Grants Awarded

Date of Award
December 2016

Amount of Award
$50,000

Layperson Summary
HLH is a life-threatening clinical syndrome characterized by hyperactivated immune response and its related pathological damages. HLH is usually triggered by extrinsic reasons such as infection, autoimmune and cancer with or without genetic defects on cytotoxic pathway. Chemotherapy drug based regimen is widely used for controlling the overwhelming immune cascades, but harbors substantial side effect and still some patients are resistant to it. Novel therapeutic targets are urgently needed to be explored. HIF-1α plays an essential role in regulation of immune response in both innate and adaptive immune system. We recently generated inducible hypoxia inducible factor-1α (HIF-1α) transgenic mice in which HIF-1α can be induced in all hematopoietic cells. They developed HLH phenotypes which faithfully recapitulates a variety of HLH clinial and immune features. We hypothesize that high level of HIF-1α is the common mediator of HLH, thus, expression of HIF-1α will be evaluated in human HLH specimens as well as two well established HLH mice models-LCMV/Prf-/- and repeated CpG injection mice models. Genetic knockout or pharmacologic inhibition of HIF-1α will be performed in these two mice models. Expression of high level of HIF-1α in macrophages and monocytes cannot induce HLH like phenotype, whereas high level of HIF-1α in dendritic cells(DCs) as well as macrophages and monocytes is sufficient to induce HLH-like phenotype. We hypothesized that DCs play an essential role in HIF-1α induced HLH. To prove it, we will deplete DCs in our HIF-1α induced HLH model to see whether HLH phenotype can be blocked or not. NK cells are known to be responsible for diminishing the activated DCs and macrophages. In HLH patients, as well as several HLH mouse models including our mouse model, defective NK cells were commonly found. Adaptive infusion of functional NK cells has been a promising therapeutic method for cancer, thus, we will test adaptive infusion of activated NK cells with syngeneic and allogeneic NK cells. By focusing on the novel mechanism of HIF-1α activation in HLH and novel targeted therapy in this proposal, we expect to reveal the central pathobiologic mediator of HLH and provide novel targeted treatment with reduced toxicity and prolonged survival for HLH patients.