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)

When immunocompetent cells are transferred to an allogeneic, immunologically compromised host a complex series of cellular events are initiated, referred to as graft versus host disease. This results in widespread organ damage with fibrosis being a prominent feature. The pathologic fibrosis may result from an increase in fibroblast numbers, an increase in collagen produced from individual fibroblasts, or a combination of the two processes. The relative contribution of fibroblast replication to the pathologic fibrosis seen in graft versus host disease has not been directly determined previously, and this is the main object of this paper. Graft versus host disease was induced by the transfer of lymphoid cells from B10D2 mice to irradiated Balb/c recipients. In order to study the mitotic activity of dermal cells following bone marrow transplantation, a thymidine anologue, bromo-deoxyuridine (BrDU), was administered to mice using an osmotically driven, implantable infusion device. The labeled cells were visualized immuno-histochemically and studied at weekly intervals. There is intense mitotic activity in the basal layer of the epidermis and the acrosyringal epithelium from the second week. Evidence of increased mitotic activity in the epidermis persisted until the fifth week post-transplantation. Fibroblast replication was seen from the end of the third post-transplant week. Dermal collagen deposition also occurred at this time. Peak mitotic activity was present at the end of the fourth week and was less pronounced by the fifth week. It was especially evident in the upper dermis where the developing collagen layer was being deposited. To our knowledge this is the first direct demonstration of fibroblast proliferation in an immunologically mediated fibrotic disorder. It is concluded that fibroblast replication is an important mechanism leading to the pathologic fibrosis seen in graft versus host disease and, by analogy, probably other types of immunologically mediated fibrosis.
 ...
PMID:Mitotic activity in the dermis of mice during graft versus host disease: the role of fibroblast replication in dermal fibrosis. 146 92

We explored the pathologic changes in the skin of mice undergoing a chronic graft-versus-host (GVH) reaction. In rodents and in man, chronic GVH includes the deposition of excess collagen in the skin-a reaction which resembles idiopathic scleroderma. GVH disease across minor histocompatibility barriers was produced by injecting B10.D2 cells into irradiated BALB/c mice. These strains are identical at the H-2 and Mls loci but differ in minor histocompatibility antigens. Control BALB/c mice received irradiation and BALB/c cells. Serial skin biopsies were taken and studied for histological changes characteristic of chronic GVHD, for mast cell density, and for the deposition of immunoreactants. GVHD was produced in B10.D2----BALB/c mice as measured by body weight loss and the production of skin changes including dermal fibrosis, loss of fat and appendages, and a mononuclear cell infiltrate. Dermal mast cells, assessed by toluidine blue staining, were normal at Day 11, but had disappeared by Days 21-63 and returned to normal by Day 104. Immunoglobulins IgG, IgA, and IgM appeared at the dermo-epidermal junction and along the basement membrane zone of hair follicles. This deposition was maximal at Day 42 and waned thereafter. Thus the appearance of immunoglobulins in the skin was maximal when mast cell staining was minimal. The changes in this GVHD model leading to a scleroderma-like picture in the skin are compatible with an immune etiology for the fibrosis. Vasodilation following liberation of mast cell mediators would facilitate the deposition of immunoglobulins. The disappearance of mast cell staining may be caused by extensive degranulation. We postulate an interaction between GVHD-activated T cells, mast cell stimulation, fibroblast activation, and fibrosis.
 ...
PMID:Chronic graft-versus-host disease as a model for scleroderma. II. Mast cell depletion with deposition of immunoglobulins in the skin and fibrosis. 401 62

Dermal fibrosis, loss of cutaneous appendages, and loss of subcutaneous fat are the main manifestations of chronic graft-versus-host disease (cGVHD) in mice. Mast cells (MC) may have a role in cGVHD. To investigate this point we have evaluated the effect of a MC stabilizer (nedocromil sodium) and a MC activator (compound 48/80) on skin manifestations in a murine model of cGVHD (B10.D2-->BALB/c). Mice were treated with nedocromil sodium (5 mg/day) or compound 48/80 (10 micrograms/day) from day -3 until day 15. Nedocromil ameliorated the skin features of cGVHD while compound 48/80 caused skin changes reminiscent of mild cGVHD in control mice. In addition nedocromil normalized peritoneal MC numbers and skin MC numbers and their activation state in the cGVHD mice. On the other hand compound 48/80 caused a complete disappearance of toluidine blue stainable peritoneal MC from cGVHD and control mice and decreased skin MC in controls. In summary, MC activation may play a negative role in the skin changes seen in cGVHD while MC stabilization ameliorates the skin manifestations of cGVHD and therefore may have a therapeutic benefit.
 ...
PMID:Nedocromil sodium ameliorates skin manifestations in a murine model of chronic graft-versus-host disease. 913 76

The effect of dermal application of halofuginone-an inhibitor of collagen type I synthesis-on skin collagen and collagen alpha1(I) gene expression in an animal model of scleroderma and chronic graft versus host disease (cGvHD) was evaluated. Halofuginone-containing cream was applied on the tight-skin mouse (Tsk) and skin biopsies were taken for collagen staining by sirius red and for collagen alpha1(I) gene expression by in situ hybridization. In addition, cell proliferation was evaluated by immunostaining for proliferation cell nuclear antigen (PCNA) alone or in combination with collagen alpha1(I) probe. The number of mast cells was assessed by toluidine blue. Dermal application of halofuginone (0.01%) for 60 days was as good as systemic administration (1 microg/mouse/day) in reducing collagen alpha1(I) gene expression in skin biopsy and almost as good in reducing skin width. Halofuginone was stable and effective only at acidic pH. The effect of halofuginone (0.03%) was time-dependent. After 40 days of daily treatment, a significant reduction in the collagen alpha1(I) gene expression was observed and further decrease was observed after 60 days. The reduction in collagen alpha1(I) gene expression and the reduction in the proliferation of dermal fibroblasts probably occur in the same subset of cells. No effect of halofuginone on the proliferation of keratinocytes or on mast cell number was observed. These results suggest that target-oriented application of halofuginone may become a novel therapy for fibrotic disorders in general and for scleroderma in particular.
 ...
PMID:Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone. 1170 55

The extravasation of leukocytes at sites of inflammation critically depends on initial shear-resistant adhesive interactions between leukocytes in blood flow and target tissue endothelium. Dermal lymphocytic infiltrates are a hallmark feature of acute cutaneous graft-versus-host disease (acGVHD) following allogeneic hematopoietic stem cell (allo-HSC) transplantation. These infiltrates occur commonly during periods of profound lymphopenia, suggesting that the dermal endothelial adhesive mechanism(s) promoting lymphocyte emigration in acGVHD are highly efficient. To examine this issue, we performed Stamper-Woodruff assays on frozen sections of biopsy specimens of cutaneous lesions occurring within 100 days of HSC transplantation in 22 autologous hematopoietic stem cell transplant (auto-HSCT) and 25 allo-HSCT recipients. By using this shear-based assay, we observed lymphocyte adherence to papillary dermal vascular structures in all punch biopsy specimens of allo-HSCT recipients who had clinicohistologic evidence of acGVHD and who were not receiving steroids, whereas no lymphocyte adherence was observed within skin specimens from allo-HSCT recipients who did not develop acGVHD. Within the group of auto-HSCT recipients, 2 of 22 skin biopsies demonstrated lymphocyte binding to dermal vessels. Among allo-HSCT patients receiving steroid therapy for acGVHD, lymphocyte binding to dermal endothelium was abrogated prior to resolution of rash in those who responded, yet binding was persistent in skin from one patient whose rash did not respond to steroid therapy. Collectively, these data indicate that the papillary endothelium of skin in acGVHD displays heightened capacity to support lymphocyte adhesion under shear stress conditions and suggest that down-modulation of this endothelial adhesive capability may be one mechanism by which steroids abrogate acGVHD reactions.
 ...
PMID:In vitro adherence of lymphocytes to dermal endothelium under shear stress: implications in pathobiology and steroid therapy of acute cutaneous GVHD. 1239 84

The precise contribution(s) of skin dendritic cells (DCs) to immune responses in the skin has not been well delineated. We developed an intradermal (i.d.) injection model in which CD8+ T (OT-I) cells that express ovalbumin (OVA) peptide-specific TCRs (Valpha2/Vbeta5) are delivered directly to the dermis of transgenic (Tg) mice expressing OVA in the epidermis. After i.d. injection, these mice reliably develop skin graft-versus-host disease (GVHD) by day 7. To determine the relative contribution of Langerhans cells (LCs) to the ensuing GVHD-like reaction, we generated K14-OVA x Langerin-diphtheria-toxin-receptor (Langerin-DTR) Tg mice to allow conditional ablation of LCs in the epidermis. To delineate the role of dermal DCs (dDCs) in the reaction, we also generated K14-OVA Tg chimeras using beta(2)-microglobulin-deficient (beta(2)m) congenic donor bone marrow cells. Dermal DCs in these mice cannot present OVA to autoreactive T cells (OT-I cells), whereas the LCs are antigen presentation-competent. Unexpectedly, OT-I cell injection into diphtheria toxin (DT)-treated beta(2)m --> K14-OVA x Langerin-DTR Tg mice resulted in skin GVHD. Thus, in vivo, both LC and dDC appear to be dispensable for the induction of keratinocyte-directed, CD8-mediated effector immune responses. Furthermore and surprisingly, OVA-expressing epidermal cells depleted of LCs that could not initiate allogeneic epidermal lymphocyte reactions activated naive OT-I cells in vitro. These results indicate that keratinocytes may function as accessory cells competent to prime naive skin-reactive T cells.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub.
 ...
PMID:Keratinocytes function as accessory cells for presentation of endogenous antigen expressed in the epidermis. 1990 42

Dermal mucinosis is characterized by the deposition of glycosaminoglycans (mucin), either focally or diffusely within the dermis. This may occur as a primary idiopathic disorder or secondary to several dermatoses, most notably lupus erythematous, scleroderma, and dermatomyositis. The authors present an unusual finding of dermal mucinosis in association with chronic sclerodermoid graft-versus-host disease.
...
PMID:Dermal Mucinosis in Chronic Sclerodermoid Graft-Versus-Host Disease. 2632 57