Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven’t been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL’s immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvβ3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvβ3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvβ3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvβ3-selective antagonist to maintain glomerular filtration.
Kwi Hye Koh, Yanxia Cao, Steve Mangos, Nicholas J. Tardi, Ranadheer R. Dande, Ha Won Lee, Beata Samelko, Mehmet M. Altintas, Vincent P. Schmitz, Hyun Lee, Kamalika Mukherjee, Vasil Peev, David J. Cimbaluk, Jochen Reiser, Eunsil Hahm
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.
Yueqin Zhou, Sharon Carmona, A.K.M.G. Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W. Dorn II, Shaomei Wang, Cathleen M. Lutz, Robert H. Baloh
Terence K. Lee, Saravana R.K. Murthy, Niamh X. Cawley, Savita Dhanvantari, Stephen M. Hewitt, Hong Lou, Tracy Lau, Stephanie Ma, Thanh Huynh, Robert A. Wesley, Irene O. Ng, Karel Pacak, Ronnie T. Poon, Y. Peng Loh
Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strategy for CMT2A.
Keiko Iwata, Luca Scorrano
The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endotypes are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergen-specific immunotherapy and biologic therapies that target key molecules driving the Th2 response are already used in the clinic, and a wave of novel drug candidates are under development. In-depth analysis of the cells and tissues of patients treated with such targeted interventions provides a wealth of information on the mechanisms that drive allergies and tolerance to allergens. Here, we aim to deliver an overview of the current state of specific inhibitors used in the treatment of allergy, with a particular focus on asthma and atopic dermatitis, and provide insights into the roles of these molecules in immunological mechanisms of allergic disease.
Willem van de Veen, Mübeccel Akdis
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF–secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti–PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti–PD-1/PD-L1 antibody for T cell–inflamed tumors such as PDACs treated with vaccine therapy.
Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng
Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calcium-activated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOX5-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenation-induced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.
Ana I. Casas, Pamela W.M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabê de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, Harald H.H.W. Schmidt
Accumulating evidence demonstrates that CD8+ T cells contribute to protection from severe dengue virus (DENV) disease and vaccine efficacy. Nevertheless, molecular programs associated with DENV-specific CD8+ T cell subsets have not been defined. Here, we studied the transcriptomic profiles of human DENV-specific CD8+ T cells isolated after stimulation with DENV epitopes from donors who had been infected with DENV multiple times and would therefore be expected to have significant levels of adaptive immunity. We found that DENV-specific CD8+ T cells mainly consisted of effector memory subsets, namely CD45RA−CCR7− effector memory (Tem) and CD45RA+CCR7− effector memory re-expressing CD45RA (Temra) cells, which enacted specific gene expression profiles upon stimulation with cognate antigens. DENV-specific CD8+ T cell subsets in general, and Temra cells in particular, were fully activated and polyfunctional, yet associated with relatively narrow transcriptional responses. Furthermore, we found that DENV-specific CD8+ Tem and Temra cells showed some unique T cell receptor features in terms of overlap and variable (V) gene usage. This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce.
Yuan Tian, Mariana Babor, Jerome Lane, Grégory Seumois, Shu Liang, N.D. Suraj Goonawardhana, Aruna D. De Silva, Elizabeth J. Phillips, Simon A. Mallal, Ricardo da Silva Antunes, Alba Grifoni, Pandurangan Vijayanand, Daniela Weiskopf, Bjoern Peters, Alessandro Sette
Survivors of sepsis and other forms of critical illness frequently experience significant and disabling cognitive and affective disorders. Inflammation, ischemia, and glial cell dysfunction contribute to this persistent brain injury. In this issue of the JCI, Hippensteel et al. show that endothelial injury in animal models of sepsis or endotoxemia leads to shedding of heparan fragments from the endothelial glycocalyx. These fragments directly sequester brain-derived neurotrophic factor and impair hippocampal long-term potentiation, an electrophysiologic correlate of memory. The authors further explore the specific characteristics of heparan fragments that bind neurotrophins and the presence of these fragments in the circulation of patients who survive sepsis. This study highlights an important mechanism by which vascular injury can impair brain function.
Benjamin H. Singer
Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor–mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O– and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O– and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.
Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Schmidt
Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An “immune-cold” microenvironment with an absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC.
Tina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Muñoz Ramos, Michael Trevor Hallett, John Stagg, Réjean Lapointe, Atilla Omeroglu, Sarkis Meterissian, Laurence Buisseret, Gert Van den Eyden, Roberto Salgado, Marie-Christine Guiot, Benjamin Haibe-Kains, Morag Park
In this issue of the JCI, Casas et al. define a previously unknown role of the NADPH oxidase catalytic subunit NOX5 in cerebral infarction. Using a mouse expressing human NOX5 in the endothelium, the investigators show that NOX5 is activated and plays a deleterious role in promoting edema, infarction, and ultimately, worsened neurological function following cerebral ischemia. They provide evidence that this is due to the breakdown of the blood-brain barrier (BBB) and that a unique pharmacological inhibitor of NOX5, ML090, if given early, around the time of reoxygenation, can maintain BBB integrity. Future studies of NOX5 inhibition in humans, particularly in the setting of thrombolysis, are warranted.
Luciana Simão do Carmo, Bradford C. Berk, David G. Harrison
Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV+ mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV+ mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV+ mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV+ mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.
Harald Krenzlin, Prajna Behera, Viola Lorenz, Carmela Passaro, Mykola Zdioruk, Michal O. Nowicki, Korneel Grauwet, Hong Zhang, Magdalena Skubal, Hirotaka Ito, Rachel Zane, Michael Gutknecht, Marion B. Griessl, Franz Ricklefs, Lai Ding, Sharon Peled, Arun Rooj, C. David James, Charles S. Cobbs, Charles H. Cook, E. Antonio Chiocca, Sean E. Lawler
In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β–mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1–dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.
James V. McCann, Lin Xiao, Dae Joong Kim, Omar F. Khan, Piotr S. Kowalski, Daniel G. Anderson, Chad V. Pecot, Salma H. Azam, Joel S. Parker, Yihsuan S. Tsai, Alisa S. Wolberg, Stephen D. Turner, Kohei Tatsumi, Nigel Mackman, Andrew C. Dudley
Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen–driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
Nurit P. Azouz, Marc E. Rothenberg
A rapidly developing paradigm for modern health care is a proactive and individualized response to patients’ symptoms, combining precision diagnosis and personalized treatment. Precision medicine is becoming an overarching medical discipline that will require a better understanding of biomarkers, phenotypes, endotypes, genotypes, regiotypes, and theratypes of diseases. The 100-year-old personalized allergen-specific management of allergic diseases has particularly contributed to early awareness in precision medicine. Polyomics, big data, and systems biology have demonstrated a profound complexity and dynamic variability in allergic disease between individuals, as well as between regions. Escalating health care costs together with questionable efficacy of the current management of allergic diseases facilitated the emergence of the endotype-driven approach. We describe here a precision medicine approach that stratifies patients based on disease mechanisms to optimize management of allergic diseases.
Ioana Agache, Cezmi A. Akdis
Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid–related orphan receptor α (RORα) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications.
Retinoic acid–related orphan receptor α (RORα) is considered a key regulator of polarization in liver macrophages that is closely related to nonalcoholic steatohepatitis (NASH) pathogenesis. However, hepatic microenvironments that support the function of RORα as a polarity regulator were largely unknown. Here, we identified maresin 1 (MaR1), a docosahexaenoic acid (DHA) metabolite with a function of specialized proresolving mediator, as an endogenous ligand of RORα. MaR1 enhanced the expression and transcriptional activity of RORα and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet–induced NASH in a RORα-dependent manner. Surprisingly, RORα increased the level of MaR1 through transcriptional induction of 12-lipoxygenase (12-LOX), a key enzyme in MaR1 biosynthesis. Furthermore, we demonstrated that modulation of 12-LOX activity enhanced the protective function of DHA against NASH. Together, these results suggest that the MaR1/RORα/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH.
Yong-Hyun Han, Kyong-Oh Shin, Ju-Yeon Kim, Daulat B. Khadka, Hyeon-Ji Kim, Yong-Moon Lee, Won-Jea Cho, Ji-Young Cha, Bong-Jin Lee, Mi-Ock Lee
Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilm-negative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free ApcMinΔ850/+;Il10–/– or ApcMinΔ850/+ and specific pathogen–free ApcMinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.
Sarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, Cynthia L. Sears
Background: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes. Methods: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1. Results: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21. Conclusion: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.
Eléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, Behazine Combadière