Phytohemagglutinin-activated human T cells induce lethal graft-versus-host disease in cyclophosphamide and anti-CD122 conditioned NOD/SCID mice
ABSTRACT Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Much of our knowledge regarding GVHD comes from experiments on the mouse hematopoietic system due to ethical and technical constraints. Thus, in vivo GVHD models of the human immune system are required. In this study, we report an effective and reliable protocol for xenogeneic GVHD (xeno-GVHD) model induction using NOD/SCID mice, in which mice underwent a conditioning regimen consisting of intraperitoneal injection of cyclophosphamide and anti-CD122, followed by transfusion of phytohemagglutinin-activated human peripheral blood mononuclear cells containing 1 × 10(7) T cells, which has not been reported previously. The present model can be utilized to study human immune cell function in vivo and elucidate the mechanisms underlying the pathogenesis of human GVHD. In addition, this model system can help researchers to rapidly determine whether proposed therapeutic strategies for GVHD are efficient in vivo and will elucidate the underlying mechanisms of drugs and cells to be investigated. Furthermore, such a protocol will undoubtedly be very helpful to laboratories that have no available sources of irradiation.
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ABSTRACT: Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2rgamma(null)) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2rgamma(null) mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 x 10(6) PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-alpha signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly.Clinical & Experimental Immunology 08/2009; 157(1):104-18. DOI:10.1111/j.1365-2249.2009.03933.x · 3.28 Impact Factor
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ABSTRACT: Historically, graft-versus-host disease (GVHD) beyond 100 days after hematopoietic cell transplantation (HCT) was called chronic GVHD, even if the clinical manifestations were indistinguishable from acute GVHD. In 2005, the National Institutes of Health (NIH) sponsored a consensus conference that proposed new criteria for diagnosis and classification of chronic GVHD for clinical trials. According to the consensus criteria, clinical manifestations rather than time after transplantation should be used in clinical trials to distinguish chronic GVHD from late acute GVHD, which includes persistent, recurrent, or late-onset acute GVHD. We evaluated major outcomes according to the presence or absence of NIH criteria for chronic GVHD in a retrospective study of 740 patients diagnosed with historically defined chronic GVHD after allogeneic HCT between 1994 and 2000. The presence or absence of NIH criteria for chronic GVHD showed no statistically significant association with survival, risks of nonrelapse mortality or recurrent malignancy, or duration of systemic treatment. Antecedent late acute GVHD was associated with an increased risk of nonrelapse mortality and prolonged treatment among patients with NIH chronic GVHD. Our results support the consensus recommendation that, with appropriate stratification, clinical trials can include patients with late acute GVHD as well as those with NIH chronic GVHD.Blood 06/2009; 114(3):702-8. DOI:10.1182/blood-2009-03-208983 · 9.78 Impact Factor
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. Donor T cells from the allografts are critical for the success of this effective therapy. Unfortunately these T cells not only recognize and attack the disease cells/tissues but also the other normal tissues of the recipient as "foreign" or "nonself" and cause severe, immune-mediated toxicity, graft-versus-host disease (GVHD). Several insights into the complex pathophysiology of GVHD have been gained from recent experimental observations, which show that acute GVHD is a consequence of interactions between both the donor and the host innate and adaptive immune systems. These insights have identified a role for a variety of cytokines, chemokines, novel T-cell subsets (naĩve, memory, regulatory, and NKT cells) and for non-T cells of both the donor and the host (antigen presenting cells, delta T cells, B cells, and NK cells) in modulating the induction, severity, and maintenance of acute GVHD. This review will focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations.Translational Research 11/2007; 150(4):197-214. DOI:10.1016/j.trsl.2007.06.003 · 4.04 Impact Factor