Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

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.

Modeling de novo leukemogenesis from human cord blood with MN1 and NUP98HOXD13

“…CTL mice died with signs of graft-versushost disease, such as hypocellular BM and T-cell infiltration of the spleen. [10][11][12] Based on myeloid phenotype, blast count, and inability of disease transplantability, we concluded that MN1 alone induces a transient myeloproliferation, but not AML.…”

Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses

“…In this study, we have demonstrated a significant difference between a selective CD28 blockade strategy with FR104 and the direct blocking of CD80/86 with CTLA4-Ig in a preclinical transplantation model. It is worth noting that, in this model, human T cells are activated (12) and infiltrate the graft by day 21 after adoptive transfer of human PBMCs (15). FR104 is therefore a powerful immunosuppressant, as it has the capacity to suppress T cells that are already activated and to rescue a skin graft from rejection after the process has already been set into action.…”

“…We therefore assessed expression levels of skin-homing molecules that may affect the migration of leukocytes into the skin graft. Cutaneous lymphocyte antigen (CLA) and C-C chemokine receptor 4 (CCR4) are key human skin homing molecules (10,11) and have been shown to be important for Treg function in humanized mouse systems (12,13). We found that the majority of CD8 + T lymphocytes in the peripheral blood expressed surface CLA 28 days after adoptive transfer and that only FR104 was able to suppress CLA expression (59% ± 10.6% vs. 8% ± 4.3%, saline vs. FR104, P < 0.01, Figure 4A).…”

Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells

“…[21][22][23] We next compared the xenoreactive capacity of 5 3 10 6 CB vs PB T cells in tumor-free NSG mice. In mice receiving PB T cells, we observed the onset of xenoreactivity 3 weeks following T-cell injection: all mice developed ruffled fur, lethargy, and weight loss 3 weeks after T-cell injections (supplemental Figure 4A).…”