scholarly journals Low dose dexamethasone in combination with Remdesivir does not cause immune dysregulation

2021 ◽  
Author(s):  
Kalyan Reddy Kannan ◽  
Kshiraja Damerla ◽  
Sasikala Mitnala ◽  
Venkata Krishna Vemula ◽  
Naveen Reddy P ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Neutralizing Antibodies ◽  
Immune Dysregulation ◽  
Post Treatment ◽  
Combination Group ◽  
Cd4 Cells ◽  
Rt Pcr ◽  
Cd8 Cells ◽  
Cell Responses ◽  
Cell Mediated Immune Response

Abstract BackgroundThe administration of Remdesivir/Dexamethasone combination on T and B cell responses in patients with COVID-19 is sparse. To compare cell mediated immune response in patients treated with only Remdesivir and Remdesivir/dexamethasone combinationStudy DesignProspective, cohort studyMethodsRT-PCR positive SARS-CoV-2 patients (n=49) were enrolled. Patients not requiring O2-supplementation were on remdesivir and those requiring were on remdesivir/dexamethasone. Baseline parameters (complete blood picture, inflammatory markers), T and B cells (flow cytometry: day 5 and 30) and neutralizing antibodies (chemiluminescence: day 30) were estimated. Students “t’’ test was used to evaluate the differences.ResultsOf the 49 patients, 26 (Mean age-44.68±13.45) were treated with remdesivir and 23 (Mean age-48.33±14.76) with remdesivir/dexamethasone combination. While blood counts and immune cells increased, inflammatory markers decreased post treatment in both the groups. A significant increase in WBC (6357±981Vs10700±1363; p=0.01), absolute neutrophil counts (4578±711Vs8256±1323; p=0.01) with decrease in levels of CRP (31±7.1Vs10±4.2; p=0.01), D-Dimer (172.3±8Vs118.1±12; p=0.0005), IL6 (17.6±3.8Vs1.72±0.2; p=0.0001), CD4 cells (2681±86Vs1256±369; p=0.0003), CD8 cells (1749±88 Vs 1256±221; p=0.01) and neutralizing antibodies were seen post treatment in the combination group. Correction of hypoxia and maintenance of oxygen >95% was also noted. ConclusionRemdesivir/dexamethasone combination given to patients requiring oxygen supplementation is safe at 4-6mg/day and showed a marked decrease in inflammation and no immune dysregulation.

Th2.rapa Cell Treatment of Established Murine Acute GVHD Is Abrogated by IL-2 Therapy and T Regulatory Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2169-2169
Author(s):  
Jason E. Foley ◽  
Jacopo Mariotti ◽  
Shoba Amarnath ◽  
Soo Han ◽  
Michael Eckhaus ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Treg Cell ◽  
Treg Cells ◽  
Th2 Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cell Product ◽  
Cell Responses ◽  
Th2 Cell ◽  
Ifn Γ

Abstract Rapamycin-generated donor Th2 cells attenuate established acute murine GVHD (Foley et al, JI, 2005) and are dependent in part upon IL-4 and IL-10 secretion (ASBMT Meeting, 2007). That is, Th2.rapa cell recipients (Th2 infusion, d 14 post-BMT) had increased survival relative to GVHD controls (post-BMT survival, median days; 33.7±0.4 vs. 24.8±1.2; p=0.0002) whereas recipients of IL-4 or IL-10 knockout Th2.rapa cells did not have increased survival (28.9±0.3 and 24.6±0.2 days, respectively; p=NS). These data indicate that Th2.rapa cells operate through a Th2-type mechanism rather than a Treg cell mechanism; in addition, we found that Th2.rapa cells expressed low levels of the Treg cell transcription factor, Foxp3 (<5% CD4+Foxp3+). Additional experiments were performed to further investigate a potential role of Treg cell biology to Th2.rapa cell therapy. First, we hypothesized that IL-2 therapy may promote Th2.rapa cell expansion and efficacy in a manner analogous to IL-2 promotion of Treg cell responses in vivo. Second, we hypothesized that enrichment of the Th2.rapa cell product with natural (unmanipulated) Treg cells may enhance an anti-GVHD effect. Contrary to our first hypothesis, we found that IL-2 therapy (50,000 IU bid; d14–18 post-BMT) reduced the number of splenic Th2.rapa cells at d 19 post-BMT (CD90.1-marked cells, million [M]/spleen; 5.0±0.4 [no IL-2] vs. 2.3±0.4 [+IL-2]; p=<0.001) and increased the number of unmanipulated donor CD4+ cells (CD45.2-marked cells, M/spleen; 16.6±0.7 [no IL-2] vs. 26.6±2.4 [+IL-2]; p=0.004) and CD8+ cells (15.9±1.7 [no IL-2] vs. 23.9±2.4 [+IL-2]; p=0.03). IL-2 therapy also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 3501±179 [no IL-2] to 1116±261 [+IL-2], p=<0.0001; IL-10 reduced from 707±56 [no IL-2] to 288±37 [+IL-2], p=0.0002; and IFN-γ increased from 81±22 [no IL-2] to 320±97 [+IL-2], p=0.042). Importantly, for Th2.rapa cell recipients, IL-2 therapy reduced post-BMT survival (d post-BMT; 42.0±0.5 [no IL-2] vs. 33.8±1.0 [+IL-2], p=<0.0001). With regard to our second hypothesis, we found that addition of Treg cells to the Th2.rapa cell product (Treg to Th2.rapa cell ratio, 1:10) reduced the number of Th2.rapa cells at d 19 post-BMT (M/spleen; 16.6±1.3 [no Treg] vs. 7.9±1.2 [+ Treg], p=0.0012) and increased the number of unmanipulated donor CD4+ cells (M/spleen; 12.4±0.7 [no Treg] vs. 20.7±0.8 [+Treg], p=<0.0001) and CD8+ cells (M/spleen; 8.4±0.8 [no Treg] vs. 16.1±1.4 [+Treg], p= 0.0014). Treg cell co-infusion also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 497±47 [no Treg] to 100±15 [+ Treg]; p=<0.0001); IL-10 reduced from 160±32 [no Treg] to 27±7 [+Treg]; p= 0.004; and IFN-γ increased from 83±5 [no Treg] to 230±40 [+Treg]; p=0.006). Finally, for Th2.rapa cell recipients, co-infusion of Treg cells reduced post-BMT survival (median d post-BMT; 44.2±1.1 [no Treg] vs. 30.7±1.3 [+Treg]; p=0.0002). In conclusion, interventions that promote Treg cell responses, namely infusion of IL-2 and co-administration of natural Treg cells, reduce Th2.rapa cell promotion of IL-4 and IL-10 post-BMT and reduce the Th2 cell-mediated survival advantage against established GVHD. Because IL-4 and IL-10 are required for Th2.rapa cell therapy of GVHD in this model, these new data indicate that Treg cells abrogate Th2.rapa cell therapy by inhibiting the Th2 cell effector response.

scholarly journals Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Linling He ◽  
Anshul Chaudhary ◽  
Xiaohe Lin ◽  
Cindy Sou ◽  
Tanwee Alkutkar ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Heptad Repeat ◽  
T Cell Epitopes ◽  
Vaccine Strategy ◽  
Cell Responses ◽  
Self Assembling ◽  
Protein Nanoparticles ◽  
Main Target ◽  
Repertoire Sequencing

AbstractEbola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display.

scholarly journals HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 134
Author(s):  
Zekun Mu ◽  
Barton F. Haynes ◽  
Derek W. Cain
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cytotoxic T Cell ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Broadly Neutralizing Antibody ◽  
Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

scholarly journals Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer L. Kruse ◽  
Megha M. Vasavada ◽  
Richard Olmstead ◽  
Gerhard Hellemann ◽  
Benjamin Wade ◽  
...  
Keyword(s):  
Treatment Response ◽  
Inflammatory Markers ◽  
Rating Scale ◽  
Antidepressant Medication ◽  
Post Treatment ◽  
Therapeutic Modality ◽  
Depression Treatment ◽  
Open Label ◽  
Time Interaction ◽  
Baseline Levels

AbstractInflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

scholarly journals THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii473-iii473
Author(s):  
Ignacio Iñigo-Marco ◽  
Marisol Gonzalez-Huarriz ◽  
Marc García-Moure ◽  
Ibon Tamayo ◽  
Sandra Hervas ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy ◽  
Functional Studies ◽  
Cell Diversity

Abstract The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.

Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 180-183 ◽  
Author(s):  
Carl E. Mackewicz ◽  
Baikun Wang ◽  
Sunil Metkar ◽  
Matthew Richey ◽  
Christopher J. Froelich ◽  
...  
Keyword(s):  
T Cells ◽  
Antiviral Activity ◽  
Cd8 T Cells ◽  
Culture Media ◽  
Cd4 Cells ◽  
Antiviral Protein ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Anti Hiv ◽  
Primary Granule

Abstract In HIV infection, CD8+ cells show cytotoxic and noncytotoxic anti-HIV activity. The latter function is mediated, at least in part, by a secreted antiviral protein, the CD8+ cell antiviral factor (CAF). Because antiviral effector molecules, such as perforin and granzymes, reside in the exocytic granules of CD8+ T cells, we examined the possibility that granules contain CAF-like activity. CD8+ cells from HIV-infected individuals showing strong CAF-mediated antiviral activity were induced to release their granule constituents into culture media. Within 1 hour of stimulation, high levels of granzyme B (a primary granule constituent) were found in the culture fluids of previously activated CD8+ cells. The same culture fluids contained no or very low amounts of CAF activity, as measured with HIV-infected CD4+ cells. Maximal levels of CAF activity were not observed until 5 or 7 days after stimulation, consistent with typical CAF production kinetics. In addition, extracts of granules purified from antiviral CD8+ cells did not show any CAF activity, whereas the cytoplasmic fraction of these cells showed substantial levels of antiviral activity. These findings suggest that CAF does not reside at appreciable levels in the exocytic granules of antiviral CD8+ T cells. (Blood. 2003;102: 180-183)

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

scholarly journals Effects of classical swine fever virus infection on the porcine leukocyte subsets

2000 ◽  
Vol 48 (1) ◽  
pp. 35-42 ◽  
Author(s):  
H. J. Schubert ◽  
P. Soós ◽  
K. R. Depner
Keyword(s):  
Flow Cytometry ◽  
Virus Infection ◽  
Viral Antigen ◽  
Classical Swine Fever ◽  
Virus Antigen ◽  
Lower Percentage ◽  
Cd4 Cells ◽  
Double Positive ◽  
Cd8 Cells ◽  
Acute Form

The effects of classical swine fever (CSF) virus infection on the porcine leukocyte subsets were investigated by flow cytometry in acute, chronic and convalescent forms of the disease. The virus antigen could be first detected in the monocytes on postinfection (p.i.) day 10 while in the lymphocytes on p.i. day 13. It could be established that the ratio of CD6+ cells decreased until p.i. day 6, but afterwards it started to increase and reached different values. The CD4+CD8+, the CD8+ and the CD6- cells were obviously higher virus positive than the CD4+ and the CD4-CD8-subsets, but essentially all subsets could be infected. The ratio of CD8+ cells increased during the disease, while the number of double positive cells decreased, and that of the CD4+ cells was variable. The viral antigen could be detected in a lower percentage of the CD4+CD8+, CD8+, CD6+ and CD6- cells of the pigs affected with the chronic form of the disease than in those with the acute form. During the experiments no viral antigen could be detected in the leukocytes of the pig that became convalescent, though the changes in its leukocyte subsets were very similar to those seen in pigs in which the viral antigen could be detected. The studies have revealed that essentially all leukocyte subsets can be infected with the CSF virus, but in very different amounts.

Sign in / Sign up

Export Citation Format

Share Document