Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (3)

Search Parameters:
Keywords = CD28 homodimer interface

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
11 pages, 2272 KiB  
Review
Subduing the Inflammatory Cytokine Storm
by Raymond Kaempfer
Int. J. Mol. Sci. 2024, 25(20), 11194; https://doi.org/10.3390/ijms252011194 - 18 Oct 2024
Cited by 2 | Viewed by 1791
Abstract
The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response (“cytokine storm”) harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the [...] Read more.
The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response (“cytokine storm”) harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the context of the coronavirus pandemic, yet bacterial sepsis, severe wound infections and toxic shock provide other prominent examples. The problem of the cytokine storm is compounded by the increasing incidence of multidrug-resistant bacterial strains. We created an incisive molecular tool for analyzing the role of the B7/CD28 costimulatory axis in the human inflammatory response. To attenuate the cytokine storm underlying infection pathology, yet preserve host defenses, we uniquely targeted the engagement of CD28 with its B7 co-ligands by means of short peptide mimetics of the human CD28 and B7 receptor homodimer interfaces. These peptides are not only effective tools for dissecting mechanism but also serve to attenuate the inflammatory response as a broad host-oriented therapeutic strategy against the cytokine storm. Indeed, such peptides protect mice from lethal Gram-positive bacterial superantigen-induced toxic shock even when dosed in molar amounts well below that of the superantigen and show promise in protecting humans from the severe inflammatory disease necrotizing soft tissue infections (‘flesh-eating’ bacterial sepsis) following traumatic wound injuries. Full article
(This article belongs to the Special Issue Latest Advances in Cytokine Storm)
Show Figures

Figure 1

14 pages, 2605 KiB  
Article
Crystal Structure of a Chimeric Antigen Receptor (CAR) scFv Domain Rearrangement Forming a VL-VL Dimer
by Jonah Cheung, Shagun Wazir, David R. Bell, James N. Kochenderfer, Wayne A. Hendrickson and Philippe Youkharibache
Crystals 2023, 13(4), 710; https://doi.org/10.3390/cryst13040710 - 21 Apr 2023
Cited by 3 | Viewed by 5232
Abstract
Chimeric Antigen Receptor T-cell (CAR-T) immunotherapies are dependent upon designed transmembrane proteins to bind target antigens and stimulate an immune response. The success or failure of these CARs is only partially predictable, yet recent work has highlighted the importance of antigen binding scFvs [...] Read more.
Chimeric Antigen Receptor T-cell (CAR-T) immunotherapies are dependent upon designed transmembrane proteins to bind target antigens and stimulate an immune response. The success or failure of these CARs is only partially predictable, yet recent work has highlighted the importance of antigen binding scFvs driving distinct oligomerization states with varied CAR-T efficacy. Here, we sought to determine the extracellular structure of the anti-CD19 CAR 47G4-CD828Z. Unexpectedly, the resolved crystal structure revealed an IgVL homodimer bound along an inverted VL|VL interface. We found that the VL-VH linker, designed to be cleavage resistant, was cleaved, and the VH and CAR hinge domains were absent from the crystal structure lattice. Molecular Dynamics simulations revealed that the inverted VL|VL interface was more stable than the canonical VL|VL configuration. Our work substantiates the need to interrogate the scFv structure and CAR oligomerization state for optimal CAR-T design. Full article
(This article belongs to the Topic Advanced Structural Crystals)
Show Figures

Figure 1

6 pages, 989 KiB  
Review
Bacterial Superantigen Toxins, CD28, and Drug Development
by Raymond Kaempfer
Toxins 2018, 10(11), 459; https://doi.org/10.3390/toxins10110459 - 6 Nov 2018
Cited by 13 | Viewed by 6259
Abstract
During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate [...] Read more.
During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant. Full article
(This article belongs to the Special Issue From Toxins to Drugs)
Show Figures

Graphical abstract

Back to TopTop