A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect.

The utility of allogeneic stem cell transplantation for treating hematologic malignancies is enhanced by the graft vs. tumor (GvT) effect, but limited by graft vs. host disease (GvHD). Studies involving the inhibition of CD73 by genetic or pharmacologic means suggest that the levels of CD73-generated adenosine may be manipulated to control GvHD, while maintaining the GvT effect.

Ectonucleotidases in solid organ and allogeneic hematopoietic cell transplantation.

Extracellular nucleotides are ubiquitous signalling molecules which modulate distinct physiological and pathological processes. Nucleotide concentrations in the extracellular space are strictly regulated by cell surface enzymes, called ectonucleotidases, which hydrolyze nucleotides to the respective nucleosides. Recent studies suggest that ectonucleotidases play a significant role in inflammation by adjusting the balance between ATP, a widely distributed proinflammatory danger signal, and the anti-inflammatory mediator adenosine. There is increasing evidence for a central role of adenosine in alloantigen-mediated diseases such as solid organ graft rejection and acute graft-versus-host disease (GvHD). Solid organ and hematopoietic cell transplantation are established treatment modalities for a broad spectrum of benign and malignant diseases. Immunological complications based on the recognition of nonself-antigens between donor and recipient like transplant rejection and GvHD are still major challenges which limit the long-term success of transplantation. Studies in the past two decades indicate that purinergic signalling influences the severity of alloimmune responses. This paper focuses on the impact of ectonucleotidases, in particular, NTPDase1/CD39 and ecto-5'-nucleotidase/CD73, on allograft rejection, acute GvHD, and graft-versus-leukemia effect, and on possible clinical implications for the modulation of purinergic signalling after transplantation.

Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease.

Extracellular ATP and adenosine have immunoregulatory roles during inflammation. Elevated extracellular ATP is known to exacerbate GVHD, and the pharmacologic activation of the adenosine A2A receptor is protective. However, the role of endogenous adenosine is unknown. We used gene-targeted mice and a pharmacologic inhibitor to test the role of adenosine generated by CD73/ecto-5'-nucleotidase in GVHD. In allogeneic transplants, both donor and recipient CD73 were protective, with recipient CD73 playing the dominant role. CD73 deficiency led to enhanced T-cell expansion and IFN-γ and IL-6 production, and the migratory capacity of Cd73-/- T cells in vitro was increased. However, the number of regulatory T cells and expression of costimulatory molecules on antigen-presenting cells were unchanged. A2A receptor deficiency led to increased numbers of allogeneic T cells, suggesting that signaling through the A2A receptor via CD73-generated adenosine is a significant part of the mechanism by which CD73 limits the severity of GVHD. Pharmacologic blockade of CD73 also enhanced graft-versus-tumor activity. These data have clinical implications, as both the severity of GVHD and the strength of an alloimmune antitumor response could be manipulated by enhancing or blocking CD73 activity or adenosine receptor signaling depending on the clinical indication.

Thymosin ß4 induces folding of the developing optic tectum in the chicken (Gallus domesticus).

Thymosin ß4 (Tß4) is a highly conserved G-actin binding polypeptide with multiple intra- and extracellular functions. While stem-cell activation as well as promotion of cell survival and migration by Tß4 have been investigated in various in vitro and in vivo studies, there are few data on the implications of Tß4 in brain development. In the present study we analyzed Tß4 expression in the developing optic tectum of the chicken (Gallus domesticus) and performed in ovo retroviral transduction and plasmid electroporation for overexpression and knockdown of Tß4. We found marked Tß4 expression in the tectal plate and in all neuronal layers of later developmental stages, but not in the ventricular zone where neural stem cells reside and divide. Knockdown of Tß4 inhibited growth of Tß4-depleted hemispheres, whereas overexpression of Tß4 led to the production of neuroepithelial folds resembling gyri and sulci, which are not normally present in avian brains. The mechanism yielding enhanced growth of Tß4 overexpressing hemispheres involved enhanced proliferation, thus indicating an impact of Tß4 on the neural stem cell and/or progenitor cell population. In summary, we found that due to its effects on proliferation, Tß4 expression has a large impact on neuroepithelial and macroscopic brain development.