 and 12 months. Tolerability was assessed by diary cards filled by the parents for 5 successive days after immunization. Immunogenicity was assessed by determination of anti-HBs antibody. RESULTS: Of 205 neonates 153 were in the Bio-Hep-B group and 52 were in the Engerix-B group. Both vaccines were well-tolerated and all infants became seroprotected (anti-HBs > 10 mIU/ml). After the first dose a significantly higher proportion of neonates seroconverted in the Bio-Hep-B group than in the Engerix-B group (83% vs. 34%; P < 0.001); this difference in seroresponse was even more pronounced for those achieving seroprotective concentrations (> 10.0 mIU/ml) after the first dose: 54% vs. 7%, respectively (P < 0.001). Geometric mean concentrations were significantly higher at all points in the Bio-Hep-B group. CONCLUSION: Both vaccines were well-tolerated and immunogenic. Bio-Hep-B, despite its low dose, was significantly more immunogenic and elicited more rapid antibody response. This finding has implication for future vaccine programs in regions where maternal screening for hepatitis B virus surface antigen and administration of hepatitis B immunoglobulin are not routinely practiced at birth for infants of hepatitis B virus carrier mothers.

Female↗
PubMed2001

Tolerability and immunogenicity of an eleven-valent pneumococcal conjugate vaccine in healthy toddlers.

BACKGROUND: A need to increase the serotype coverage of pneumococcal conjugate vaccines exists. The use of a single carrier protein may cause overload of the carrier and decrease the immune response by not providing sufficient carrier-specific T helper cell support. A vaccine composed of a mixture of tetanus- and diphtheria-conjugated polysaccharides (PS) is a potential solution to this issue. OBJECTIVES: The aim of this study was to assess the tolerability and immunogenicity in healthy toddlers of an 11-valent pneumococcal conjugate vaccine that uses both tetanus and diphtheria toxoids as carriers. We explored the effect of an aluminum adjuvant on safety and immunogenicity by comparing the vaccine with and without adjuvant. METHODS: Twenty Finnish and 23 Israeli toddlers received the conjugate vaccine with or without aluminum adjuvant. Safety data were recorded for 5 days after vaccination. Sera were obtained before and 28 days after the immunization. IgG antibodies to the 11 vaccine-type PSs were determined by enzyme immunoassay. RESULTS: No serious adverse events occurred. The formulation with the adjuvant tended to induce fewer local but more systemic reactions than the non-adjuvant-containing formulation. Both vaccine formulations induced significant IgG increases for the vaccine-specific PSs. Types 3 and 7F were the most immunogenic; antibodies reached a concentration of 1 microg/ml in all individuals. Conjugates of types 6B, 14 and 23F were the weakest immunogens; antibodies reached the concentration of 1 microg/ml in 36, 27 and 32% of the individuals in the nonadjuvant group and in 53, 38 and 53% in the adjuvant group, respectively. CONCLUSIONS: An 11-valent mixed carrier pneumococcal conjugate vaccine is safe and immunogenic in toddlers. The use of an adjuvant do not seem to offer any significant benefit.

Adjuvants, Immunologic↗
PubMed1999

Immunogenicity of variable regions of hepatitis C virus proteins: selection and modification of peptide epitopes to assess hepatitis C virus genotypes by ELISA.

The immunogenicity of variable regions of hepatitis C virus (HCV) proteins was studied by ELISA by using 543 synthetic peptides from 120 variable regions and 90 sera from HCV-infected patients. Some regions from certain genotypes were less immunogenic, or even non-immunogenic, compared with their equivalents in other genotypes. However, the mean recognition of all peptides from genotypes 1a, 1b and 3 by sera infected with genotypes 1a, 1b and 3, respectively, showed no significant differences, suggesting a similar overall immunogenicity of variable regions from these genotypes. Proteins NS4a, NS4b and NS5a were found to be the most immunogenic. Recognition of individual peptides by the sera of infected patients showed that the humoral response against HCV is patient-dependent. The work shows that 15-mer peptides may encompass several B-cell epitopes. These epitopes may lie in slightly different positions in different genotypes. Thirty-one percent of the 543 peptides were recognized by some of the 35 healthy donors. This may be a reflection of the large number of antigens to which they had been exposed, but it may also reflect a strategy of HCV to respond to immune pressure. After selection and modification, a set of 40 peptides was used to assess genotypes 1a, 1b, 1, 2 and 3 in the sera of HCV-infected patients, with sensitivities of 34.1, 48.5, 68.8, 58.3 and 48.9% and specificities of 100, 99.1, 97.1, 99.5 and 99%, respectively. The overall sensitivity and specificity for the assessment of genotypes 1, 2 and 3 were 64 and 98%, respectively.

Amino Acid Sequence↗
PubMed1989

Route-related variation in the immunogenicity of killed Salmonella enteritidis vaccine: role of antigen presenting cells.

In order to assess the role of the route of immunization on the immunogenicity of killed Salmonella vaccine, mice were immunized with killed S. enteritidis by intraperitoneal (i.p.) and intradermal (i.d.) routes. Whereas the former was non-immunogenic, the i.d. immunization generated an excellent delayed-type hypersensitivity response; further, i.p. immunization could even suppress the subsequent i.d. immunization. Since the peritoneal macrophages (MO) are known to be particularly low in Ia or MHC-class II antigens, so essential for antigen presentation, the non-immunogenicity by i.p. route was thought to be due to their poor presentation efficiency. Poly I: poly C, an interferon inducer, is known to enhance the MHC-class II expression; hence effect of poly I: poly C treatment on the immunogenicity of the killed vaccine by i.p. route was tested and indeed the non-immunogenicity was corrected. Poor efficiency of presentation of S. enteritidis antigen by peritoneal cells and its improvement by prior poly I: poly C treatment was further confirmed by in vitro lymphocyte transformation test using primed T cells and peritoneal cells from normal and poly I: poly C treated mice. Poly I: poly C treatment also enhanced expression of Ia antigens on peritoneal cells.

Animals↗
PubMed1991

Capacity of CD8+ T cells to reject immunogenic variants of a spontaneous murine carcinoma: lack of non-specific (NK1.1+) effector mechanisms.

Class I MHC-expressing (Ia-) immunogenic (imm +) variants, which elicit a strong syngeneic host immune rejection response, can be isolated following 5-azacytidine treatment from the MHC-negative non-immunogenic (imm-) murine carcinoma cell line SP1 (10.1 subclone). In the present study, we have shown that CD4-depleted CD8+ T cells are both necessary and sufficient for the rejection process. Treatment of semi-syngeneic B6 X CBA F1 mice with anti-NK1.1 antibodies had no effect on the rejection of immunogenic variants, although the splenic NK (natural killer) activity of recipients was fully abrogated. Thus NK1.1+ effectors, which include most NK and LAK (lymphokine activated killer) cells, are most likely not involved in the rejection process. This finding was supported by a complete lack of NK susceptibility of SP1 cells in vitro, although variable killing by LAK and poly-I: C-induced killer cells was observed. To assess the role of NK1.1-LAK and other non-T killers (e.g. cytolytic macrophages) in vivo, we determined the specificity of the rejection process. We examined the ability of immune animals to reject a mixture of non-immunogenic parent tumour cells (or cells of an unrelated syngeneic tumour) and of the variant tumour cells used for the initial immunization. Growth of the parent tumour cells was unaffected while the same animals rejected the immunogenic tumour cells. Our findings support a primary role of tumour-specific CD8+ T cells in the rejection of imm+ variants with no detectable involvement of non-specific effector cells in the tumour destruction process.

Adenocarcinoma↗
PubMed1997

Synthetic peptide vaccines: palmitoylation of peptide antigens by a thioester bond increases immunogenicity.

Synthetic peptides have frequently been used to immunize animals. However, peptides less than about 20 to 30 amino acids long are poor immunogens. In general, to increase its immunogenicity, the presentation of the peptide should be improved, and molecular weight needs to be increased. Many attempts have been made to couple peptide immunogens to different carrier proteins [e.g. keyhole limpet haemocyanin (KLH) or ovalbumin]. This leads to very complex structures, however. We used a controlled conjugation of a peptide to a single long-chain fatty acid like palmitic acid by a thioester or an amide bond. It was found that these S-palmitoylated peptides were much more immunogenic than N-palmitoylated peptides and at least similar to KLH-conjugated peptides with respect to appearance and magnitude of induced antibodies (canine parvovirus) or immunocastration effect (gonadotropin-releasing hormone). For chemical synthesis of thioesters, we established conditions for solution and solid-phase synthesis. In both phases, Cys(SBut) could only be deprotected efficiently using phosphines, and S-acylation was accomplished using standard coupling at pH 5. We speculate that, in vivo, the presence of an appropriate fatty acid chain, chemically linked through a labile thioester bond, greatly enhances immunogenicity, because it represents a favourable substrate for cleavage by cellular thioesterases in cells of the immune system.

Amino Acid Sequence↗
PubMed2005

Herpesvirus saimiri immortalization of Aotus T lymphocytes specific for an immunogenically modified peptide of Plasmodium falciparum merozoite surface antigen 2.

The Plasmodium merozoite surface antigen 2 (MSA2) is one of several candidates for a protective vaccine against malaria. Previous studies have shown that antibodies directed against the MSA2 variable region are not protective and that constant regions are non-immunogenic. However, modified peptides derived from constant regions can be rendered immunogenic and partially protective in Aotus monkeys. In this study, we reveal the establishment, using in vitro Herpesvirus samiri (HVS) infection, of an Aotus monkey T-cell line (AnTMSA2) specific for a modified immunogenic and partially protective peptide derived from a constant and highly conserved region of MSA2 (SKYSNTFINNAYNMSIRRSM). AnTMSA2 is a CD4 T lymphocyte expressing high levels of MHC class II molecules, CD58 and CD2, which are important for proliferation and growth. AnTMSA2 proliferates specifically in response to the modified monomeric MSA2 peptide sequence. It is also capable of specific antigen recognition after glycine-cysteine-polymerized sequence processing and presentation by autologous APC. Interestingly, AnTMSA2 presents cross-reactivity with D-peptide analogues in which residues in positions 8 and 9 were changed for NDID residues. Therefore, at least for this particular sequence, polymerized D-peptides could be used for immunizing animals without losing the immunogenic epitope. AnTMSA2 presents a cytokine profile corresponding to a Th0-like pattern, which suggests that as a result of HVS immortalization AnTMSA2 is in transit from a Th2 to a Th1 pattern. Taken together our results suggest that Th2 T-cell induction and/or T-cell cross-reactivity generation by the modified peptide could be responsible for the immunogenic conversion observed in Aotus monkeys and that D-peptide analogues with longer half-lives could provide an alternative for inducing protective immunity.

Amino Acid Sequence↗
PubMed2006

Relative immunogenicity of Fya and K antigens in a Caucasian population, based on HLA class II restriction analysis.

BACKGROUND: It has long been known that relative immunogenicity is a characteristic of protein red blood cell (RBC) antigens, but the mechanisms remain unclear. The aim of this work was to elucidate the mechanisms underlying this relative immunogenicity. STUDY DESIGN AND METHODS: Two RBC antigens were used as a model--the highly immunogenic K antigen (KEL1) and the less immunogenic Fya antigen (FY1)--and analyzed the distribution of DRB1* molecules in two groups of Caucasian individuals producing anti-Fya (n = 29) or anti-K (n = 30) alloantibodies. These experimental results were compared to the results generated by TEPITOPE, a DRB1* peptide-binding motif prediction algorithm. RESULTS: It was found that within the anti-Fya group, the DRB1*04 phenotypic frequency was 100 percent, indicating that the DRB1*04 molecule is the restriction molecule. In the anti-K group, numerous DRB1* molecules were identified, demonstrating a high degree of histocompatibility promiscuity, corresponding to the predominant molecules in the Caucasian population. These findings were confirmed by TEPITOPE. CONCLUSION: These results strongly suggest that protein RBC intrinsic immunogenicity depends on the distribution of DRB1* restriction molecules.

Algorithms↗