Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease.
Biol Blood Marrow Transplant
; 24(8): 1563-1574, 2018 08.
Article
em En
| MEDLINE
| ID: mdl-29678638
ABSTRACT
Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4+ and CD8+ T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rgnull mice. CD4+ T cells and, to a lesser extent, CD8+ T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4+ T cells also supported the activation and proliferation of CD8+ T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4+ T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4+ T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC)+/+ mice but not in MHC-/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD.
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
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Apresentação de Antígeno
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Xenoenxertos
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Doença Enxerto-Hospedeiro
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Células Apresentadoras de Antígenos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article