Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT

The ability to increase the base of support and recover stability is limited in its generalisation for different balance perturbation tasks

Background The assessment of stability recovery performance following perturbations contributes to the determination of fall resisting skills. This study investigated the association between stability recovery performances in two perturbation tasks (lean-and-release versus tripping). Methods Healthy adults (12 young: 24 ± 3 years; 21 middle-aged: 53 ± 5 years; 11 old: 72 ± 5 years) were suddenly released from a forward-inclined position attempting to recover stability with a single step. In a second task, all participants experienced a mechanically induced trip during treadmill walking. To assess dynamic stability performance, the antero-posterior margin of stability (MoS), the base of support (BoS), and the rate of increase in BoS were determined at each foot touchdown (TD) for both tasks. Results Only weak to moderate correlations in dynamic stability performance parameters were found between the two tasks (0.568 > r > 0.305, 0.001 < p < 0.04). A separation of participants according to the number of steps required to regain stability in the lean-and-release task revealed that multiple- (more than one step) compared to single-steppers showed a significantly lower MoS at TD (p = 0.003; g = 1.151), lower BoS at TD (p = 0.019; g = 0.888) and lower rate of increase in BoS until TD (p = 0.002; g = 1.212) after release. Despite these profound subgroup differences in the lean-and-release task, no differences between multiple- and single-steppers were observed in the stability recovery performance during tripping. Conclusion The results provide evidence that the ability to effectively control dynamic stability following a sudden balance disturbance in adults across a wide age range is limited in its generalisation for different perturbation tasks

Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset

Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T-cells. However not donor T-cells but neutrophils reach the sites of tissue injury first and therefore could be a potential target for GVHD-prevention. A detailed analysis of neutrophil fate during acute GVHD and impact on T-cells is difficult due to the short life-span of this cell type. By using a novel photoconverter reporter system we show that neutrophils that had been photoconverted in the ileum post-conditioning later migrated to mesenteric lymph nodes (mLN). This neutrophil migration was dependent on the intestinal microflora. In the mLN neutrophils colocalized with T-cells and presented antigen on MHC-II, thereby impacting T-cell expansion. Pharmacological JAK1/2 inhibition reduced neutrophil influx into the mLN and MHC-II expression thereby interfering with an early event in acute GVHD pathogenesis. In agreement with this finding, neutrophil-depletion reduced aGVHD. We conclude that neutrophils are attracted to the ileum, where the intestinal barrier is disrupted, and then migrate to the mLN where they participate in alloantigen-presentation. JAK1/2-inhibition can interfere with this process, which provides a potential therapeutic strategy to prevent early events of tissue damage-related innate immune cell activation and ultimately GVHD