scholarly journals A baseline transcriptional signature associates with clinical malaria risk in RTS,S/AS01-vaccinated African children

2021 ◽  
Author(s):  
Gemma Moncunill ◽  
Jason Carnes ◽  
William Chad Young ◽  
Lindsay Nicole Carpp ◽  
Stephen De Rosa ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Clinical Malaria ◽  
Malaria Risk ◽  
Phase 3 ◽  
Peripheral Blood Mononuclear ◽  
Transcriptional Signature ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Trial Participants

In a phase 3 trial in African infants/children, the RTS,S/AS01 (GSK) vaccine showed moderate efficacy against clinical malaria. We aimed to identify RTS,S/AS01-induced signatures associated with clinical malaria by analyzing antigen-stimulated peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (one month post-third dose). RTS,S/AS01 vaccination was associated with downregulation of B-cell and monocyte-related blood transcriptional modules (BTMs) and upregulation of T-cell related BTMs, as well as higher month 3 (vs baseline) circumsporozoite protein (CSP)-specific CD4+ T-cell responses. There were few RTS,S/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of BTMs associated with dendritic cells and with monocytes (among others) correlated with malaria risk. A cross-study analysis supported generalizability of the baseline dendritic cell- and monocyte-related BTM correlations with malaria risk to healthy, malaria-naive adults, suggesting inflammatory monocytes may inhibit protective RTS,S/AS01-induced responses.

scholarly journals Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue

2019 ◽  
Vol 3 (17) ◽  
pp. 2668-2678 ◽  
Author(s):  
Wojciech Jankowski ◽  
Joseph McGill ◽  
H. A. Daniel Lagassé ◽  
Stepan Surov ◽  
Gary Bembridge ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Factor Viia ◽  
Protein Product ◽  
Factor Ix ◽  
Factor Vii ◽  
Phase 3 ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Generation Activity

Abstract Vatreptacog alfa (VA), a recombinant activated human factor VII (rFVIIa) variant with 3 amino acid substitutions, was developed to provide increased procoagulant activity in hemophilia patients with inhibitors to factor VIII or factor IX. In phase 3 clinical trials, changes introduced during the bioengineering of VA resulted in the development of undesired anti-drug antibodies in some patients, leading to the termination of a potentially promising therapeutic protein product. Here, we use preclinical biomarkers associated with clinical immunogenicity to validate our deimmunization strategy applied to this bioengineered rFVIIa analog. The reengineered rFVIIa analog variants retained increased intrinsic thrombin generation activity but did not elicit T-cell responses in peripheral blood mononuclear cells isolated from 50 HLA typed subjects representing the human population. Our algorithm, rational immunogenicity determination, offers a broadly applicable deimmunizing strategy for bioengineered proteins.

scholarly journals Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321731
Author(s):  
Dominik Aschenbrenner ◽  
Maria Quaranta ◽  
Soumya Banerjee ◽  
Nicholas Ilott ◽  
Joanneke Jansen ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Personalised Medicine ◽  
Mononuclear Phagocytes ◽  
Cytokine Network ◽  
Peripheral Blood Mononuclear ◽  
Transcriptional Signature ◽  
Inflammatory Monocytes ◽  
Transcriptomic Signature ◽  
Inflammatory Bowel

ObjectiveDysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.DesignWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.ResultsWe characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.ConclusionOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

scholarly journals Analysis of CD4+ T-Cell Responses to Human Papillomavirus (HPV) Type 11 L1 in Healthy Adults Reveals a High Degree of Responsiveness and Cross-Reactivity with Other HPV Types

2002 ◽  
Vol 76 (15) ◽  
pp. 7418-7429 ◽  
Author(s):  
O. Martin Williams ◽  
Keith W. Hart ◽  
Eddie C. Y. Wang ◽  
Colin M. Gelder
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
In Vitro Selection ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Hpv Types

ABSTRACT Human papillomavirus type 11 (HPV-11) infection causes genital warts and recurrent respiratory papillomatosis. While there is compelling evidence that CD4+ T cells play an important role in immune surveillance of HPV-associated diseases, little is known about human CD4+ T-cell recognition of HPV-11. We have investigated the CD4+ T-cell responses of 25 unrelated healthy donors to HPV-11 L1 virus-like particles (VLP). CD4+ T-cell lines from 21 of 25 donors were established. Cell sorting experiments carried out on cells from six donors demonstrated that the response was located in the CD45RAlow CD45ROhigh memory T-cell population. To determine the peptide specificity of these responses, epitope selection was analyzed by using 95 15-mer peptides spanning the entire HPV-11 L1 protein. No single region of L1 was immunodominant; responders recognized between 1 and 10 peptides, located throughout the protein, and peptide responses fell into clear HLA class II restricted patterns. Panels of L1 peptides specific for skin and genital HPV were used to show that the L1 CD4+ T-cell responses were cross-reactive. The degree of cross-reactivity was inversely related to the degree of L1 sequence diversity between these viruses. Finally, responses to HPV-11 L1 peptides were elicited from ex vivo CD45RO+ peripheral blood mononuclear cells, demonstrating that recognition of HPV-11 was a specific memory response and not due to in vitro selection during tissue culture. This is the first study of CD4+ T-cell responses to HPV-11 in healthy subjects and demonstrates marked cross-reactivity with other skin and genital HPV types. This cross-reactivity may be of significance for vaccine strategies against HPV-associated clinical diseases.

scholarly journals Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

2008 ◽  
Vol 83 (3) ◽  
pp. 1501-1510 ◽  
Author(s):  
Rosemarie D. Mason ◽  
Sheilajen Alcantara ◽  
Viv Peut ◽  
Liyen Loh ◽  
Jeffrey D. Lifson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIVmac251 infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4+ T-cell responses (mean, 5.9% ± 1.3% of all CD4+ T cells) and to a lesser extent SIV-specific CD8+ T-cell responses (mean, 0.7% ± 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4+ T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4+ T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide-pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted.

scholarly journals T-Cell-Stimulating Protein A Elicits Immune Responses during Meningococcal Carriage and Human Disease

2005 ◽  
Vol 73 (8) ◽  
pp. 4684-4693 ◽  
Author(s):  
Karen Robinson ◽  
Karl G. Wooldridge ◽  
Damien B. Wells ◽  
Amal Hasan ◽  
Ian Todd ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Protein A ◽  
Invasive Disease ◽  
Th2 Cells ◽  
Meningococcal Infection ◽  
Igg Antibodies ◽  
T Helper ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses

ABSTRACT In recognition of the need for immunological memory-inducing components for future Neisseria meningitidis group B vaccines, we previously searched the proteome of N. meningitidis and identified T-cell-stimulating protein A (TspA). This study was designed to confirm the immunogencity of TspA and to examine the subset of T-helper cell responses to the protein in patients and nasopharyngeal carriers. The tspA gene was reconstructed, cloned, and expressed in Escherichia coli, and the recombinant TspA (rTspA) protein was affinity purified. T-cell proliferative responses to rTspA were detected in the peripheral blood mononuclear cells (PBMCs) of convalescent patients and carriers, confirming that TspA-specific T-cell responses were stimulated by invasive disease and nasopharyngeal colonization. Following stimulation of PBMCs with meningococcal lysate, increased frequencies of both Th1 and Th2 cells were observed, indicating that, as during carriage, invasive meningococcal disease induced an unbiased T-helper subset response. A similar unbiased T-helper response was also detected against rTspA in the PBMCs of convalescent patients. The response of PBMCs from the carriers to TspA stimulation, however, was very weak, and the frequencies of cytokine-positive CD4 cells were not significantly greater than the frequencies in unstimulated control cultures. All of the patients and carriers responded with serum antimeningococcal immunoglobulin G (IgG) antibodies, while four of six samples from patients and 5 of 14 samples from carriers contained detectable anti-rTspA IgG antibodies. Taken together, the results of this study confirmed the immunogenicity of TspA in humans during natural meningococcal infection, and therefore, TspA is worthy of further investigation as a possible T-cell stimulating component of future vaccines.

scholarly journals Selective abrogation of antigen-specific human B cell responses by antigen-ricin conjugates.

1982 ◽  
Vol 156 (2) ◽  
pp. 634-639 ◽  
Author(s):  
D J Volkman ◽  
A Ahmad ◽  
A S Fauci ◽  
D M Neville
Keyword(s):  
T Cell ◽  
B Cell ◽  
Antibody Production ◽  
Specific Antibody ◽  
Mononuclear Cells ◽  
Pokeweed Mitogen ◽  
Cell Repertoire ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
B Cell Responses

The feasibility of selectively eliminating human antigen-specific B cell responses by treating cells in vitro with antigen covalently linked to a cell toxin was examined. Tetanus toxoid (TT) was conjugated to the toxin ricin via a thioether linkage. Peripheral blood mononuclear cells from recently immunized subjects were preincubated for 2 h with TT-ricin in the presence of lactose. Antigen was then removed, and the cells from recently immunized subjects were preincubated for 2 h with TT-ricin in the presence of lactose. Antigen was then removed, and the cells were stimulated with pokeweed mitogen to induce antibody production. TT-specific antibody production was completely abrogated by preincubation with TT-ricin but not by TT alone or a mixture of TT and ricin. In contrast, polyclonal immunoglobulin production was not diminished by TT-ricin. This selective abrogation was also seen when B cells alone were preincubated with TT-ricin and a source of T cell help was later provided. T cell blastogenic responses to TT remained intact after TT-ricin exposure. Thus, antigen-toxin conjugates are capable of selectively eliminating specific antibody-producing B cell clones, while leaving intact the remainder of the B cell repertoire.

scholarly journals JC Virus-Specific Immune Responses in Human Immunodeficiency Virus Type 1 Patients with Progressive Multifocal Leukoencephalopathy

2009 ◽  
Vol 83 (9) ◽  
pp. 4404-4411 ◽  
Author(s):  
Nina Khanna ◽  
Marcel Wolbers ◽  
Nicolas J. Mueller ◽  
Christian Garzoni ◽  
Renaud A. Du Pasquier ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Mononuclear Cells ◽  
Jc Virus ◽  
T Cell Responses ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4+ T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4+ T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4+ T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.

scholarly journals Evaluation of Antigen-Specific T-Cell Responses with a Miniaturized and Automated Method

2008 ◽  
Vol 15 (12) ◽  
pp. 1811-1818 ◽  
Author(s):  
Giuseppina Li Pira ◽  
Federico Ivaldi ◽  
Chiara Dentone ◽  
Elda Righi ◽  
Valerio Del Bono ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Immunity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Automated Method ◽  
Cell Immunity

ABSTRACT The evaluation of antigen-specific T-cell responses is helpful for both research and clinical settings. Several techniques can enumerate antigen-responsive T cells or measure their products, but they require remarkable amounts of peripheral blood mononuclear cells (PBMCs). Since screening numerous antigens or testing samples from pediatric or lymphopenic patients is hampered in clinical practice, we refined a miniaturized, high-throughput assay for T-cell immunity. Antigens and cells in 10-μl volumes were dispensed into 1,536-well culture plates precoated with anti-gamma interferon (anti-IFN-γ) antibodies. After being cultured, the wells were developed by enzyme-linked immunosorbent assay for bound cytokine. Miniaturization and automation allowed quantitation of antigen-specific responses on 104 PBMCs. This method was applied for epitope mapping of mycobacterial antigens and was used in the clinic to evaluate T-cell immunity to relevant opportunistic pathogens by using small blood samples. A comparison with conventional methods showed similar sensitivity. Therefore, current flow cytometric methods that provide information on frequency and phenotype of specific T cells can be complemented by this assay that provides extensive information on cytokine concentrations and profiles and requires 20- to 50-fold fewer PBMCs than other analytical methods.

Sign in / Sign up

Export Citation Format

Share Document