Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For circulating lymphocytes to migrate to inflammatory sites, they must first adhere to the target tissue endothelium with sufficient strength to overcome the shear forces of blood flow. We previously reported that dermal papillary vessels in acute graft-versus-host disease (aGVHD) support shear-resistant lymphocyte adherence. We now identify the relevant adhesion molecule(s) directing this binding, showing that interactions between lymphocyte CD44 and hyaluronic acid (HA) expressed on dermal vessels in aGVHD alone confer this shear-resistant attachment. Native HA deposits on vascular endothelium support lymphocyte adherence, whereas HA immobilized on plastic does not. HA expressed at dermal endothelium in aGVHD is thus specialized to support lymphocyte adherence under flow conditions, and CD44-HA interactions may contribute to lymphocytotropism to skin in aGVHD.
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PMID:CD44-hyaluronic acid interactions mediate shear-resistant binding of lymphocytes to dermal endothelium in acute cutaneous GVHD. 1450 94

Graft versus host disease (GVHD) is triggered by host antigen-presenting cells (APCs) that activate donor T cells to proliferate and differentiate, but which APC-activated donor T-cell subsets mediate GVHD versus beneficial antitumor effects is not known. Using a CD8(+) T cell-dependent mouse model of human GVHD, we found that host dendritic cell (DC)-induced CD44(hi)CD8(+) effector/memory T cells were functionally defective in inducing GVHD, whereas CD44(lo)CD8(+) naive phenotype T cells were extremely potent GVHD inducers. Depletion of CD44(lo)CD8(+) T cells from host DC-stimulated T cells before transplantation prevented GVHD without impairing their antitumor activity in vivo. Compared with CD44(lo)CD8(+) T cells, CD44(hi)CD8(+) T cells expressed high levels of Fas and were efficiently deleted in vivo following transplantation. These results suggest that ex vivo allogeneic DC stimulation of donor CD8(+) T cells may be useful for the prevention of GVHD and for optimizing antitumor therapies in vivo.
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PMID:Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. 1476 32

Interleukin-15 (IL-15) is a gamma-common cytokine that plays an important role in the development, survival, and proliferation of natural killer (NK), NK T, and CD8+ T-cells. We administered IL-15 to recipients of an allogeneic bone marrow transplantation (allo BMT) to determine its effects on immune reconstitution. Posttransplantation IL-15 administration significantly increased donor-derived CD8+ T (mostly CD122(+)CD44(+)CD8+ T-cells), NK, and NK T-cells at day +28 in young and old recipients of allo BMT. This was associated with enhanced T-cell and NK-cell function. IL-15 stimulated homeostatic proliferation of donor CD8+ T-cells in recipients of carboxyfluorescein diacetate succinimidyl ester-labeled donor T-cell infusions. Posttransplantation IL-15 administration also resulted in a decrease in apoptotic CD8+ T-cells, an increase in Bcl-2-expressing CD8+ T-cells, and an increase in the fraction of Ki67+ proliferative NK and CD8+ T-cells in recipients of allo BMT. IL-15 did not exacerbate graft-versus-host disease (GVHD) in recipients of T-cell-depleted BMT but could aggravate GVHD in some cases in recipients of a T-cell-repleted BMT. Finally, we found that IL-15 administration could enhance graft-versus-leukemia activity. In conclusion, IL-15 can be administered safely to recipients of a T-cell-depleted allo BMT to enhance CD8+ T, NK, and NK T-cell reconstitution.
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PMID:Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. 1528 Feb 5

Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells. Using the C3H.SW anti-C57BL/6 (B6) mouse model of human GVHD directed against minor histocompatibility Ags, we found that donor CD8(+) T cells secreting high levels of IFN-gamma in GVHD B6 mice receiving C3H.SW naive CD8(+) T cells peaked by day 14, declined by day 28 after transplantation, and persisted thereafter, corresponding to the kinetics of a memory T cell response. Donor CD8(+) T cells recovered on day 42 after allogeneic bone marrow transplantation expressed the phenotype of CD44(high)CD122(high)CD25(low), were able to homeostatically survive in response to IL-2, IL-7, and IL-15 and rapidly proliferated upon restimulation with host dendritic cells. Both allogeneic effector memory (CD44(high)CD62L(low)) and central memory (CD44(high)CD62L(high)) CD8(+) T cells were identified in B6 mice with ongoing GVHD, with effector memory CD8(+) T cells as the dominant (>80%) population. Administration of these allogeneic memory CD8(+) T cells into secondary B6 recipients caused virulent GVHD. A similar allogeneic memory CD4(+) T cell population with the ability to mediate persistent GVHD was also identified in BALB/b mice receiving minor histocompatibility Ag-mismatched B6 T cell-replete bone marrow transplantation. These results indicate that allogeneic memory T cells are generated in vivo during GVH reactions and are able to cause GVHD, resulting in persistent host tissue injury. Thus, in vivo blockade of both alloreactive effector and memory T cell-mediated host tissue injury may prove to be valuable for GVHD prevention and treatment.
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PMID:Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease. 1572 19

We have previously shown that amotosalen HCl (S-59 psoralen)-treated donor splenocytes, which have limited proliferative capacity in vitro, can protect major histocompatibility complex-mismatched bone marrow transplant (BMT) recipients from lethal murine cytomegalovirus infection without causing graft-versus-host disease. In this study, we further investigated the effects of amotosalen-treated donor T cells on immune reconstitution after allogeneic BMT. We were surprised to find that amotosalen-treated donor T cells persisted long-term in vivo, comprising 6% to 10% on average of the T-cell compartment of transplant recipients at 4 months after transplantation. Donor T cells derived from amotosalen-treated splenocytes were predominantly polyclonal CD44 hi/int CD8 + memory T cells and were functionally active, synthesizing interferon gamma in response to stimulation with murine cytomegalovirus antigen. Amotosalen-treated donor T cells, reisolated from BMT recipients' spleens >/=4 months after transplantation, proliferated in vitro, thus indicating repair of amotosalen-mediated DNA cross-links. Compared with infusion of untreated donor splenocytes, amotosalen-treated cells enhanced thymopoiesis by bone marrow-derived stem cells in BMT recipients. However, amotosalen treatment abrogated the thymopoietic activity of lymphoid progenitor cells among the donor splenocytes. Thus, infusion of amotosalen-treated donor T cells produced rapid immune reconstitution after major histocompatibility complex-mismatched BMT by transferring long-lived polyclonal memory T cells with antiviral activity and also by enhancing bone marrow-derived thymopoiesis. This is a novel approach to adoptive immunotherapy in allogeneic BMT.
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PMID:Amotosalen-treated donor T cells have polyclonal antigen-specific long-term function without graft-versus-host disease after allogeneic bone marrow transplantation. 1574 35

Human placenta-derived mononuclear cells (MNC) were isolated by a Percoll density gradient and cultured in mesenchymal stem cell (MSC) maintenance medium. The homogenous layer of adherent cells exhibited a typical fibroblast-like morphology, a large expansive potential, and cell cycle characteristics including a subset of quiescent cells. In vitro differentiation assays showed the tripotential differentiation capacity of these cells toward adipogenic, osteogenic and chondrogenic lineages. Flow cytometry analyses and immunocytochemistry stain showed that placental MSC was a homogeneous cell population devoid of hematopoietic cells, which uniformly expressed CD29, CD44, CD73, CD105, CD166, laminin, fibronectin and vimentin while being negative for expression of CD31, CD34, CD45 and alpha-smooth muscle actin. Most importantly, immuno-phenotypic analyses demonstrated that these cells expressed class I major histocompatibility complex (MHC-I), but they did not express MHC-II molecules. Additionally these cells could suppress umbilical cord blood (UCB) lymphocytes proliferation induced by cellular or nonspecific mitogenic stimuli. This strongly implies that they may have potential application in allograft transplantation. Since placenta and UCB are homogeneous, the MSC derived from human placenta can be transplanted combined with hematopoietic stem cells (HSC) from UCB to reduce the potential graft-versus-host disease (GVHD) in recipients.
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PMID:Mesenchymal stem cells derived from human placenta suppress allogeneic umbilical cord blood lymphocyte proliferation. 1604 17

Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44(lo)CD62L(hi)CD8(+) T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8(+) T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44(lo)CD62L(hi)CD8(+) T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.
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PMID:Host-reactive CD8+ memory stem cells in graft-versus-host disease. 1633 66

Supplementation of mesenchymal stem cells (MSCs) during hematopoietic stem cell (HSC) transplantation alleviates complications such as graft-versus-host disease, leading to a speedy recovery of hematopoiesis. To meet this clinical demand, a fast MSC expansion method is required. In the present study, we examined the feasibility of using a rotary bioreactor system to expand MSCs from isolated bone marrow mononuclear cells. The cells were cultured in a rotary bioreactor with Myelocult medium containing a combination of supplementary factors, including stem cell factor and interleukin-3 and -6. After 8 days of culture, total cell numbers, Stro-1(+)CD44(+)CD34(-) MSCs, and CD34(+)CD44(+)Stro-1(-) HSCs were increased 9-, 29-, and 8-fold, respectively. Colony-forming efficiency-fibroblast per day of the bioreactor-treated cells was 1.44-fold higher than that of the cells without bioreactor treatment. The bioreactor-expanded MSCs showed expression of primitive MSC markers endoglin (SH2) and vimentin, whereas markers associated with lineage differentiation, including osteocalcin (osteogenesis), type II collagen (chondrogenesis), and C/EBP-alpha (CCAAT/enhancer-binding protein-alpha) (adipogenesis), were not detected. Upon induction, the bioreactor-expanded MSCs were able to differentiate into osteoblasts, chondrocytes, and adipocytes. We conclude that the rotary bioreactor with the modified Myelocult medium reported in this study may be used to rapidly expand MSCs.
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PMID:Bioreactor expansion of human adult bone marrow-derived mesenchymal stem cells. 1672 60

We previously found that CD8 T cells from IFN-gamma gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-gamma inhibits GVHD in a parent --> F1 (B6 --> B6D2F1) allogeneic HCT (allo-HCT) model. IFN-gamma was strongly protective against GVHD in this parent --> F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from WT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-gamma. In consequence, the numbers of activated/effector (ie, CD25+, CD62L-, and CD44(high)) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-gamma negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-gamma could augment the severity of GVHD in patients undergoing allo-HCT.
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PMID:An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation. 1722 52

Strong proliferative capacity and the ability to differentiate into the derivative cell types of three embryonic germ layers are the two important characteristics of embryonic stem cells. To study whether the mesenchymal stem cells from human fetal bone marrow (hfBM-MSCs) possess these embryonic stem cell-like biological characteristics, hfBM-MSCs were isolated from bone barrows and further purified according to the different adherence of different kinds of cells to the wall of culture flask. The cell cycle of hfBM-MSCs and MSC-specific surface markers such as CD29, CD44, etc were identified using flow cytometry. The expressions of human telomerase reverse transcriptase (hTERT), the embryonic stem cell-specific antigens, such as Oct4 and SSEA-4 were detected with immunocytochemistry at the protein level and were also tested by RT-PCR at the mRNA level. Then, hfBM-MSCs were induced to differentiate toward neuron cells, adipose cells, and islet B cells under certain conditions. It was found that 92.3% passage-4 hfBM-MSCs and 96.1% passage-5 hfBM-MSCs were at G(0)/G(1) phase respectively. hfBM-MSCs expressed CD44, CD106 and adhesion molecule CD29, but not antigens of hematopoietic cells CD34 and CD45, and almost not antigens related to graft-versus-host disease (GVHD), such as HLA-DR, CD40 and CD80. hfBM-MSCs expressed the embryonic stem cell-specific antigens such as Oct4, SSEA-4, and also hTERT. Exposure of these cells to various inductive agents resulted in morphological changes towards neuron-like cells, adipose-like cells, and islet B-like cells and they were tested to be positive for related characteristic markers. These results suggest that there are plenty of MSCs in human fetal bone marrow, and hfBM-MSCs possess the embryonic stem cell-like biological characteristics, moreover, they have a lower immunogenic nature. Thus, hfBM-MSCs provide an ideal source for tissue engineering and cellular therapeutics.
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PMID:[Proliferative capacity of mesenchymal stem cells from human fetal bone marrow and their ability to differentiate into the derivative cell types of three embryonic germ layers]. 1856 Jul 36


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