Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

Abstract

Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT) with current therapies limited to general immunosuppression. Humanized mouse models of GVHD are emerging as valuable intermediaries to allow translation of findings from allogeneic mouse models to humans to prevent and treat this disease, but such models require further characterization. In this study, humanized mice were generated by injecting immunodeficient non-obese diabetic severe combined immunodeficiency interleukin (IL)-2 receptor γ common chain null (NSG) mice with human peripheral blood mononuclear cells (hPBMCs). Clinical GVHD development was assessed using established scoring criteria (weight loss, posture, activity, fur texture and skin integrity). Differences between humanized NSG mice that developed clinical or subclinical GVHD were then compared. Both groups of mice demonstrated similar frequencies of human leukocyte engraftment. In contrast, mice that developed clinical GVHD demonstrated increased histological damage compared to mice with subclinical GVHD. Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4 + :CD8 + T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD. These cellular and molecular changes could be used as potential markers of disease progression in this preclinical model. This study also provides further insights into GVHD development which may be relevant to human HSCT recipients.

A single‐nucleotide polymorphism in the human ENTPD1 gene encoding CD39 is associated with worsened graft‐versus‐host disease in a humanized mouse model

“…The worsened GVHD in hCD39 AG/GG mice was accompanied by an increase in the hCD4 + :hCD8 + T‐cell ratio compared with hCD39 AA mice. This is in line with previous observations, in which humanized NSG mice with clinical GVHD have higher hCD4 + :hCD8 + T‐cell ratios than those with subclinical GVHD 48 . Notably, the increased hCD4 + :hCD8 + T‐cell ratio, and more severe GVHD, in hCD39 AG/GG mice corresponded to increased splenic hIFNγ expression in these mice compared with hCD39 AA mice.…”

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

“…Sixteen of fifty mice died or were culled between 5.5 and 7 months prior to any surgeries. These animals, as well as several www.nature.com/scientificreports/ others, showed signs of clinically significant graft-versus-host disease (GVHD) including weight loss, reduced activity, postural changes such as hunching, fur ruffling, and skin that was noticeably white, wrinkled, and flaking, consistent with chronic GVHD of the skin in humans 44 and reports of GVHD in NSG mice 45 (Fig. 1d).…”

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

“…APCP‐injected mice ( n = 9) demonstrated significantly greater weight loss over the 10 weeks than saline‐injected mice ( n = 9) ( P = 0.0350) (Figure a). APCP‐mice demonstrated signs of GVHD (classified as a clinical score ≥3) from 38 days onward, while saline‐injected mice demonstrated signs of GVHD from 45 days; however, clinical scores were similar over 10 weeks ( P = 0.1711) (Figure b). Moreover, APCP‐ and saline‐injected mice exhibited identical median survival times (MSTs) (57 days and 57 days, respectively, P = 0.2634) and similar mortality over 10 weeks (100% and 78%, respectively, P = 0.2059) (Figure c).…”

“…Experiments involving human blood and mice were approved by the respective Human and Animal Ethics Committees (University of Wollongong, Wollongong, Australia). A humanized mouse model of GVHD was used as described previously using human blood from two males and one female healthy adult donor. Briefly, hPBMCs, isolated by density centrifugation using Ficoll‐Paque PLUS (GE Healthcare, Uppsala, Sweden), were injected intra‐peritoneally (i.p.)…”