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Ted M. Ross - One of the best experts on this subject based on the ideXlab platform.

  • DNA epitope vaccine containing Complement Component C3d enhances anti-amyloid-beta antibody production and polarizes the immune response towards a Th2 phenotype.
    Journal of neuroimmunology, 2008
    Co-Authors: Nina Movsesyan, Ted M. Ross, Mikayel Mkrtichyan, Irina Petrushina, David H Cribbs, Michael G Agadjanyan, Anahit Ghochikyan
    Abstract:

    We have engineered a DNA epitope vaccine that expresses 3 self-B cell epitopes of Abeta(42) (3Abeta(1-11)), a non-self T helper (Th) cell epitope (PADRE), and 3 copies of C3d (3C3d), a Component of Complement as a molecular adjuvant, designed to safely reduce CNS Abeta. Immunization of mice with 3Abeta(1-11)-PADRE epitope vaccine alone generated only moderate levels of anti-Abeta antibodies and a pro-inflammatory T helper (Th1 phenotype) cellular immune response. However, the addition of 3C3d to the vaccine construct significantly augmented the anti-Abeta humoral immune response and, importantly, shifted the cellular immune response towards the potentially safer anti-inflammatory Th2 phenotype.

  • DNA epitope vaccine containing Complement Component C3d enhances anti-amyloid-β antibody production and polarizes the immune response towards a Th2 phenotype
    Journal of Neuroimmunology, 2008
    Co-Authors: Nina Movsesyan, Ted M. Ross, Mikayel Mkrtichyan, Irina Petrushina, David H Cribbs, Michael G Agadjanyan, Anahit Ghochikyan
    Abstract:

    Abstract We have engineered a DNA epitope vaccine that expresses 3 self-B cell epitopes of Aβ 42 (3Aβ 1–11 ), a non-self T helper (Th) cell epitope (PADRE), and 3 copies of C3d (3C3d), a Component of Complement as a molecular adjuvant, designed to safely reduce CNS Aβ. Immunization of mice with 3Aβ 1–11 -PADRE epitope vaccine alone generated only moderate levels of anti-Aβ antibodies and a pro-inflammatory T helper (Th1 phenotype) cellular immune response. However, the addition of 3C3d to the vaccine construct significantly augmented the anti-Aβ humoral immune response and, importantly, shifted the cellular immune response towards the potentially safer anti-inflammatory Th2 phenotype.

  • A minimum CR2 binding domain of C3d enhances immunity following vaccination
    Advances in experimental medicine and biology, 2006
    Co-Authors: Joseph F. Bower, Ted M. Ross
    Abstract:

    The degradation product of the third (C3) Complement Component, C3d, links innate and adaptive immunity, and the covalent attachment of C3d to an antigen enhances antigen-specific immune responses. C3d has been hypothesized to enhance immunity by direct interaction with Complement receptor 2 (CR2/CD21) on immune cells. However, the domains on C3d important for CR2 binding have been controversial, with various studies reaching contradictory conclusions. In addition, the concept of B-cell activation via CR2 by C3d has been questioned, since mice lacking CR2 still elicit C3d-enhanced immunity following vaccination. Therefore, the goal of this study was to determine if a peptide representing one of the proposed CR2 binding domains of C3d could substitute for the entire protein and enhance antigen-specific immunity. Mice (BALB/c) were vaccinated with the HIV-1 gp120 envelope glycoprotein (Envgp120) alone or fused to multiple copies of the murine C3d or a twenty-eight amino-acid peptide (P28) containing a minimum CR2 binding domain. Each immunogen was expressed from DNA plasmid in vivo or injected as purified recombinant protein. The fusion of the P28 peptide to Envgp120 enhanced both humoral and cell-mediated immune responses with similar efficiency as Envgp120 conjugated to C3d. The fusion of C3d or P28 to Envgp120 elicited higher-titer anti-Env specific antibody, enhanced avidity maturation of the elicited antibody, and elicited higher numbers of IFN-γ and IL-4 secreting cells compared to Envgp120 immunizations. This CR2-binding domain specific 28 amino acid peptide can substitute for the entire C3d molecule and enhance immunity. These results indicate that the adjuvant properties of C3d are associated with CR2 interaction.

  • protection against influenza virus infection by intranasal administration of C3d fused hemagglutinin
    Vaccine, 2003
    Co-Authors: Ted M. Ross, Izumi Watanabe, Shinichi Tamura, Takeshi Ichinohe, Hidehiro Takahashi, Hirofumi Sawa, Joe Chiba, Takeshi Kurata
    Abstract:

    For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the Complement Component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.

  • Enhancement of antibodies to the human immunodeficiency virus type 1 envelope by using the molecular adjuvant C3d.
    Journal of virology, 2003
    Co-Authors: Thomas D. Green, David C. Montefiori, Ted M. Ross
    Abstract:

    DNA vaccines expressing the envelope (Env) protein of the human immunodeficiency virus have been relatively ineffective at generating high-titer long-lasting neutralizing antibodies in a variety of animal models. In this study the murine and human homologues of the Complement Component C3d were used in a DNA vaccine to enhance the titers of antibody to Env. Initially plasmids expressing a secreted form of Env (sgp120) fused to one two or three copies of the murine homologue of C3d (mC3d) were constructed. Mice were inoculated with four vaccinations of DNA or two DNA vaccinations followed by two boosts of affinitypurified gp120 protein. Analyses of titers demonstrated that multiple copies of mC3d coupled to sgp120 induced long-lasting high-titer anti-Env antibody. Priming mice with sgp120-mC3d-DNA followed by inoculation of purified gp120 protein elicited the strongest antibody titers; however the avidity maturation of the antibody was accelerated in the mice inoculated with sgp120-mC3d3-DNA. In addition DNAs expressing sgp120 fused to three copies of the human homologue of C3d (hC3d3) efficiently enhanced the anti-Env antibody in rabbits. Lastly antisera from both mice and rabbits vaccinated with DNA expressing sgp120-C3d3 elicited higher titers of neutralizing antibody than did nonfused forms of Env. These results indicate that C3d conjugated to sgp120 enhances the antibody responses to Env compared to non-C3d fused forms of Env and this approach may be one way to overcome the poor ability of DNA vaccines to generate antibodies to Env. Originally published Journal of Virology Vol. 77 No. 3 Feb 2003

Anahit Ghochikyan - One of the best experts on this subject based on the ideXlab platform.

Tina Ristau - One of the best experts on this subject based on the ideXlab platform.

  • impact of the common genetic associations of age related macular degeneration upon systemic Complement Component C3d levels
    PLOS ONE, 2014
    Co-Authors: Tina Ristau, Constantin Paun, Lebriz Ersoy, Moritz Hahn, Yara Lechanteur, Carel B Hoyng, Eiko K De Jong, Mohamed R Daha, Bernd Kirchhof, Anneke Den I Hollander
    Abstract:

    Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the Complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic Complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of Complement factor H (CFH) genes and Complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56x10-7), AMD phenotype (p = 1.15x10-11) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87x10-6), higher body mass index (p = 1.00x10-13), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60x10-6) in CFH, rs4151667 (p = 1.01x10-5) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic Complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic Complement activation.

  • Allergy is a protective factor against age-related macular degeneration.
    Investigative ophthalmology & visual science, 2014
    Co-Authors: Tina Ristau, Lebriz Ersoy, Moritz Hahn, Yara Lechanteur, Carel B Hoyng, Mohamed R Daha, Anneke I. Den Hollander, Sascha Fauser
    Abstract:

    PURPOSE: To investigate the role of allergy on AMD. METHODS: Age-related macular degeneration staging was performed for 3585 individuals (1878 from Cologne, Germany, and 1707 from Nijmegen, The Netherlands). Interviewer-assisted questionnaires were evaluated for the factors smoking, use of corticosteroids, and history of allergy, including causative allergens. Serum Complement Component C3d and C3 levels were measured and the C3d:C3 ratio was calculated. Associations of allergy with AMD/late AMD were assessed by logistic regression analysis; C3d:C3 ratio was compared between groups. RESULTS: The discovery cohort from Cologne included 864 AMD patients and 1014 controls; 495 patients had late AMD. Positive history of allergy showed strong protective effects on the phenotype AMD (OR 0.52; P = 3.42 x 10(-9)) and late AMD (OR 0.32; P = 2.57 x 10(-13)). Subclassification in allergy-provoking agents showed significant protective effects in all groups. After adjustment for age, sex, smoking, and corticosteroid use, protective effects for AMD (OR 0.75; P = 0.018) and late AMD (OR 0.49; P = 2.87 x 10(-5)) were confirmed. Although the C3d:C3 ratio was higher in AMD/late AMD patients (both P < 0.001), there was no association with allergy in AMD (P = 0.22). The protective effect of allergy on AMD was confirmed in the replication cohort from Nijmegen (P = 0.002 for AMD; P = 0.0001 for late AMD). CONCLUSIONS: Allergy has a protective effect on the development of AMD independent of the provoking allergen, which cannot be explained by Complement activation. Further investigations are necessary to elucidate the molecular mechanisms underlying the protective effect of allergy on AMD.

Thomas D. Green - One of the best experts on this subject based on the ideXlab platform.

  • Enhancement of antibodies to the human immunodeficiency virus type 1 envelope by using the molecular adjuvant C3d.
    Journal of virology, 2003
    Co-Authors: Thomas D. Green, David C. Montefiori, Ted M. Ross
    Abstract:

    DNA vaccines expressing the envelope (Env) protein of the human immunodeficiency virus have been relatively ineffective at generating high-titer long-lasting neutralizing antibodies in a variety of animal models. In this study the murine and human homologues of the Complement Component C3d were used in a DNA vaccine to enhance the titers of antibody to Env. Initially plasmids expressing a secreted form of Env (sgp120) fused to one two or three copies of the murine homologue of C3d (mC3d) were constructed. Mice were inoculated with four vaccinations of DNA or two DNA vaccinations followed by two boosts of affinitypurified gp120 protein. Analyses of titers demonstrated that multiple copies of mC3d coupled to sgp120 induced long-lasting high-titer anti-Env antibody. Priming mice with sgp120-mC3d-DNA followed by inoculation of purified gp120 protein elicited the strongest antibody titers; however the avidity maturation of the antibody was accelerated in the mice inoculated with sgp120-mC3d3-DNA. In addition DNAs expressing sgp120 fused to three copies of the human homologue of C3d (hC3d3) efficiently enhanced the anti-Env antibody in rabbits. Lastly antisera from both mice and rabbits vaccinated with DNA expressing sgp120-C3d3 elicited higher titers of neutralizing antibody than did nonfused forms of Env. These results indicate that C3d conjugated to sgp120 enhances the antibody responses to Env compared to non-C3d fused forms of Env and this approach may be one way to overcome the poor ability of DNA vaccines to generate antibodies to Env. Originally published Journal of Virology Vol. 77 No. 3 Feb 2003

  • C3d enhancement of neutralizing antibodies to measles hemagglutinin.
    Vaccine, 2001
    Co-Authors: Thomas D. Green, Harriet L. Robinson, Bruce R. Newton, Paul A. Rota, Ted M. Ross
    Abstract:

    Measles remains a major cause of worldwide infant mortality despite the use of current live attenuated vaccines. New approaches to measles virus (MV) vaccine development are critical to interrupt the spread of MV. In this study, we report the results using a DNA vaccine expressing a fusion of the measles hemagglutinin (H) protein and the Complement Component, C3d, to enhance the titers of neutralizing antibody. Plasmids were generated that expressed a secreted (s) form of H and the same form fused to three tandem copies of the murine homologue of C3d (sH-3C3d). Analysis of titers of the antibody raised in vaccinated mice indicated that immunizations with the DNA expressing sH-3C3d had higher titers of anti-H antibodies compared to serum from mice vaccinated with DNA expressing sH only. In addition, sH-3C3d elicited higher neutralizing antibody titers that inhibited MV induced plaque formation.

  • Enhanced avidity maturation of antibody to human immunodeficiency virus envelope: DNA vaccination with gp120-C3d fusion proteins.
    AIDS research and human retroviruses, 2001
    Co-Authors: Ted M. Ross, Thomas D. Green, David C. Montefiori, Harriet L. Robinson
    Abstract:

    DNA vaccination can elicit both humoral and cellular immune responses and can confer protection against several pathogens. However, DNA vaccines expressing the envelope (Env) protein of human immunodeficiency virus (HIV) have been relatively ineffective at generating high titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, we report that fusion of Env and the Complement Component, C3d, in a DNA vaccine, enhances the titers of antibody to Env. Plasmids were generated that expressed a secreted form of Env (sgp120) from three isolates of HIV and these same forms fused to three tandem copies of the murine homologue of C3d (sgp120-3C3d). Analyses of titers and avidity maturation of the raised antibody indicated that immunizations with each of the sgp120-3C3d-expressing DNAs accelerated both the onset and the avidity maturation of antibody to Env.

Raja Rajalingam - One of the best experts on this subject based on the ideXlab platform.

  • OR18 C3d-Binding de novo donor-specific HLA antibodies and antibody-mediated rejection of kidney transplants
    Human Immunology, 2015
    Co-Authors: Dessislava Kopchaliiska, Manpreet Singh, Owen Buenaventura, Vasishta Tatapudi, Stephen J. Tomlanovich, Raja Rajalingam
    Abstract:

    Aim Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of HLA antibodies to bind Complement Component C3d allows accurate risk stratification at the time of AMR diagnosis. Methods Sera from kidney transplant recipients, who underwent a protocol or for-cause kidney biopsy and had detectable de novo DSA (by One Lambda) at the time of biopsy (median 3.8 yrs post-tx), were included in this study. These serum samples were re-tested using the Immucor single antigen beads with and without C3d detection system. Results This study included samples from 123 kidney recipients (70 males; 14 re-Tx; 46 LD) transplanted in our center between 1989 and 2011. Fifty-seven patients (46%) had C3d-binding DSA. Most C3d-binding DSAs were high MFI DSAs (11700 + 5188), and only 4/57 (7%) C3d-binding DSAs had 5000 MFI. Seventy percent of the patients with C3d-binding DSA (40/57) had AMR (18 aAMR and 22 cAMR) and C4d-positive biopsies; twenty-six percent (15/57) had ACR, and four percent (2/57) had negative biopsies. Fifty-two present of the patients (34/66) in the C3d-negative DSA group had DSA with MFI 5000. Some of the weak and moderate DSA detected by One Lambda single antigen bead reagents were not detected with the Immucor SAB. Among the patients with C3d-negative DSA, thirty-five percent (23/66) had AMR (7 aAMR and 16 cAMR); twelve percent (8/66) had ACR and thirty-three percent (22/66) had C4d-positive biopsies. In most cases 15/22 (68%), the C4d-positive biopsies were observed in patients with strong DSA (MFI > 5000). Conclusions Our data indicate a strong correlation between the presence of C3d-binding DSAs and AMR. C3d-binding antibodies seem to be prevalent to stronger antibodies. Further studies are needed to evaluate whether the presence of C3d-binding donor-specific antibodies can predict AMR and identify patients who are at increased risk of allograft failure. Download : Download full-size image