scholarly journals Vaccination with Recombinant N-Terminal Domain of Als1p Improves Survival during Murine Disseminated Candidiasis by Enhancing Cell-Mediated, Not Humoral, Immunity

2005 ◽  
Vol 73 (2) ◽  
pp. 999-1005 ◽  
Author(s):  
Ashraf S. Ibrahim ◽  
Brad J. Spellberg ◽  
Valentina Avenissian ◽  
Yue Fu ◽  
Scott G. Filler ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Immune Modulation ◽  
Passive Immunization ◽  
Bloodstream Infections ◽  
Delayed Type Hypersensitivity ◽  
Disseminated Candidiasis ◽  
Terminal Domain ◽  
Deficient Mice ◽  
Stimulation Of

ABSTRACT Candida spp. are opportunistic fungal pathogens that are among the most common causes of nosocomial bloodstream infections. The mortality attributable to disseminated candidiasis is 40 to 50% despite antifungal therapy. Clearly, new strategies are needed to prevent this life-threatening infection. Because risk factors for disseminated candidiasis are well defined and frequently of limited duration, vaccination is an appealing prophylactic strategy. We have identified a cell surface protein, Als1p, that mediates adherence of Candida albicans to a variety of human substrates and plastic. Here we report that immunizing BALB/c mice with the recombinant N-terminal domain of Als1p (rAls1p-N) improved survival during a subsequent challenge with a lethal inoculum of C. albicans. The protective 20-μg dose of rAls1p-N significantly increased Candida stimulation of Th1 splenocytes and increased in vivo delayed-type hypersensitivity. In contrast, antibody titers did not correlate with protection. Finally, the vaccine was not protective in T-cell-deficient mice but was protective in B-cell-deficient mice. These data indicate that the mechanism of action of the rAls1p-N vaccine is stimulation of cell-mediated, rather than humoral, immunity against C. albicans. The majority of efforts to date have focused on the development of passive immunization strategies to prevent or treat disseminated candidiasis. In contrast, our results provide proof of principle for vaccination with an adhesin of C. albicans and emphasize the potential for cell-mediated immune modulation as a prophylactic or therapeutic strategy against disseminated candidiasis.

scholarly journals Electrical Stimulation for Immune Modulation in Cancer Treatments

2022 ◽  
Vol 9 ◽  
Author(s):  
Ritopa Das ◽  
Sofia Langou ◽  
Thinh T. Le ◽  
Pooja Prasad ◽  
Feng Lin ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Immune System ◽  
Immune Modulation ◽  
Cancer Treatments ◽  
Different Types ◽  
Specific Antigens ◽  
High Doses ◽  
T Cell Transfer ◽  
Deficient Mice ◽  
Stimulation Of

Immunotherapy is becoming a very common treatment for cancer, using approaches like checkpoint inhibition, T cell transfer therapy, monoclonal antibodies and cancer vaccination. However, these approaches involve high doses of immune therapeutics with problematic side effects. A promising approach to reducing the dose of immunotherapeutic agents given to a cancer patient is to combine it with electrical stimulation, which can act in two ways; it can either modulate the immune system to produce the immune cytokines and agents in the patient’s body or it can increase the cellular uptake of these immune agents via electroporation. Electrical stimulation in form of direct current has been shown to reduce tumor sizes in immune-competent mice while having no effect on tumor sizes in immune-deficient mice. Several studies have used nano-pulsed electrical stimulations to activate the immune system and drive it against tumor cells. This approach has been utilized for different types of cancers, like fibrosarcoma, hepatocellular carcinoma, human papillomavirus etc. Another common approach is to combine electrochemotherapy with immune modulation, either by inducing immunogenic cell death or injecting immunostimulants that increase the effectiveness of the treatments. Several therapies utilize electroporation to deliver immunostimulants (like genes encoded with cytokine producing sequences, cancer specific antigens or fragments of anti-tumor toxins) more effectively. Lastly, electrical stimulation of the vagus nerve can trigger production and activation of anti-tumor immune cells and immune reactions. Hence, the use of electrical stimulation to modulate the immune system in different ways can be a promising approach to treat cancer.

scholarly journals Simple Nanoparticles from the Assembly of Cationic Polymer and Antigen as Immunoadjuvants

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 105 ◽  
Author(s):  
Yunys Pérez-Betancourt ◽  
Bianca de Carvalho Lins Fernandes Távora ◽  
Mônica Colombini ◽  
Eliana L. Faquim-Mauro ◽  
Ana Maria Carmona-Ribeiro
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Hydrodynamic Diameter ◽  
Spherical Nanoparticles ◽  
Diallyldimethylammonium Chloride ◽  
The One ◽  
Antigen Presenting ◽  
Th 1 ◽  
Positively Charged ◽  
Stimulation Of

Since antigens are negatively charged, they combine well with positively charged adjuvants. Here, ovalbumin (OVA) (0.1 mg·mL−1) and poly (diallyldimethylammonium chloride) (PDDA) (0.01 mg·mL−1) yielded PDDA/OVA assemblies characterized by dynamic light scattering (DLS) and scanning electron microscopy (SEM) as spherical nanoparticles (NPs) of 170 ± 4 nm hydrodynamic diameter, 30 ± 2 mV of zeta-potential and 0.11 ± 0.01 of polydispersity. Mice immunization with the NPs elicited high OVA-specific IgG1 and low OVA-specific IgG2a production, indicating a Th-2 response. Delayed-type hypersensitivity reaction (DTH) was low and comparable to the one elicited by Al(OH)3/OVA, suggesting again a Th-2 response. PDDA advantages as an adjuvant were simplicity (a single-component adjuvant), low concentration needed (0.01 mg·mL−1 PDDA) combined with antigen yielding neglectable cytotoxicity, and high stability of PDDA/OVA dispersions. The NPs elicited much higher OVA-specific antibodies production than Al(OH)3/OVA. In vivo, the nano-metric size possibly assured antigen presentation by antigen-presenting cells (APC) at the lymph nodes, in contrast to the location of Al(OH)3/OVA microparticles at the site of injection for longer periods with stimulation of local dendritic cells. In the future, it will be interesting to evaluate combinations of the antigen with NPs carrying both PDDA and elicitors of the Th-1 response.

Early pregnancy factor has immunosuppressive and growth factor properties

1992 ◽  
Vol 4 (4) ◽  
pp. 411 ◽  
Author(s):  
H Morton ◽  
AC Cavanagh ◽  
S Athanasas-Platsis ◽  
KA Quinn ◽  
BE Rolfe
Keyword(s):  
Growth Factor ◽  
Early Pregnancy ◽  
Passive Immunization ◽  
Immunological Response ◽  
Reversed Phase ◽  
Tumour Cells ◽  
Delayed Type Hypersensitivity ◽  
Early Pregnancy Factor

Early pregnancy factor (EPF) was first described as a pregnancy-associated substance, although recent studies suggest a more general link with cell development. It is a product of actively dividing cells and its apparent functional importance to them suggests its potential as a regulator of cell proliferation. The recent discovery of EPF in platelets has provided a comparatively rich and readily available source of EPF. The purification procedures employed to isolate EPF from this source have also been applied to pregnancy serum and urine, medium conditioned by oestrous mouse ovaries (stimulated with prolactin and embryo-conditioned medium), medium conditioned by tumour cells, and serum from rats 24 h after partial hepatectomy (PH). In all instances, biological activity followed the same pattern throughout. Furthermore, the final active reversed-phase high-performance liquid chromatography fraction from all sources was bound specifically by immobilized anti-EPF monoclonal antibodies (MAbs), indicating that the active fractions produced from these diverse sources are very closely related, if not identical. Some differences have been observed in the behaviour of EPF in various conditions. EPF is produced by proliferating tumour cells and by liver cells post-PH, and passive immunization studies with anti-EPF MAbs have shown that these cells need EPF for survival. In contrast, EPF has not been detected as a product of the pre-embryo, and addition of anti-EPF MAbs to embryo cultures does not adversely affect development from the 2-cell to the blastocyst stage. Although the pre-embryo is not dependent on EPF for its development in vitro, neutralization of EPF in vivo by anti-EPF MAbs retards its development. Thus, EPF appears to play an indirect role in maintaining the pre-embryo. By virtue of its ability to suppress the delayed-type hypersensitivity reaction, it has been suggested that EPF might act as an immunological response modifier of the maternal immune system. Alternatively, the effect of EPF on lymphocytes may be to reduce the expression of all or some cytokines and this could inhibit development. Whether or not EPF acts more directly as an autocrine growth factor from around the time of implantation, when the embryo first begins synthesis of EPF, is not known and remains to be investigated.

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 Distinct interactions of eIF4A and eIF4E with RNA helicase Ded1 stimulate translation in vivo

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Suna Gulay ◽  
Neha Gupta ◽  
Jon R Lorsch ◽  
Alan G Hinnebusch
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Translation Initiation ◽  
Rna Helicase ◽  
Preinitiation Complex ◽  
Terminal Domain ◽  
Dead Box ◽  
Stimulation Of

Yeast DEAD-box helicase Ded1 stimulates translation initiation, particularly of mRNAs with structured 5'UTRs. Interactions of the Ded1 N-terminal domain (NTD) with eIF4A, and Ded1-CTD with eIF4G, subunits of eIF4F, enhance Ded1 unwinding activity and stimulation of preinitiation complex (PIC) assembly in vitro. However, the importance of these interactions, and of Ded1-eIF4E association, in vivo were poorly understood. We identified separate amino acid clusters in the Ded1-NTD required for binding to eIF4A or eIF4E in vitro. Disrupting each cluster selectively impairs native Ded1 association with eIF4A or eIF4E, and reduces cell growth, polysome assembly, and translation of reporter mRNAs with structured 5'UTRs. It also impairs Ded1 stimulation of PIC assembly on a structured mRNA in vitro. Ablating Ded1 interactions with eIF4A/eIF4E unveiled a requirement for the Ded1-CTD for robust initiation. Thus, Ded1 function in vivo is stimulated by independent interactions of its NTD with eIF4E and eIF4A, and its CTD with eIF4G.

scholarly journals EVALUATION OF IN VIVO IMMUNOMODULATORY ACTIVITY OF AQUEOUS AND ETHANOLIC EXTRACT OF CAPPARIS MOONII

2020 ◽  
pp. 63-66
Author(s):  
VANITA G KANASE ◽  
SHRUTI SHETTIGAR
Keyword(s):  
Antibody Titer ◽  
Ethanolic Extract ◽  
Experimental Methods ◽  
Delayed Type Hypersensitivity ◽  
Phagocytic Index ◽  
Immunomodulatory Activity ◽  
Dried Fruits ◽  
Carbon Clearance ◽  
Stimulation Of

Objective: The present study was intended to evaluate the in vivo immunomodulatory activity of aqueous and ethanolic extract of dried fruits of Capparis moonii Wight. Methods: The effect of both the extracts was evaluated by carbon clearance assay in mice, and they showed a significant increase in the phagocytic index at 50, 100, and 200 mg/kg dose. The effect of the extracts on delayed-type hypersensitivity (DTH) and antibody titer assay was evaluated in ovalbumin immunized mice. Results: Both extracts showed a significant effect on DTH response and stimulation of antibody titer at 200 mg/kg dose. The effects of the extracts in cyclophosphamide-induced myelosuppression mice were also statistically significant. Conclusion: The studies demonstrated specific and non-specific immunostimulating properties of both the ethanol and aqueous extract of C. moonii fruits in various in vivo experimental methods suggesting its therapeutic usefulness in immunocompromised conditions.

scholarly journals Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection

2002 ◽  
Vol 70 (4) ◽  
pp. 2151-2158 ◽  
Author(s):  
Douglas E. Jones ◽  
Mark R. Ackermann ◽  
Ulrike Wille ◽  
Christopher A. Hunter ◽  
Phillip Scott
Keyword(s):  
Leishmania Major ◽  
Chronic Phase ◽  
Leishmania Amazonensis ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Th2 Response ◽  
Th1 Response ◽  
Response Expression ◽  
Deficient Mice

ABSTRACT C3H and C57BL/6 mice are resistant to Leishmania major but develop chronic lesions with persistent parasite loads when they are infected with Leishmania amazonensis. These lesions develop in the absence of interleukin-4 (IL-4), indicating that susceptibility to this parasite is not a result of development of a Th2 response. Expression of the cytokine IL-10 during infection could account for the lack of IL-12 expression and poor cell-mediated immunity towards the parasite. Therefore, we tested the hypothesis that IL-10 plays a central role in downmodulating the Th1 response after L. amazonensis infection. Infection of C57BL/6 IL-10-deficient mice indicated that in the absence of IL-10 there was early enhancement of a Th1 response, which was downregulated during the more chronic stage of infection. In addition, although there were 1- to 2-log reductions in the parasite loads within the lesions, the parasites continued to persist, and they were associated with chronic lesions whose size was similar to that of the control lesions. These experiments indicated that L. amazonensis resistance to killing in vivo is only partially dependent on expression of host IL-10. However, IL-10-deficient mice had an enhanced delayed-type hypersensitivity response during the chronic phase of infection, indicating that there were Th1 type effector cells in vivo at this late stage of infection. These results indicate that although IL-10 plays a role in limiting the Th1 response during the acute infection phase, other immunomodulatory factors are responsible for limiting the Th1 response during the chronic phase.

scholarly journals Humoral immune responses in CD40 ligand-deficient mice.

1994 ◽  
Vol 180 (5) ◽  
pp. 1889-1900 ◽  
Author(s):  
B R Renshaw ◽  
W C Fanslow ◽  
R J Armitage ◽  
K A Campbell ◽  
D Liggitt ◽  
...  
Keyword(s):  
T Cell ◽  
Humoral Immunity ◽  
Bacterial Infections ◽  
Keyhole Limpet Hemocyanin ◽  
Cd40 Ligand ◽  
Antibody Responses ◽  
Humoral Immune ◽  
T Cell Subpopulations ◽  
Deficient Mice

Individuals with X-linked hyper-IgM syndrome fail to express functional CD40 ligand (CD40L) and, as a consequence, are incapable of mounting protective antibody responses to opportunistic bacterial infections. To address the role of CD40L in humoral immunity, we created, through homologous recombination, mice deficient in CD40L expression. These mice exhibited no gross developmental deficiencies or health abnormalities and contained normal percentages of B and T cell subpopulations. CD40L-deficient mice did display selective deficiencies in humoral immunity; basal serum isotype levels were significantly lower than observed in normal mice, and IgE was undetectable. Furthermore, the CD40L-deficient mice failed to mount secondary antigen-specific responses to immunization with a thymus-dependent antigen, trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH). By contrast, the CD40L-deficient mice produced antigen-specific antibody of all isotypes except IgE in response to the thymus-independent antigen, DNP-Ficoll. These results underscore the requirement of CD40L for T cell-dependent antibody responses. Moreover, Ig class switching to isotypes other than IgE can occur in vivo in the absence of CD40L, supporting the notion that alternative B cell signaling pathways regulate responses to thymus-independent antigens.

scholarly journals Impact of the Pla Protease Substrate α2-Antiplasmin on the Progression of Primary Pneumonic Plague

2015 ◽  
Vol 83 (12) ◽  
pp. 4837-4847 ◽  
Author(s):  
Justin L. Eddy ◽  
Jay A. Schroeder ◽  
Daniel L. Zimbler ◽  
Lauren E. Bellows ◽  
Wyndham W. Lathem
Keyword(s):  
Immune Modulation ◽  
Dependent Manner ◽  
Pneumonic Plague ◽  
Content Type ◽  
Protease Substrate ◽  
Ultimate Outcome ◽  
Pulmonary Inflammatory Response ◽  
Deficient Mice

Many pathogens usurp the host hemostatic system during infection to promote pathogenesis.Yersinia pestis, the causative agent of plague, expresses the plasminogen activator protease Pla, which has been shownin vitroto target and cleave multiple proteins within the fibrinolytic pathway, including the plasmin inhibitor α2-antiplasmin (A2AP). It is not known, however, if Pla inactivates A2APin vivo; the role of A2AP during respiratoryY. pestisinfection is not known either. Here, we show thatY. pestisdoes not appreciably cleave A2AP in a Pla-dependent manner in the lungs during experimental pneumonic plague. Furthermore, following intranasal infection withY. pestis, A2AP-deficient mice exhibit no difference in survival time, bacterial burden in the lungs, or dissemination from wild-type mice. Instead, we found that in the absence of Pla, A2AP contributes to the control of the pulmonary inflammatory response during infection by reducing neutrophil recruitment and cytokine production, resulting in altered immunopathology of the lungs compared to A2AP-deficient mice. Thus, our data demonstrate that A2AP is not significantly affected by the Pla protease during pneumonic plague, and although A2AP participates in immune modulation in the lungs, it has limited impact on the course or ultimate outcome of the infection.

Role of Sgk1 in salt and potassium homeostasis

2005 ◽  
Vol 288 (1) ◽  
pp. R4-R10 ◽  
Author(s):  
Volker Vallon ◽  
Peer Wulff ◽  
Dan Yang Huang ◽  
Johannes Loffing ◽  
Harald Völkl ◽  
...  
Keyword(s):  
Apical Membrane ◽  
Plasma Aldosterone ◽  
In Vivo Studies ◽  
Distal Nephron ◽  
Arterial Blood ◽  
Normotensive Subjects ◽  
Deficient Mice ◽  
Stimulation Of

Aldosterone plays a pivotal role in NaCl and K+ homeostasis by stimulation of Na+ reabsorption and K+ secretion in the aldosterone-sensitive distal nephron (ASDN). Recent studies demonstrated that the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by aldosterone in the ASDN and that polymorphisms of the kinase associate with arterial blood pressure in normotensive subjects. This review discusses the role of Sgk1 in NaCl and K+ homeostasis as evidenced by in vivo studies, including those in Sgk1-deficient mice. The studies indicate that Sgk1 is not absolutely required for Na+ reabsorption and K+ secretion in the ASDN. On a standard NaCl and K+ diet, modestly enhanced plasma aldosterone concentrations appear sufficient to establish a compensated phenotype in the absence of Sgk1. The kinase is necessary, however, for upregulation of transcellular Na+ reabsorption in the ASDN. This may involve Sgk1-mediated stimulation of basolateral Na+-K+-ATPase as well as retention of epithelial Na+ channel, ENaC, in the apical membrane. Such an upregulation is a prerequisite for adequate adaptation of 1) renal NaCl reabsorption during restricted dietary NaCl intake, as well as 2) K+ secretion in response to enhanced K+ intake. Thus gain-of-function mutations of Sgk1 are expected to result in renal NaCl retention and enhanced K+ secretion. Further studies are required to elucidate renal and nonrenal aldosterone-induced effects of Sgk1, the role of other Sgk1 activators, as well as the link of Sgk1 polymorphisms to arterial hypertension in humans.

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