Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4 T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis.

By promoting the cytotoxic function of CD8 T cells, immune checkpoint inhibitor therapy, programmed cell death protein-1 (PD-1), effectively inhibits tumor growth in renal cell carcinoma. Yet, as many as 87% of cancer patients do not respond to immune checkpoint therapy. Importantly, cytotoxic CD8 T cell function crucially relies on CD4 T helper cell cytokines, in particular, tumor necrosis factor beta (TNFβ) and its CD8 T cell receptor (TNFR2) in the opposing manner as immune checkpoints and their receptors.

Alphataxin, an Orally Available Small Molecule, Decreases LDL Levels in Mice as a Surrogate for the LDL-Lowering Activity of Alpha-1 Antitrypsin in Humans.

The abundant blood protein α1-proteinase inhibitor (α1PI, Αlpha-1, α1-antitrypsin, ) is known to bind to the active site of granule-associated human leukocyte elastase (HLE-G). Less well known is that binding of α1PI to cell surface HLE (HLE-CS) induces lymphocyte locomotion mediated by members of the low density lipoprotein receptor family (LDL-RFMs) thereby facilitating low density lipoprotein (LDL) clearance. LDL and α1PI were previously shown to be in negative feedback regulation during transport and clearance of lipoproteins.

Development of Immature CD4CD8T Cells Into Mature CD4 T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls.

Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with the abundant blood protein α1proteinase inhibitor (α1PI, α1-antitrypsin, Alpha-1), a process that induces internalization of aggregated functionally-related receptors, including CD4 and the T cell antigen receptor, while simultaneously promoting cellular locomotion. We sought to determine whether augmenting α1PI blood concentration would promote the locomotion of immature T cells through the thymus and generate new CD4 T cells.

A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.

Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g.

The α-test: rapid cell-free CD4 enumeration using whole saliva.

There is an urgent need for affordable CD4 enumeration to monitor HIV disease. CD4 enumeration is out of reach in resource-limited regions due to the time and temperature restrictions, technical sophistication, and cost of reagents, in particular monoclonal antibodies to measure CD4 on blood cells, the only currently acceptable method. A commonly used cost-saving and time-saving laboratory strategy is to calculate, rather than measure certain blood values.

α1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease.

Background: The regulation of adult stem cell migration through human hematopoietic tissue involves the chemokine CXCL12 (SDF-1) and its receptor CXCR4 (CD184). In addition, human leukocyte elastase (HLE) plays a key role. When HLE is located on the cell surface (HLE(CS)), it acts not as a proteinase, but as a receptor for α(1)proteinase inhibitor (α(1)PI, α(1)antitrypsin, SerpinA1).

NF-kappaB signaling, elastase localization, and phagocytosis differ in HIV-1 permissive and nonpermissive U937 clones.

To identify positive or negative factors for HIV-1 infectivity, clones from the U937 promonocytic cell line that express similar levels of CD4 and CXCR4, but differ in HIV-1 susceptibility, were compared. In contrast to HIV-1 permissive clone 10 (plus), nonpermissive clone 17 (minus) was adherent to coverslips coated with chemokines, was phagocytic, killed bacteria, and expressed human leukocyte elastase (HLE) in a granule-like compartment (HLEG) that was never detected at the cell surface (HLECS). In contrast to the minus clone, the plus clone expressed HLE on the cell surface and was adherent to coverslips coated with the HLECS ligands alpha1proteinase inhibitor (alpha1PI, alpha1antitrypsin) and the HIV-1 fusion peptide.