Research News

Congratulations to our collaborator Mark Boothby on the acceptance of his PNAS paper

April 2019

Hypoxia-inducible factors in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity

T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4+ T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CXCR5+ follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.

Phase II study on HIF-PHI vadadustat in hemodialysis patients

Effects of Vadadustat on Hemoglobin Concentrations in Patients Receiving Hemodialysis Previously Treated with Erythropoiesis Stimulating Agents

April 2018

Erythropoiesis-stimulating agents (ESAs) can correct anemia in chronic kidney disease (CKD) but are associated with increased risks of cardiovascular events. Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain (HIF-PHD) dioxygenases, is an oral investigational agent in development for the treatment of anemia in patients with CKD.

In a 16-week, open-label, multicenter, Phase 2 trial, Haase and colleagues evaluated vadadustat in 94 patients receiving maintenance hemodialysis previously maintained on ESA therapy. Patients were converted to vadadustat and assigned to a prospective dose cohort: 300 mg daily, 450 mg daily, or 450 mg thrice weekly. The primary endpoints were the mean hemoglobin change from baseline to mid-trial and from baseline to end-of-trial.

No significant changes in hemoglobin concentrations were observed for the two time points in any of the three treatment groups. Hemoglobin concentrations remained stable after conversion from ESA therapy for the duration of the trial, with a single excursion >13 g/dL. Plasma concentrations of vadadustat or its metabolites were not affected by hemodialysis.

Post-hoc analyses found no association between the final vadadustat dose and achieved hemoglobin, baseline hepcidin, C-reactive protein, or previous ESA dose. The overall incidence of adverse events (AEs) was comparable across treatment groups. No deaths occurred during the study. No serious AEs were attributed to vadadustat.

In summary this new study concluded that Vadadustat maintained hemoglobin concentrations in patients on hemodialysis previously receiving ESA therapy.

click here for link to erythropoiesis, iron metabolism and renal anemia

click here to access media files on renal anemia

Haase lab identifies a new role for HIF-PHD oxygen sensors in kidney development

December 2017

Insufficient oxygenation during pregnancy negatively influences kidney development, which predisposes to chronic kidney disease at later stages in life. Kobayashi et al. demonstrate that deletion of HIF prolyl-hydroxylase (PHD) 2 and 3, in FoxD1 lineage cells reduces kidney size and inhibits nephrogenesis in mice. Temporo-spatial expression pattern and studies on additional knockouts suggest the involvement of hypoxia-inducible factor (HIF)-2. More …

click here to read the associated commentary in Kidney International

click here for link to research themes in the Haase lab