scholarly journals An International Epidemiology Study to Determine the Prevalence of Preexisting Cell-Mediated Immunity to Adeno-Associated Virus (AAV) in Adults with Severe Hemophilia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5794-5794
Author(s):  
Kavitha S. Rajavel ◽  
John C. Chapin ◽  
Ying Tang
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Hemophilia A ◽  
Peptide Pool ◽  
Cell Mediated Immunity ◽  
Severe Hemophilia ◽  
Adult Males ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Plasma Factor

Abstract Introduction: Adeno-associated virus (AAV) is a versatile gene therapy vector utilized widely in clinical gene transfer studies. AAV serotype 8 (AAV8) has been used successfully as a vector in liver-directed gene transfer in hemophilia clinical trials, and a recombinant AAV8 vector is used currently in Shire's BAX 888 clinical study (NCT03370172) for the treatment of patients with severe hemophilia A. However, 1 recognized limitation of intravenous administration of recombinant AAV is the barrier posed by preexisting immunity against AAV and the cross-reactivity of anti-AAV antibodies between various serotypes that results from natural exposure to the wild-type viruses. Neutralizing antibodies (NAbs) resulting from humoral immune responses can compromise vector transduction, and reactivation of memory T cells from cell-mediated immune responses can abrogate transgene expression and eliminate transduced cells. Understanding the prevalence of cell-mediated immune responses in the hemophilia population and the association between cell-mediated and humoral immunity is important in developing effective gene therapies. Objectives: To determine the prevalence of preexisting immunity towards AAV8 and AAV2 in the adult population of patients with hemophilia A and B, and to characterize the association between cell-mediated immunity and humoral immunity. Methods: In this ongoing study, peripheral blood samples were collected at outpatient visits from adult males (age 18-75 years) with severe hemophilia A (plasma factor VIII [FVIII] activity <1%) or hemophilia B (plasma factor IX [FIX] activity ≤2%) for determination of immunity towards AAV8 and AAV2. Patients could elect to participate in a single baseline visit or in the longitudinal study arm for up to 3 annual visits. Patients with inhibitors or a history of inhibitors to FVIII or FIX, an underlying lymphocyte disorder, or currently receiving cytotoxic chemotherapy, monoclonal antibodies, immunoglobulins, immunosuppression, or systemic antiviral therapy were excluded. The cell-mediated immune response against AAV8 peptide antigens was quantified using an interferon-γ enzyme-linked ImmunoSpot (ELISPOT) assay to determine the number of T cells responsive to 3 different pools of AAV8 capsid-specific protein fragments. Each AAV8 antigen pool consisted of 50-60 nonoverlapping peptides composed of 15 amino acid residues. Results were considered positive if the signal was >3 times above the background and >60 cells/million. Serum was collected for assessment of humoral immunity (AAV8 NAbs or AAV2 NAbs) using a cell-based transduction inhibition assay (titer cutoff: ≥1:5). Results: A total of 41 patients have enrolled in the study to date (mean ± SD age: 33.8 ± 11.1 years) and ELISPOT data are available for 37 patients. Of those with available data, 9/37 patients (24.3%) had a positive ELISPOT to ≥1 of the 3 AAV8 peptide pools tested. One patient tested positive for peptide pool 1, 3 for peptide pool 2, and 7 for peptide pool 3 (2 patients [5.6%] tested positive for both pools 2 and 3). Of the 9 patients with positive AAV8-specific ELISPOT results, 6 (66.7%) also had a positive result for AAV8 NAbs, while of 27 patients with negative ELISPOT results, 11 (40.7%) had a positive result for AAV8 NAbs. Conclusions: The results from this ongoing international epidemiology study demonstrate that the prevalence of preexisting cell-mediated immunity to AAV8 resulting from natural exposure to wild-type AAV is approximately 1 in 4 adult males with severe hemophilia A or B. Furthermore, there appears to be a correlation between cell-mediated and humoral immune responses, as two thirds of patients with positive AAV8-specific ELISPOT results also tested positive for AAV8 NAbs. Understanding the relationship between cell-mediated and humoral immunity and how it may affect an individual's response to AAV-based gene therapy will be key to successfully developing this novel therapy. Disclosures Rajavel: Shire: Employment, Equity Ownership. Chapin:Shire: Employment, Equity Ownership. Tang:Shire: Employment.

scholarly journals CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response.

1996 ◽  
Vol 183 (5) ◽  
pp. 2129-2142 ◽  
Author(s):  
P Borrow ◽  
A Tishon ◽  
S Lee ◽  
J Xu ◽  
I S Grewal ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Humoral Immunity ◽  
Cd4 T Cells ◽  
Antiviral Immunity ◽  
Ctl Response ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Deficient Mice

The ligand for CD40 (CD40L) is expressed on the surface of activated CD4+ T cells and its role in T-B cell collaborations and thymus-dependent humoral immunity is well established. Recently, by generating CD40L-knockout mice, we have confirmed its previously described role in humoral immunity and defined another important function of this molecule in the in vivo clonal expansion of antigen-specific CD4+ T cells. Here, we investigated the potential in vivo role of CD40L in antiviral immunity by examining the immune response mounted by CD40L-deficient mice following infection with lymphocytic choriomeningitis virus (LCMV), Pichinde virus, or vesicular stomatitis virus. Humoral immune responses of CD40L-deficient mice to these viruses were severely compromised, although moderate titres of antiviral IgM and some IgG2a were produced by virus-infected CD40L-deficient mice by a CD4+ T cell-independent mechanism. By contrast, CD40L-deficient mice made strong primary CTL responses to all three viruses. Interestingly however, although memory CTL activity was detectable in CD40L-deficient mice two months after infection with LCMV, the memory CTL response was much less efficient than in wild-type mice. Together, the results show that CD40-CD40L interactions are required for strong antiviral humoral immune responses, and reveal a novel role for CD40L in the establishment and/or maintenance of CD8+ CTL memory.

scholarly journals T/Tn immunotherapy avoiding immune deviation

2016 ◽  
Vol 29 (4) ◽  
pp. 812-817 ◽  
Author(s):  
Hye-Youn Son ◽  
Vasso Apostolopoulos ◽  
Chul-Woo Kim
Keyword(s):  
Tumor Growth ◽  
Humoral Immunity ◽  
Keyhole Limpet Hemocyanin ◽  
Blood Type ◽  
Mammary Adenocarcinoma ◽  
Cell Mediated Immunity ◽  
Immune Deviation ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Mammary Adenocarcinoma Cell

Tumor immunotherapy, capable of inducing both cellular and humoral immune responses, is an attractive treatment strategy for cancer. It has been reported that the inactivation of cell-mediated immunity by hyper-activation of humoral immunity—referred to as immune deviation—does not inhibit tumor growth. We investigated the ability of several adjuvants to elicit Thomsen-Friedenreich (T/Tn)-specific humoral immunity while avoiding immune deviation and conferring protection against tumorigenesis. T/Tn (9:1) antigen was purified from blood type O erythrocytes donated by healthy Korean volunteers. Immunization was performed using T/Tn only, T/Tn mixed with Freund’s adjuvant (T/Tn+FA), keyhole limpet hemocyanin (KLH)-conjugated T/Tn mixed with FA (KLH-T/Tn+FA), or oxidized mannan-conjugated T/Tn mixed with FA (ox-M-T/Tn+FA). Anti-T/Tn antibodies were generated in the T/Tn+FA, KLH-T/Tn+FA, and ox-M-T/Tn+FA groups. The antibody level was highest in the KLH-T/Tn+FA group. Mice immunized with ox-M-T/Tn+FA showed specific complement-dependent cytotoxicity, and were protected against T/Tn-positive mammary adenocarcinoma cell challenge, although anti-T/Tn antibody levels were the highest in the KLH-T/Tn+FA group. These results demonstrate that an ox-M-conjugated T/Tn vaccine mixed with FA can promote cellular immunity while moderating the humoral immune response, thereby effectively inhibiting tumor growth.

scholarly journals ESAT-6 Subunit Vaccination againstMycobacterium tuberculosis

2000 ◽  
Vol 68 (2) ◽  
pp. 791-795 ◽  
Author(s):  
Lise Brandt ◽  
Martin Elhay ◽  
Ida Rosenkrands ◽  
Erik B. Lindblad ◽  
Peter Andersen
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
Adjuvant Activity ◽  
Humoral Immune ◽  
Cellular Immune Responses ◽  
Humoral Immune Responses ◽  
Monophosphoryl Lipid A ◽  
Cellular Immune

ABSTRACT The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell-mediated immunity in the early phase of tuberculosis (TB) in TB patients as well as in various animal models. The purpose of our study was to evaluate the potential of ESAT-6 in an experimental TB vaccine. We started out using dimethyl dioctadecylammonium bromide (DDA), an adjuvant which has been demonstrated to be efficient for the induction of cellular immune responses and has been used successfully before as a delivery system for TB vaccines. Here we demonstrate that, whereas immune responses to both short-term-culture filtrate and Ag85B are efficiently induced with DDA, this adjuvant was inefficient for the induction of immune responses to ESAT-6. Therefore, we investigated the modulatory effect of monophosphoryl lipid A (MPL), an immunomodulator which in different combinations has demonstrated strong adjuvant activity for both cellular and humoral immune responses. We show in the present study that vaccination with ESAT-6 delivered in a combination of MPL and DDA elicited a strong ESAT-6-specific T-cell response and protective immunity comparable to that achieved withMycobacterium bovis BCG.

scholarly journals Level of nutrition and age at weaning: effects on humoral immunity in young calves

1994 ◽  
Vol 71 (2) ◽  
pp. 239-248 ◽  
Author(s):  
J. M. Pollock ◽  
T. G. Rowan ◽  
J. B. Dixon ◽  
S. D. Carter
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Total Protein ◽  
Dry Matter ◽  
Keyhole Limpet Haemocyanin ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Bronchoalveolar Washings ◽  
Milk Substitute ◽  
Weaning Age

Thirty-two calves were studied to determine the effects of level of nutrition (400 and 1000 g (air-dry matter) milk substitute per d) and age at weaning (5, 9 and 13 weeks) on humoral immune responses measured in serum and bronchoalveolar washings (BAW). All calves were immunized with Keyhole limpet haemocyanin (KLH) at 3 weeks of age, and with horse erythrocytes (HRBC) 1 d after weaning. Feeding the higher level of nutrition compared with the lower level decreased anti-HRBC titres and serum IgG2 and IgA responses to KLH (P < 0·05). Weaning at 5 compared with 9 weeks of age decreased serum anti-HRBC responses (P < 0·05), but weaning age had no effect on anti-KLH responses (P > 0·5). Feeding the higher level of nutrition increased total protein (P < 005) and IgG2 concentrations (P < 0·01) in BAW. The results showed that variation in husbandry conditions that is within conventional limits affects humoral immune responses in young, artificially-reared calves.

scholarly journals Melioidosis Patient Survival Correlates With Strong IFN-γ Secreting T Cell Responses Against Hcp1 and TssM

2021 ◽  
Vol 12 ◽  
Author(s):  
Sineenart Sengyee ◽  
Atchara Yarasai ◽  
Rachan Janon ◽  
Chumpol Morakot ◽  
Orawan Ottiwet ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Clinical Manifestations ◽  
T Cell Responses ◽  
Peptide Pool ◽  
Humoral Immune ◽  
Cell Responses ◽  
Humoral Immune Responses ◽  
Healthy Donors ◽  
Ifn Γ

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a serious infectious disease with diverse clinical manifestations. The morbidity and mortality of melioidosis is high in Southeast Asia and no licensed vaccines currently exist. This study was aimed at evaluating human cellular and humoral immune responses in Thai adults against four melioidosis vaccine candidate antigens. Blood samples from 91 melioidosis patients and 100 healthy donors from northeast Thailand were examined for immune responses against B. pseudomallei Hcp1, AhpC, TssM and LolC using a variety of cellular and humoral immune assays including IFN-γ ELISpot assays, flow cytometry and ELISA. PHA and a CPI peptide pool were also used as control stimuli in the ELISpot assays. Hcp1 and TssM stimulated strong IFN-γ secreting T cell responses in acute melioidosis patients which correlated with survival. High IFN-γ secreting CD4+ T cell responses were observed during acute melioidosis. Interestingly, while T cell responses of melioidosis patients against the CPI peptide pool were low at the time of enrollment, the levels increased to the same as in healthy donors by day 28. Although high IgG levels against Hcp1 and AhpC were detected in acute melioidosis patients, no significant differences between survivors and non-survivors were observed. Collectively, these studies help to further our understanding of immunity against disease following natural exposure of humans to B. pseudomallei as well as provide important insights for the selection of candidate antigens for use in the development of safe and effective melioidosis subunit vaccines.

scholarly journals The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection

2020 ◽  
Vol 101 (8) ◽  
pp. 791-797 ◽  
Author(s):  
Paul Kellam ◽  
Wendy Barclay
Keyword(s):  
Infectious Disease ◽  
Immune Response ◽  
Immune Responses ◽  
Humoral Immunity ◽  
Research Needs ◽  
Human Coronavirus ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Human Coronaviruses ◽  
Novel Coronavirus

SARS-CoV-2 is a novel coronavirus that is the causative agent of coronavirus infectious disease 2019 (COVID-19). As of 17 April 2020, it has infected 2 114 269 people, resulting in 145 144 deaths. The timing, magnitude and longevity of humoral immunity is not yet understood for SARS-CoV-2. Nevertheless, understanding this is urgently required to inform the likely future dynamics of the pandemic, to guide strategies to allow relaxation of social distancing measures and to understand how to deploy limiting vaccine doses when they become available to achieve maximum impact. SARS-CoV-2 is the seventh human coronavirus to be described. Four human coronaviruses circulate seasonally and cause common colds. Two other coronaviruses, SARS and MERS, have crossed from animal sources into humans but have not become endemic. Here we review what is known about the human humoral immune response to epidemic SARS CoV and MERS CoV and to the seasonal, endemic coronaviruses. Then we summarize recent, mostly non-peer reviewed, studies into SARS-CoV-2 serology and reinfection in humans and non-human primates and summarize current pressing research needs.

scholarly journals Helminth Protein Vaccine Induced Follicular T Helper Cell for Enhancement of Humoral Immunity againstSchistosoma japonicum

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Jingyao Zhang ◽  
Wenjuan Gao ◽  
Qirui Guo ◽  
Bobo Huang ◽  
Bin Wang ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Humoral Immunity ◽  
Molecular Targets ◽  
T Helper Cell ◽  
Protein Vaccine ◽  
T Helper ◽  
Humoral Immune ◽  
Tfh Cells ◽  
Humoral Immune Responses

Protein vaccines combined with adjuvants have been widely used to induce immune responses, especially the humoral immune response, against molecular targets including parasites. Follicular T helper (Tfh) cells are the specialized providers of B-cell help, however, the induction of Tfh cells in protein vaccination has been rarely studied. Here, we report that theSchistosoma japonicumrecombinant protein (SjGST-32) combined with tacrolimus (FK506) augmented the induction of Tfh cells, which expressed the canonical markers CXCR5, BCL6, and IL-21, and enhanced the humoral immune responses in BALB/c mice. Furthermore, the expression of IL-21R on germinal center (GC) B cells and memory B cells increased in immunized mice, which indicated that IL-21 from the induced Tfh cells interacted with IL-21R for activation of B cells and maintenance of long-lived humoral immunity. Our results suggest that helminth protein vaccine combined with FK506 induces Tfh cell for stimulating humoral immune responses and inducing long-lived humoral immunity.

scholarly journals Notch2-dependent DC2s mediate splenic germinal center responses

2018 ◽  
Vol 115 (42) ◽  
pp. 10726-10731 ◽  
Author(s):  
Carlos G. Briseño ◽  
Ansuman T. Satpathy ◽  
Jesse T. Davidson ◽  
Stephen T. Ferris ◽  
Vivek Durai ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Humoral Immunity ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Formation ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Follicular Helper

CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.

scholarly journals Methamphetamine Compromises the Adaptive B Cell-Mediated Immunity to Antigenic Challenge in C57BL/6 Mice

2021 ◽  
Vol 3 ◽  
Author(s):  
Anum N. Mitha ◽  
Daniela Chow ◽  
Valerie Vaval ◽  
Paulina Guerrero ◽  
Dormarie E. Rivera-Rodriguez ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Adaptive Immunity ◽  
Humoral Immunity ◽  
Cell Mediated Immunity ◽  
Limited Information ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
The Impact

Methamphetamine (METH) is a substance of abuse that causes dysregulation of the innate and adaptive immunity in users. B cells are involved in the humoral component of the adaptive immunity by producing and secreting antibodies (Abs). METH modifies Ab production, although limited information on the impact of this psychostimulant on antigen (Ag)-specific humoral immune responses is available. Since T cell-dependent and T cell-independent Ags are involved in the activation of B lymphocytes, we explored the role of METH on humoral immunity to ovalbumin (OVA; T cell-dependent) and bacterial lipopolysaccharide (LPS; T cell-independent) in C57BL/6 mice. We demonstrated that METH extends the infiltration of B cells into pulmonary and splenic tissues 7 days post-Ag challenge. METH impairs Ab responses in the blood of animals challenged with OVA and LPS. Furthermore, METH diminishes the expression and distribution of IgM on B cell surface, suggesting a possible detrimental impact on users' humoral immunity to infection or autoimmunity.

scholarly journals The Dynamics of Humoral Immune Responses Following SARS-CoV-2 Infection and the Potential for Reinfection

2020 ◽  
Author(s):  
Paul Kellam ◽  
Wendy Barclay
Keyword(s):  
Infectious Disease ◽  
Immune Response ◽  
Immune Responses ◽  
Humoral Immunity ◽  
Research Needs ◽  
Human Coronavirus ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Human Coronaviruses ◽  
Novel Coronavirus

SARS-CoV-2 is a novel coronavirus that is the causative agent of Coronavirus infectious disease 2019 (COVD-19). As of the 17th April 2020, it has infected 2 114 269 people resulting in 145 144 deaths. The timing, magnitude and longevity of humoral immunity is not yet understood for SARS-CoV-2. Nevertheless, understanding this is urgently required to inform the likely future dynamics of the pandemic, to guide strategies to allow relaxation of social distancing measures and to understand how to deploy limiting vaccine doses when they become available to achieve maximum impact. SARS-CoV-2 is the seventh human coronavirus to be described. Four human coronaviruses circulate seasonally and cause common colds. Two other coronaviruses, SARS and MERS, have crossed from animal sources into humans but have not become endemic. Here we review what is known about the human humoral immune response to epidemic SARS CoV and MERS CoV and to the seasonal, endemic coronaviruses. Then we summarize recent, mostly non-peer reviewed studies into SARS-CoV-2 serology and reinfection in humans and non-human primates and summarize current pressing research needs.

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