Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice

Abstract

Despite the increasing use of humanized mouse models to study new approaches of graft-versus-host disease (GVHD) prevention, the pathogenesis of xenogeneic GVHD (xGVHD) in these models remains misunderstood. The aim of this study is to describe this pathogenesis in NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice infused with human PBMCs and to assess the impact of the expression of HLA-A0201 by NSG mice cells (NSG-HLA-A2/HHD mice) on xGVHD and graft-versus-leukemia (GvL) effects, by taking advantage of next-generation technologies. We found that T cells recovered from NSG mice after transplantation had upregulated expression of genes involved in cell proliferation, as well as in TCR, co-stimulatory, IL-2/STAT5, mTOR and Aurora kinase A pathways. T cells had mainly an effector memory or an effector phenotype and exhibited a Th1/Tc1-skewed differentiation. TCRβ repertoire diversity was markedly lower both in the spleen and lungs (a xGVHD target organ) than at infusion. There was no correlation between the frequencies of specific clonotypes at baseline and in transplanted mice. Finally, expression of HLA-A0201 by NSG mice led to more severe xGVHD and enhanced GvL effects toward HLA-A2+ leukemic cells. Altogether our data demonstrate that the pathogenesis of xGVHD shares important features with human GVHD and that NSG-HLA-A2/HHD mice could serve as better model to study GVHD and GvL effects.

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

“…Finally, along with the impact of Th17 coinjection, results from the first set of our experiments (PBMC versus Th17 coinjection, 4 different donors) also suggested significant interdonor variability in xGVHD severity and lethality. This finding is in accordance with previous reports from our group [34] and others [29]. Compared with mouse-to-mouse allogeneic models of aGVHD characterized by fixed genetic and immunologic disparities between donors and recipients (within a determined model), this xGVHD model uses human PBMC donors with high genetic diversity.…”

“…More specifically, little is known about the potential implication of Th17 cells in xGVHD pathogenesis in NOG/NSG mice. Indeed, although some groups have reported the presence of human Th17 cells at the time of xGVHD, Th17 cells represent only a small fraction of CD4 + T cells in blood, lymphoid tissue, and xGVHD target organs [23,26,34,36]. This may be due to low levels of human pro-Th17 cytokines in that model, which limit naive cell polarization toward Th17 fate in vivo after their transfer in mice.…”

“…Over the past several decades, humanized murine models of xenogeneic GVHD (xGVHD) have been developed via the injection of human peripheral blood mononuclear cells (PBMCs) into severely immunodeficient NOD/Shi-scid IL2rg-null (NOG) or NOD/LtSz-scid IL2rg-null (NSG) mice [23][24][25][26][27][28][29][30][31][32]. These models are T cell dependent, and main triggers of T cell activation and expansion are xenogeneic MHC (H-2) class I and class II molecules [23,30,33,34] and xenogeneic costimulatory signals [27,35]. Previous studies have demonstrated a crucial interplay between CD4 + and CD8 + T cells during xGVHD [23,35]; however, the concrete role of individual T cell subsets has not yet been fully elucidated.…”

High activation and skewed T cell differentiation are associated with low IL-17A levels in a hu-PBL-NSG-SGM3 mouse model of HIV infection

“…a). Consistent with the xenogeneic reaction in hu‐PBL‐NSG‐SGM3 mice , HIV − mice exhibited a massive differentiation of CD4 + and CD8 + T cells to an effector memory profile, with the consequent decrease of naive cells (Fig. b–e).…”

“…To explore if the hu‐PBL‐NSG‐SGM3 mouse model recapitulates the deficiency in IL‐17A secretion during HIV infection, we evaluated plasma levels of IL‐17A in the three groups of mice throughout monitoring time. Interestingly, in contrast to a previous report where low levels of IL‐17A were found in hu‐PBL‐NSG mice , we observed a progressive increase of plasma IL‐17A in HIV − mice, which was sustained for up to 7 weeks post‐engraftment (Fig. a).…”