Abstract
The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγnull), notably the NOD-scid IL-2Rγnull (NSG) and BALB/c-Rag2 null IL-2Rγnull (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45+ compartment and higher engraftment levels of CD3+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (TEM) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting TEM-cell driven GvHD.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) can be a potential curative therapy for a variety of malignant and nonmalignant hematological diseases
Hu-peripheral blood mononuclear cells (PBMC) NSG and Hu-PBMC BALB/c-Rag2null IL-2Rcnull (BRG) mice are currently used as reliable models of human-into-mouse xenogeneic Graft-versus-Host Disease (GvHD) where the engrafted cells are amenable to regulation by therapeutic agents or adoptively transferred human immune cells such as regulatory T-cells (Tregs) or tolerogenic dendritic cells [6,7,8,9,10,11,12]
BRG mice Several reports have shown that NSG and BRG mice engraft efficiently with human PBMC in the absence of host preconditioning [6,11,17,18,19], but a systematic comparison between the two strains has never been performed
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) can be a potential curative therapy for a variety of malignant and nonmalignant hematological diseases. In human acute GvHD, the characteristic involvement of specific organs strongly suggests that immune cell trafficking is essential to the pathophysiology of disease This has been linked to the expression of homing receptors that direct T-cells to specific extralymphoid tissues. Recent reports have pointed towards alterations of T-cell expression of the specific skin homing marker cutaneous lymphocyte antigen (CLA) as a predictive immunobiological marker of acute GvHD in the periphery of HSCT patients [14,15]. Such human studies employ analysis of peripheral blood because patient tissues are usually inaccessible due to obvious ethical and technical constraints. The opportunity to examine via flow cytometry the Tcell composition and reconstitution of lymphoid organs in GvHD patients is crucial for developing preventative strategies
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