subject:(effector function)

Harvard University

1. Mahan, Alison Emilia. Regulation and Programming of Antibody Effector Function through IgG Glycosylation.

Degree: PhD, Biology: Medical Sciences, Division of, 2014, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070040

► Antibodies are the defining characteristic of the humoral immune response. Their functions are diverse, including direct neutralization of pathogens and recruitment of other immune molecules… (more)

▼ Antibodies are the defining characteristic of the humoral immune response. Their functions are diverse, including direct neutralization of pathogens and recruitment of other immune molecules or cells. While most successful vaccines induce protective neutralizing antibody responses, effective vaccine-elicited neutralizing antibodies against some pathogens, including HIV, HCV, malaria, and TB, remain elusive. Thus, researchers have begun to focus on how vaccines can elicit strong non-neutralizing antibody functions, including recruitment of innate immune factors for antibody-dependent cellular cytotoxicity, complement deposition, and anti\-body-dependent phagocytosis. The antibody's constant region (Fc) mediates most effector functions through isotype and subclass selection or alteration of the structure of the Fc-attached N-glycan, which controls function with exquisite specificity. Glycan modifications are naturally induced during inflammatory conditions such as autoimmune disease and natural infection however, the specific signals that regulate Fc-glycosylation remain unknown. This dissertation sought to understand how antibody glycosylation is regulated and how it can be programmed through vaccination. To do this, we first developed a technique to analyze antibody glycan structures both of bulk Fc and antigen-specific antibodies. Using this technique, we observed significant modulation of antibody glycans during viral infection as well as in vaccine-elicited antibodies. To identify specific signals important for altering the antibody glycan, we transcriptionally profiled stimulated B cells and identified a set of innate and adaptive stimuli that regulate the genes responsible for antibody glycosylation. The results described in this dissertation begin to define the specific mechanism(s) by which infection and vaccination modulate antibody glycosylation to elicit functional antibodies that can ultimately provide effective and sustained protection from infection. Advisors/Committee Members: Alter, Galit (advisor), Ribbeck, Katharina (committee member), Anthony, Robert (committee member), Kagan, Jonathan (committee member).

Subjects/Keywords: Biology; Immunology; Virology; effector function; Fc function; glycosylation; HIV; IgG; IgG-glycan

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APA (6^th Edition):

Mahan, A. E. (2014). Regulation and Programming of Antibody Effector Function through IgG Glycosylation. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070040

Chicago Manual of Style (16^th Edition):

Mahan, Alison Emilia. “Regulation and Programming of Antibody Effector Function through IgG Glycosylation.” 2014. Doctoral Dissertation, Harvard University. Accessed December 12, 2019. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070040.

MLA Handbook (7^th Edition):

Mahan, Alison Emilia. “Regulation and Programming of Antibody Effector Function through IgG Glycosylation.” 2014. Web. 12 Dec 2019.

Vancouver:

Mahan AE. Regulation and Programming of Antibody Effector Function through IgG Glycosylation. [Internet] [Doctoral dissertation]. Harvard University; 2014. [cited 2019 Dec 12]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070040.

Council of Science Editors:

Mahan AE. Regulation and Programming of Antibody Effector Function through IgG Glycosylation. [Doctoral Dissertation]. Harvard University; 2014. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070040

Universiteit Utrecht

2. Hessell, A.J. Antibody function in neutralization and protection against HIV-1.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/34006

► The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive… (more)

▼ The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive as the HIV-1 virus has evolved multiple mechanisms to evade neutralizing antibodies. This thesis traces studies with four broadly neutralizing human monoclonal antibodies against HIV-1 (i.e. b12, 2G12, 2F5 and 4E10) covering all prominent HIV-1 neutralizing epitopes, and examines the mechanisms by which antibodies protect against HIV-1 infection in vivo. The ability to neutralize HIV-1 infection in vitro is demonstrated to be an important correlate of protection in vivo for b12, which recognizes an important epitope overlapping the CD4 binding site of HIV-1. Studies using neutralizing antibody variants of b12 harboring mutations in their Fc region however demonstrated that also antibody Fc-mediated effector functions contribute to protection. Interestingly, the ability of antibody to interact with specific receptors (Fc?R) on cells of the innate immune system was found to be critical. The studies strongly suggest that neutralization of HIV-1 alone is not sufficient and that antibodies also need to engage cellular mechanisms which target and destroy HIV-1 infected cells to achieve complete protection. Our studies provided promise for vaccine development by identification of the requirements for protection, but also disappointment, as the high antibody titers needed seemed unachievable for induction with a vaccine. Significantly, we demonstrated that a strong drawback of the traditional design of antibody protection studies in animals is that high viral doses are used that contain much more virus than is contained in human transmission events. By using an innovative experimental design, it was found that low titers of the neutralizing antibody b12 provided significant protection against repeated challenges with, physiologically relevant, low doses of virus. Importantly, the serum neutralizing titers of the protected animals were determined to be low enough so that it can be reasonably expected that such titers can be achieved by vaccination. Protection studies with 2G12, which recognizes a cluster of mannose residues on gp120 via an unusual binding mechanism, brought an additional surprise as 2G12 was found to protect at very low serum neutralizing titers even when assessed in traditional high dose challenge experiments. The unusual protective ability of 2G12 underscores the realization that the gp120 glycan shield represents an important target for vaccine design. Finally, we examined protection by 2F5 and 4E10, which are directed against a site in the highly conserved membrane proximal external region (MPER) of gp41. 2F5 and 4E10 were able to provide complete protection against a SHIV mucosal challenge. The MPER therefore represents a third possible site of attack against HIV-1 and target for vaccine design. In summary, these studies have increased our insight into the mechanisms by which antibodies contribute to protection against HIV-1 infection. Our… Advisors/Committee Members: Winkel, J.G.J. van de, Burton, D.R., Parren, P.W.H.I..

Subjects/Keywords: Geneeskunde; Immunology; antibody; HIV-1; AIDS; neutralization; mechanism of protection; gp120; gp41; vaccine; effector function

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APA (6^th Edition):

Hessell, A. J. (2009). Antibody function in neutralization and protection against HIV-1. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/34006

Chicago Manual of Style (16^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed December 12, 2019. http://dspace.library.uu.nl:8080/handle/1874/34006.

MLA Handbook (7^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Web. 12 Dec 2019.

Vancouver:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2019 Dec 12]. Available from: http://dspace.library.uu.nl:8080/handle/1874/34006.

Council of Science Editors:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/34006

University of Minnesota

3. Zumwalde, Nicholas Alan. The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation.

Degree: PhD, Microbiology, Immunology and Cancer Biology, 2013, University of Minnesota

URL: http://purl.umn.edu/151553

► CD8+ T cells are vital components to the immune system and serve as crucial effectors in the elimination of infected cells and pathogens. During the… (more)

Subjects/Keywords: CD8+ T cells; CTLA-4; Effector function; ICAM-1; Inhibition; T cell clusters

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APA (6^th Edition):

Zumwalde, N. A. (2013). The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation. (Doctoral Dissertation). University of Minnesota. Retrieved from http://purl.umn.edu/151553

Chicago Manual of Style (16^th Edition):

Zumwalde, Nicholas Alan. “The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation.” 2013. Doctoral Dissertation, University of Minnesota. Accessed December 12, 2019. http://purl.umn.edu/151553.

MLA Handbook (7^th Edition):

Zumwalde, Nicholas Alan. “The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation.” 2013. Web. 12 Dec 2019.

Vancouver:

Zumwalde NA. The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation. [Internet] [Doctoral dissertation]. University of Minnesota; 2013. [cited 2019 Dec 12]. Available from: http://purl.umn.edu/151553.

Council of Science Editors:

Zumwalde NA. The role of ICAM-1 mediated T cell:T cell interactions on CD8+ T cell effector function and differentiation. [Doctoral Dissertation]. University of Minnesota; 2013. Available from: http://purl.umn.edu/151553

Dalhousie University

4. Furlong, Suzanne Joy. Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling.

Degree: PhD, Department of Microbiology & Immunology, 2012, Dalhousie University

URL: http://hdl.handle.net/10222/15491

► Thy-1 is a glycosylphosphatidylinositol-anchored protein that is expressed on murine T lymphocytes and is involved in T cell-mediated immune responses. In the presence of costimulatory… (more)

▼ Thy-1 is a glycosylphosphatidylinositol-anchored protein that is expressed on murine T lymphocytes and is involved in T cell-mediated immune responses. In the presence of costimulatory signals, monoclonal antibody (mAb)-induced signaling through Thy-1 is associated with hallmarks of T cell activation, including IL-2 production and T cell proliferation. Thy-1-induced signaling promotes cytotoxic effector molecule expression, but is unable to trigger delivery of the lethal hit to target cells, suggesting that Thy-1 provides an incomplete T cell receptor (TcR)-like signal. However, the effect of Thy-1 signaling on cytokine production and the development of T helper (Th) cell phenotypes (Th1, Th2, Th17) remains unclear. The purpose of this work was to further our understanding of Thy-1-mediated signal transduction and the role that Thy-1 plays in the development of effector T cell responses. I found that, in the context of costimulatory signals, anti-Thy-1 mAb induced significantly less IL-2 production, CD25 expression and T cell proliferation than anti-TcR? mAb. Several key signaling molecules, including protein tyrosine kinases, zeta chain-associated protein-70 and extracellular signal-regulated kinase were activated with delayed kinetics during Thy-1-mediated T cell activation. The delayed signaling kinetics resulted in the delayed acquisition of cytotoxic effector function and also delayed delivery of the lethal hit to target cells. Interestingly, Thy-1-mediated signaling induced significantly more IL-17 and IL-4 synthesis and less IFN-? synthesis in comparison to TcR-mediated signaling. Moreover, Thy-1-activated CD4+ T cells produced high levels of IL-17 and IL-4 but minimal IFN? when restimulated with anti-Thy-1 mAb or anti-TcR? mAb with or without costimulatory signals. The unique ability of Thy-1 signaling to induce IL-17 production correlated with the expression of the Th17 lineage-specific transcription factor, retinoic orphan receptor gamma t. These observations show that Thy-1 signaling differs from TcR signaling in its ability to induce Th cell cytokines. Taken together, my findings show that Thy-1 signaling can provide the full TcR-like signal required for both the differentiation and triggering of Th cells and cytotoxic T lymphocytes, albeit with delayed kinetics in comparison to TcR signaling. They also suggest that Thy-1 signaling may be important in the development of Th2 and Th17 responses. Advisors/Committee Members: Dr. George Carayannoitis (external-examiner), Dr. Roy Duncan (graduate-coordinator), Dr. Robert Liwski (thesis-reader), Dr. Brent Johnston (thesis-reader), Dr. David Hoskin (thesis-supervisor), Received (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).

Subjects/Keywords: Signal Transduction; T cells; Dendritic Cells; T cell Activation; Cytokine Production; IL-4; IL-17; Cytotoxic Effector Function

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Furlong, S. J. (2012). Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15491

Chicago Manual of Style (16^th Edition):

Furlong, Suzanne Joy. “Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling.” 2012. Doctoral Dissertation, Dalhousie University. Accessed December 12, 2019. http://hdl.handle.net/10222/15491.

MLA Handbook (7^th Edition):

Furlong, Suzanne Joy. “Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling.” 2012. Web. 12 Dec 2019.

Vancouver:

Furlong SJ. Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling. [Internet] [Doctoral dissertation]. Dalhousie University; 2012. [cited 2019 Dec 12]. Available from: http://hdl.handle.net/10222/15491.

Council of Science Editors:

Furlong SJ. Thy-1 Signaling in T cells is Weaker and Has Delayed Signaling Kinetics, Promotes Delayed Acquisition and Triggering of Cytotoxic Effector Function, and Preferentially Promotes IL-17A and IL-4 Production in Comparison to TcR Signaling. [Doctoral Dissertation]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/15491

Arizona State University

5. Hurtado, Jonathan. Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response.

Degree: Molecular and Cellular Biology, 2019, Arizona State University

URL: http://repository.asu.edu/items/53585

► Antibodies are naturally occurring proteins that protect a host during infection through direct neutralization and/or recruitment of the innate immune system. Unfortunately, in some infections,… (more)

▼ Antibodies are naturally occurring proteins that protect a host during infection through direct neutralization and/or recruitment of the innate immune system. Unfortunately, in some infections, antibodies present unique hurdles that must be overcome for a safer and more efficacious antibody-based therapeutic (e.g., antibody dependent viral enhancement (ADE) and inflammatory pathology). This dissertation describes the utilization of plant expression systems to produce N-glycan specific antibody-based therapeutics for Dengue Virus (DENV) and Chikungunya Virus (CHIKV). The Fc region of an antibody interacts with Fcγ Receptors (FcγRs) on immune cells and components of the innate immune system. Each class of immune cells has a distinct action of neutralization (e.g., antibody dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cell-mediated phagocytosis (ADCP)). Therefore, structural alteration of the Fc region results in novel immune pathways of protection. One approach is to modulate the N-glycosylation in the Fc region of the antibody. Of scientific significance, is the plant’s capacity to express human antibodies with homogenous plant and humanized N-glycosylation (WT and GnGn, respectively). This allows to study how specific glycovariants interact with other components of the immune system to clear an infection, producing a tailor-made antibody for distinct diseases. In the first section, plant-produced glycovariants were explored for reduced interactions with specific FcγRs for the overall reduction in ADE for DENV infections. The results demonstrate a reduction in ADE of our plant-produced monoclonal antibodies in in vitro experiments, which led to a greater survival in vivo of immunodeficient mice challenged with lethal doses of DENV and a sub-lethal dose of DENV in ADE conditions. In the second section, plant-produced glycovariants were explored for increased interaction with specific FcγRs to improve ADCC in the treatment of the highly inflammatory CHIKV. The results demonstrate an increase ADCC activity in in vitro experiments and a reduction in CHIKV-associated inflammation in in vivo mouse models. Overall, the significance of this dissertation is that it can provide a treatment for DENV and CHIKV; but equally importantly, give insight to the role of N-glycosylation in antibody effector functions, which has a broader implication for therapeutic development for other viral infections.

Subjects/Keywords: Immunology; Biomedical engineering; Biology; Antibody Dependent Enhancement; Antibody Effector Function; Chikungunya Virus; Dengue Virus; Glycoengineering; Therapeutics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hurtado, J. (2019). Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response. (Doctoral Dissertation). Arizona State University. Retrieved from http://repository.asu.edu/items/53585

Chicago Manual of Style (16^th Edition):

Hurtado, Jonathan. “Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response.” 2019. Doctoral Dissertation, Arizona State University. Accessed December 12, 2019. http://repository.asu.edu/items/53585.

MLA Handbook (7^th Edition):

Hurtado, Jonathan. “Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response.” 2019. Web. 12 Dec 2019.

Vancouver:

Hurtado J. Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response. [Internet] [Doctoral dissertation]. Arizona State University; 2019. [cited 2019 Dec 12]. Available from: http://repository.asu.edu/items/53585.

Council of Science Editors:

Hurtado J. Development of N-glycan Specific Plant Produced Antibody Therapeutics for a Fine-tuned Immune Response. [Doctoral Dissertation]. Arizona State University; 2019. Available from: http://repository.asu.edu/items/53585

6. Brady, Miriam T. Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis.

Degree: 2001, RIAN

URL: http://eprints.maynoothuniversity.ie/8965/

► The evaluation of vaccines for human use requires reliable models of infection, that are predictive of protective efficacy. Traditionally whole cell pertussis vaccines (Pw) have… (more)

▼ The evaluation of vaccines for human use requires reliable models of infection, that are predictive of protective efficacy. Traditionally whole cell pertussis vaccines (Pw) have been controlled using the Kendrick test, which measures protection following intracerebral challenge with Bordetella pertussis. However, this test is unsuitable for assessing the potency o f the new acellular pertussis vaccines (Pa). In this study, it was demonstrated that protection in a murine respiratory challenge model correlates with the protective efficacy of Pa and Pw in children, but vaccine potency could not be predicted on the basis of antibody responses against individual antigens. Furthermore, the murine model was shown to be a reliable method for the determination of consistency between different batches o f Pa and Pw. This study highlights the possible applications of the murine model in the regulatory control and future development of pertussis vaccines. The murine model of infection has been used in the elucidation of the protective mechanisms induced following immunization with Pw or Pa, revealing roles for both antibody and T-cells in protection against B. p ertu ssis. It has been demonstrated that children still appear to be protected against infection, despite a rapid decline in antibody levels after vaccination. In the murine model, antibody levels quickly decline after immunization, but significant levels of protection were observed following aerosol challenge. Recall T-cell responses detectable for prolonged periods after immunization, together with an anamnestic antibody response post-challenge suggest that immunological memory is more significant in protection, than the induction of immediate antibody responses in vaccine-induced protection against B. pertussis. It has been demonstrated that Thl responses and particularly the cytokine IFN-y, play a critical role in immunity to B. pertussis. In the present study, the role of IL-12 and IL-18 in the induction of a protective Thl response to B. p ertu ssis was examined. Lack of IL-12 during primary and secondary infection effected protection only at the early stages of infection, suggesting that IL-12 plays an important role at the induction stage of the immune response to B. pertussis, but also suggests that other cytokines may be involved. IL-18 is rapidly produced in the lungs of B. p ertu ssis infected IL-1 2~'~ and wild-type mice, which may compensate for the lack of IL-12 at the later stages of infection. The importance of Thl responses and IFN-y were fiirther highlighted in this study, through the investigation of the effect of helminth infection on the outcome o f B. p ertu ssis infection, or immunization with Pw. Infection with the parasite Fasciolahepatica , was shown to suppress B. pertussis-specific Thl responses, and delay bacterial clearance from the lungs, and was also shown to inhibit this Thl response after it had become established. Furthermore, it was demonstrated that infection with F. hepatic a was capable of downregulating the Thl response induced…

Subjects/Keywords: Regulation and Effector Function; TH1; TH2; Cells; Immunity; Bordetella Pertussis

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APA (6^th Edition):

Brady, M. T. (2001). Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis. (Thesis). RIAN. Retrieved from http://eprints.maynoothuniversity.ie/8965/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Brady, Miriam T. “Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis.” 2001. Thesis, RIAN. Accessed December 12, 2019. http://eprints.maynoothuniversity.ie/8965/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Brady, Miriam T. “Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis.” 2001. Web. 12 Dec 2019.

Vancouver:

Brady MT. Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis. [Internet] [Thesis]. RIAN; 2001. [cited 2019 Dec 12]. Available from: http://eprints.maynoothuniversity.ie/8965/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Brady MT. Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis. [Thesis]. RIAN; 2001. Available from: http://eprints.maynoothuniversity.ie/8965/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

The Ohio State University

7. Horne, Phillip Howard. Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model.

Degree: PhD, Integrated Biomedical Science, 2007, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1188397900

► Organ transplantation is first choice therapy for end stage organ failure. Advances in clinical transplantation have resulted in improved short term transplant survival for… (more)

▼ Organ transplantation is first choice therapy for end stage organ failure. Advances in clinical transplantation have resulted in improved short term transplant survival for most solid organ allografts, yet long term graft survival with preserved organ function is still elusive. Current therapies effectively control conventional immune pathways contributing to transplant rejection, however unconventional rejection pathways have emerged, including CD4-independent, CD8 ⁺T cell mediated rejection, antibody-mediated acute rejection, and memory T cell-mediated rejection. These immune pathways have all been described as significant barriers to establishing long term survival of transplanted organs. A murine model of hepatocellular transplantation activates conventional as well as unconventional T cell-dependent rejection pathways. This prompted studies to investigate the activation, effector mechanisms, and peripheral phenotypes of responding rejection pathways, with emphasis on unconventional rejection. The hypothesis was that allogeneic hepatocytes promote activation of recipient CD8 ⁺T cells through exclusive expression of MHC class I (independent of recipient immune factors) which is manifest by a dominant CD8 ⁺T cell-mediated cytotoxic phenotype of rejection; only in the absence of recipient CD8 ⁺T cells, rejection deviates to a CD4 ⁺T cell-mediated immune pathway and a distinct effector mechanism. The studies showed, in contrast to the hypothesis, recipient immune factors, such as the location of hepatocyte engraftment or the presence of CD4 ⁺T helper cells, significantly influenced CD8 ⁺T cell activation, effector function and mechanism, memory responses, and susceptibility to immune therapy. The data support the modified hypothesis that CD8 ⁺T cells mature along distinct effector pathways depending on the presence of CD4 ⁺T cell help during priming with alloantigen. In the absence of recipient CD8 ⁺T cells, hepatocellular allografts initiate CD4-mediated rejection, which occurs through recipient production of cytotoxic antibody and specific destruction of engrafted parenchymal cells in cooperation with recipient macrophages. These results characterize the T cell dependent immune mechanisms of rejection and the conditions that elicit or suppress them. These studies have productively contributed to the present understanding of the effector phenotype and mechanisms of both conventional and unconventional allograft rejection pathways and highlight some possible new targets for therapy to combat rejection occurring through unconventional immune pathways. Advisors/Committee Members: Bumgardner, Ginny (Advisor).

Subjects/Keywords: Health Sciences, Immunology; CD8 <; sup>; +<; /sup>; T cell; CD4 <; sup>; +<; /sup>; T cell; graft rejection; hepatocyte; liver; cytotoxicity; alloantibody; antibody dependent cellular cytotoxicity; immune tolerance; effector function

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Horne, P. H. (2007). Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1188397900

Chicago Manual of Style (16^th Edition):

Horne, Phillip Howard. “Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model.” 2007. Doctoral Dissertation, The Ohio State University. Accessed December 12, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1188397900.

MLA Handbook (7^th Edition):

Horne, Phillip Howard. “Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model.” 2007. Web. 12 Dec 2019.

Vancouver:

Horne PH. Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model. [Internet] [Doctoral dissertation]. The Ohio State University; 2007. [cited 2019 Dec 12]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1188397900.

Council of Science Editors:

Horne PH. Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model. [Doctoral Dissertation]. The Ohio State University; 2007. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1188397900

8. Hessell, A.J. Antibody function in neutralization and protection against HIV-1.

Degree: 2009, University Utrecht

URL: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

► The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive… (more)

▼ The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive as the HIV-1 virus has evolved multiple mechanisms to evade neutralizing antibodies. This thesis traces studies with four broadly neutralizing human monoclonal antibodies against HIV-1 (i.e. b12, 2G12, 2F5 and 4E10) covering all prominent HIV-1 neutralizing epitopes, and examines the mechanisms by which antibodies protect against HIV-1 infection in vivo. The ability to neutralize HIV-1 infection in vitro is demonstrated to be an important correlate of protection in vivo for b12, which recognizes an important epitope overlapping the CD4 binding site of HIV-1. Studies using neutralizing antibody variants of b12 harboring mutations in their Fc region however demonstrated that also antibody Fc-mediated effector functions contribute to protection. Interestingly, the ability of antibody to interact with specific receptors (Fc?R) on cells of the innate immune system was found to be critical. The studies strongly suggest that neutralization of HIV-1 alone is not sufficient and that antibodies also need to engage cellular mechanisms which target and destroy HIV-1 infected cells to achieve complete protection. Our studies provided promise for vaccine development by identification of the requirements for protection, but also disappointment, as the high antibody titers needed seemed unachievable for induction with a vaccine. Significantly, we demonstrated that a strong drawback of the traditional design of antibody protection studies in animals is that high viral doses are used that contain much more virus than is contained in human transmission events. By using an innovative experimental design, it was found that low titers of the neutralizing antibody b12 provided significant protection against repeated challenges with, physiologically relevant, low doses of virus. Importantly, the serum neutralizing titers of the protected animals were determined to be low enough so that it can be reasonably expected that such titers can be achieved by vaccination. Protection studies with 2G12, which recognizes a cluster of mannose residues on gp120 via an unusual binding mechanism, brought an additional surprise as 2G12 was found to protect at very low serum neutralizing titers even when assessed in traditional high dose challenge experiments. The unusual protective ability of 2G12 underscores the realization that the gp120 glycan shield represents an important target for vaccine design. Finally, we examined protection by 2F5 and 4E10, which are directed against a site in the highly conserved membrane proximal external region (MPER) of gp41. 2F5 and 4E10 were able to provide complete protection against a SHIV mucosal challenge. The MPER therefore represents a third possible site of attack against HIV-1 and target for vaccine design. In summary, these studies have increased our insight into the mechanisms by which antibodies contribute to protection against HIV-1 infection. Our… Advisors/Committee Members: Winkel, J.G.J. van de, Burton, D.R., Parren, P.W.H.I..

Subjects/Keywords: Immunology; antibody; HIV-1; AIDS; neutralization; mechanism of protection; gp120; gp41; vaccine; effector function

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APA (6^th Edition):

Hessell, A. J. (2009). Antibody function in neutralization and protection against HIV-1. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

Chicago Manual of Style (16^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019. http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006.

MLA Handbook (7^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Web. 12 Dec 2019.

Vancouver:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Internet] [Doctoral dissertation]. University Utrecht; 2009. [cited 2019 Dec 12]. Available from: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006.

Council of Science Editors:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Doctoral Dissertation]. University Utrecht; 2009. Available from: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

9. Hessell, A.J. Antibody function in neutralization and protection against HIV-1.

Degree: 2009, University Utrecht

URL: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

► The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive… (more)

▼ The ability to induce neutralizing antibodies is generally thought to be of great importance for vaccine efficacy. In HIV-1 research this quality has been elusive as the HIV-1 virus has evolved multiple mechanisms to evade neutralizing antibodies. This thesis traces studies with four broadly neutralizing human monoclonal antibodies against HIV-1 (i.e. b12, 2G12, 2F5 and 4E10) covering all prominent HIV-1 neutralizing epitopes, and examines the mechanisms by which antibodies protect against HIV-1 infection in vivo. The ability to neutralize HIV-1 infection in vitro is demonstrated to be an important correlate of protection in vivo for b12, which recognizes an important epitope overlapping the CD4 binding site of HIV-1. Studies using neutralizing antibody variants of b12 harboring mutations in their Fc region however demonstrated that also antibody Fc-mediated effector functions contribute to protection. Interestingly, the ability of antibody to interact with specific receptors (Fc?R) on cells of the innate immune system was found to be critical. The studies strongly suggest that neutralization of HIV-1 alone is not sufficient and that antibodies also need to engage cellular mechanisms which target and destroy HIV-1 infected cells to achieve complete protection. Our studies provided promise for vaccine development by identification of the requirements for protection, but also disappointment, as the high antibody titers needed seemed unachievable for induction with a vaccine. Significantly, we demonstrated that a strong drawback of the traditional design of antibody protection studies in animals is that high viral doses are used that contain much more virus than is contained in human transmission events. By using an innovative experimental design, it was found that low titers of the neutralizing antibody b12 provided significant protection against repeated challenges with, physiologically relevant, low doses of virus. Importantly, the serum neutralizing titers of the protected animals were determined to be low enough so that it can be reasonably expected that such titers can be achieved by vaccination. Protection studies with 2G12, which recognizes a cluster of mannose residues on gp120 via an unusual binding mechanism, brought an additional surprise as 2G12 was found to protect at very low serum neutralizing titers even when assessed in traditional high dose challenge experiments. The unusual protective ability of 2G12 underscores the realization that the gp120 glycan shield represents an important target for vaccine design. Finally, we examined protection by 2F5 and 4E10, which are directed against a site in the highly conserved membrane proximal external region (MPER) of gp41. 2F5 and 4E10 were able to provide complete protection against a SHIV mucosal challenge. The MPER therefore represents a third possible site of attack against HIV-1 and target for vaccine design. In summary, these studies have increased our insight into the mechanisms by which antibodies contribute to protection against HIV-1 infection. Our… Advisors/Committee Members: Winkel, J.G.J. van de, Burton, D.R., Parren, P.W.H.I..

Subjects/Keywords: Immunology; antibody; HIV-1; AIDS; neutralization; mechanism of protection; gp120; gp41; vaccine; effector function

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hessell, A. J. (2009). Antibody function in neutralization and protection against HIV-1. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

Chicago Manual of Style (16^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019. http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006.

MLA Handbook (7^th Edition):

Hessell, A J. “Antibody function in neutralization and protection against HIV-1.” 2009. Web. 12 Dec 2019.

Vancouver:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Internet] [Doctoral dissertation]. University Utrecht; 2009. [cited 2019 Dec 12]. Available from: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006.

Council of Science Editors:

Hessell AJ. Antibody function in neutralization and protection against HIV-1. [Doctoral Dissertation]. University Utrecht; 2009. Available from: http://dspace.library.uu.nl/handle/1874/34006 ; URN:NBN:NL:UI:10-1874-34006 ; urn:isbn:978-90-6464-343-9 ; URN:NBN:NL:UI:10-1874-34006 ; http://dspace.library.uu.nl/handle/1874/34006

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