scholarly journals Substrate-induced clustering activates Trim-Away of pathogens and proteins

2020 ◽  
Author(s):  
Jingwei Zeng ◽  
Ana Filipa Santos ◽  
Aamir Mukadam ◽  
Mariana Osswald ◽  
Jakub Luptak ◽  
...  
Keyword(s):  
Immune Function ◽  
Protein Degradation ◽  
New Technology ◽  
Antiviral Response ◽  
Ring Domain ◽  
Cellular Activation ◽  
Protein Depletion ◽  
Highly Active ◽  
Normal Immune Function

SUMMARYTrim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.

Dietary Nucleotide Effects upon Immune Function in Infants

PEDIATRICS ◽  
1991 ◽  
Vol 88 (2) ◽  
pp. 359-363
Author(s):  
Jane D. Carver ◽  
Bernardo Pimentel ◽  
William I. Cox ◽  
Lewis A. Barness
Keyword(s):  
Human Milk ◽  
Immune Function ◽  
Mononuclear Cells ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Nonprotein Nitrogen ◽  
Term Infants ◽  
Group Rate ◽  
Breast Fed ◽  
Normal Immune Function

Nucleotide (NT) nitrogen, a component of nonprotein nitrogen, accounts for approximately 0.1% to 0.15% of the total nitrogen content of human milk. The results of studies in animals indicate that dietary NTs may be required for maintenance of normal immune function. Thirty-seven healthy term infants were either breast-fed (n = 9) or fed SMA formula supplemented with 33 mg of NTs per liter (n = 13, NT+) or standard SMA formula (n = 15; NT-). At 2 months of age, natural killer cell percent cytotoxicity was significantly higher in the breast-fed and NT+ groups compared with the NT- group (41.7 ± 4.7, 32.2 ± 3.4, 21.7 ± 2.2%, respectively). Interleukin-2 production by stimulated mononuclear cells was higher in the NT+ compared with the NT- group at 2 months of age (0.90 ± 0.28 U/mL, 0.27 ± 0.11 U/mL, respectively); neither formula-fed group differed significantly from the breast-fed group. Rate of growth and incidence and severity of infections did not differ significantly among dietary groups. Nucleotides may be a component of human milk that contributes to the enhanced immunity of the breast-fed infant.

Specific Inhibition of Syk Suppresses Leukocyte Immune Function and Alleviates Inflammation In Rodent Models of Rheumatoid Arthritis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1727-1727
Author(s):  
Greg Coffey ◽  
DeGuzman Francis ◽  
Mayuko Inagaki ◽  
Yvonne Pak ◽  
Suzanne Delaney ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oral Administration ◽  
Immune Function ◽  
Whole Blood ◽  
Cell Receptor ◽  
Rodent Models ◽  
Cellular Activation ◽  
Human Whole Blood ◽  
Immunomodulatory Potential

Abstract Abstract 1727 Genetic ablation of Syk in hematopoietic cells blocks various leukocyte immune functions, and protects mice from immune-complex mediated inflammation. These data have helped to identify Syk as an important therapeutic target for immune-mediated diseases. The next step is to test the hypothesis that low level, and specific, pharmacological inhibition of Syk retains the immunomodulatory potential observed with Syk genetic deficiency. With this goal in mind, we provide an update on the development of P505-15, a highly specific and potent small molecule Syk inhibitor which suppresses signaling and activation of primary human and rodent leukocyte immune function. The specificity of P505-15 was tested in a panel of 270 independent purified kinase assays at 300nM. At this concentration, Syk and 8 other kinases were inhibited by ≥ 80%. Subsequent analysis demonstrated a Syk IC50 of 1nM, whereas the next most potently inhibited kinase required an IC50 of 81nM. In a variety of cellular assays we observed potent inhibition of B cell receptor (BCR) induced Syk signaling, but not of Lyn, phorbol 12-myristate 13-acetate (PMA) induced protein kinase C, T cell receptor induced Zap70, or cytokine induced JAK1 (IL6), JAK2 (GM-CSF), or JAK1/3 (IL4) dependent STAT phosphorylation. Consistently, in Ba/F3 cell lines transformed by various kinases, P505-15 only inhibited proliferation of those cells transformed by Syk (IC50 = 0.12μM), and not by Zap70 or JAK family members (IC50 > 6μM). In human whole blood, P505-15 suppressed BCR-induced Syk signaling and cellular activation with IC50's of 0.383μM and 0.362μM, respectively. FceR1-induced basophil degranulation was similarly suppressed with an IC50 of 0.171μM. Importantly, Syk-independent signaling and cellular activation in human whole blood via PMA (B cell assays) or fMLP (basophil degranulation) was unaffected by this compound at 4μM and 1μM, respectively (the highest concentrations tested), again demonstrating its specificity of action. Oral administration of P505-15 in mice led to a reversible inhibition of Syk, with an IC50 of 0.282μM as determined by an ex vivo whole blood BCR stimulation assay. Finally, we tested the immunomodulatory potential of specific Syk inhibition in vivo using rodent models of rheumatoid arthritis. Oral administration of P505-15 resulted in statistically significant and dose-dependent anti-inflammatory activity in both the mouse collagen antibody-induced arthritis and rat collagen induced arthritis models. In each case, anti-inflammatory effects were achieved at sub-micromolar plasma concentrations in which Syk specificity was maintained. These data support the hypothesis that specific Syk inhibition can modulate immune function in vivo, and provide a therapeutic strategy for the treatment of human inflammatory disease by inhibition of this kinase. P505-15 is currently being evaluated in phase I clinical trials. Disclosures: Coffey: Portola Pharmaceuticals: Employment. Francis:Portola Pharmaceuticals: Employment. Inagaki:Portola Pharmaceuticals: Employment. Pak:Portola Pharmaceuticals: Employment. Delaney:Portola Pharmaceuticals: Employment. Betz:Portola Pharmaceuticals: Employment. Jia:Portola Pharmaceuticals: Employment. Xu:Portola Pharmaceuticals: Employment. Bauer:Portola Pharmaceuticals: Employment. Song:Portola Pharmaceuticals: Employment. Pandey:Portola Pharmaceuticals: Employment. Baker:Portola Pharmaceuticals: Employment. Hollenbach:Portola Pharmaceuticals: Employment. Phillips:Portola Pharmaceuticals: Employment. Sinha:Portola Pharmaceuticals: Employment.

scholarly journals Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes

2000 ◽  
Vol 97 (7) ◽  
pp. 3382-3387 ◽  
Author(s):  
A. Oxenius ◽  
D. A. Price ◽  
P. J. Easterbrook ◽  
C. A. O'Callaghan ◽  
A. D. Kelleher ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
T Lymphocytes ◽  
Immune Function ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Acute Hiv ◽  
Hiv 1

Bacterial Contamination of Children's Toys Used in a General Practitioner's Surgery

2000 ◽  
Vol 45 (1) ◽  
pp. 12-13 ◽  
Author(s):  
I. McKay ◽  
T.A. Gillespie
Keyword(s):  
General Practice ◽  
Inner City ◽  
Immune Function ◽  
Odds Ratio ◽  
Bacterial Contamination ◽  
Healthcare Professionals ◽  
Cross Infection ◽  
Bacterial Colonisation ◽  
Child Friendly ◽  
Normal Immune Function

General practitioners — and other healthcare professionals are encouraged to make their premises child friendly. One way of doing this is to provide toys for children to use. We looked at the appearance and bacterial colonisation of 50 toys after a busy morning surgery in an inner city general practice. The toys appeared generally unclean and 10% were contaminated by potential pathogens. Bacteria were cultured more frequently from soft toys than from hard toys (odds ratio 8.14; 95% confidence range 0.74 − 107.49). Although toys may appear to be physically dirty after use, the bacteria isolated from their surfaces are generally non-pathogenic to children with normal immune function and probably no worse than other objects in the environment. However, there does exist an appreciable (1 in 10) risk of cross-infection with the use of toys in a clinic. Toys with a hard surface are preferred as these are less likely to be contaminated and are more easily disinfected.

Immune Function and Phenotype Before and After Highly Active Antiretroviral Therapy

1999 ◽  
Vol 21 (5) ◽  
pp. 376 ◽  
Author(s):  
Sisse R. Søndergaard ◽  
Hassan Aladdin ◽  
Henrik Ullum ◽  
Jan Gerstoft ◽  
Peter Skinhøj ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Function ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Before And After

CMV colitis in early HIV infection

2000 ◽  
Vol 11 (11) ◽  
pp. 748-750 ◽  
Author(s):  
P R Smith ◽  
M Glynn ◽  
M Sheaff ◽  
C Aitken
Keyword(s):  
Hiv Infection ◽  
Immune Function ◽  
Clinical Disease ◽  
Hiv Disease ◽  
Cmv Infection ◽  
Contributing Factors ◽  
Advanced Hiv Disease ◽  
Cmv Colitis ◽  
Normal Immune Function

Cytomegalovirus (CMV) colitis is a well recognized complication of advanced HIV disease and is only rarely diagnosed in patients with normal immune function. A case of CMV colitis occurring in early HIV infection is described. Although CMV infection is normally confined to patients with advanced HIV disease, it is possible that a number of contributing factors may have led to clinical disease in this patient. CMV colitis is an important diagnosis to consider in all patients who present with a diarrhoeal illness associated with systemic features, regardless of underlying immunosuppression.

scholarly journals Effect of Latent Human Immunodeficiency Virus Infection on Cell Surface Phenotype

2002 ◽  
Vol 76 (4) ◽  
pp. 1673-1681 ◽  
Author(s):  
David G. Brooks ◽  
Jerome A. Zack
Keyword(s):  
Human Immunodeficiency Virus ◽  
Highly Active Antiretroviral Therapy ◽  
Virus Production ◽  
Cellular Interactions ◽  
Cellular Activation ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Highly active antiretroviral therapy has succeeded in many cases in suppressing virus production in patients infected with human immunodeficiency virus (HIV); however, once treatment is discontinued, virus replication is rekindled. One reservoir capable of harboring HIV in a latent state and igniting renewed infection once therapy is terminated is a resting T cell. Due to the sparsity of T cells latently infected with HIV in vivo, it has been difficult to study viral and cellular interactions during latency. The SCID-hu (Thy/Liv) mouse model of HIV latency, however, provides high percentages of latently infected cells, allowing a detailed analysis of phenotype. Herein we show that latently infected cells appear phenotypically normal. Following cellular stimulation, the virus completes its life cycle and induces phenotypic changes, such as CD4 and major histocompatibility complex class I down-regulation, in the infected cell. In addition, HIV expression following activation did not correlate with expression of the cellular activation marker CD25. The apparently normal phenotype and lack of HIV expression in latently infected cells could prevent recognition by the immune response and contribute to the long-lived nature of this reservoir.

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