The A2A receptor agonist CGS 21680 has beneficial and adverse effects on disease development in a humanised mouse model of graft-versus-host disease

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A 2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A 2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γ null (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A 2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A 2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A 2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A 2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

“…This suggests that in addition to reducing GVHD, more frequent dosing with P2X7 antagonists early after transplantation may result in improved donor immune cell engraftment and homeostasis, potentially resulting in a greater protection from opportunistic infections and cancer relapse. In regards to B cell engraftment, previous studies have repeatedly shown absent or negligible B cell engraftment in this humanised mouse model (18,28,42,43) . The action of BBG in promoting B cell engraftment in humanised mice in the current study appeared to be attributed to improved survival of these cells, as BBG prevented the loss of hB cells when cultured with limited amounts of FCS.…”

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model

“…PTCy can increase Treg number in allogeneic mouse models of GVHD [54], but there are limited data in humanized mice. We have previously observed human Tregs in humanized NSG mice with GVHD [31,38,49,[55][56][57][58]; however, PTCy is the first treatment in our laboratory to impact these cells in this model. This may validate the impact of PTCy on human Tregs in the current study.…”

Purinergic Signalling in Allogeneic Haematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

“…Contrary to allogeneic mouse models, injection of caffeine (days 0–14) did not impact weight loss, clinical score, survival, histology or serum cytokine concentrations in a humanised mouse model [ 113 ]. While injection of the A 2A agonist CGS21680 (days −2–11) had confounding effects in these mice, appearing to worsen disease by increasing weight loss and serum human IL-6 concentrations, but also potentially alleviating disease severity by reducing leukocyte infiltration into the liver and serum human TNFα concentrations [ 136 ].…”