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Am J Pathol. 2017 Jun;187(6):1380-1398. doi: 10.1016/j.ajpath.2017.02.015. Epub 2017 Apr 20.

Human Effector Memory T Helper Cells Engage with Mouse Macrophages and Cause Graft-versus-Host-Like Pathology in Skin of Humanized Mice Used in a Nonclinical Immunization Study.

Author information

1
Regenerative Biology to Reconstructive Therapies (REBIRTH), Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
2
Department of Pathology, Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Hannover, Germany.
3
Department of Airway Immunology, Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Hannover, Germany.
4
Department of Transfusion Medicine, Hannover Medical School, Hannover, Germany.
5
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
6
Clinic of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany.
7
Institute of Biostatistics, Hannover Medical School, Hannover, Germany.
8
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
9
Regenerative Biology to Reconstructive Therapies (REBIRTH), Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. Electronic address: stripecke.renata@mh-hannover.de.

Abstract

Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4+ T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4+ cells near F4/80+ mouse macrophages around hair follicles. In spleen, CD4+ cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2-type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8+ T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice.

PMID:
28432872
DOI:
10.1016/j.ajpath.2017.02.015
[Indexed for MEDLINE]

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