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

Bone marrow transplantation is employed in the treatment of a number of hematologic and malignant diseases. A major complication is the induction of graft-versus-host disease. Whereas removal of T lymphocytes from the donor marrow effectively reduces the incidence of graft-versus-host disease, the incidence of graft failure often increases when T cells are depleted from the transplanted marrow. In the current study, photoinactivation of the donor cells with 8-methoxypsoralen coupled with exposure to long-wavelength ultraviolet radiation (PUVA therapy) was used to inactivate the response of the donor T cells against the host. PUVA therapy suppressed the ability of spleen cells to respond to alloantigen in the in vitro mixed lymphocyte reaction. The induction of acute graft-versus-host disease across complete major histocompatibility barriers in lethally X-irradiated mice was significantly suppressed after bone marrow transplantation with photoinactivated bone marrow cells. Long-term survivors demonstrated allogeneic reconstitution and partial restoration of T-cell function. Because PUVA therapy had no inhibitory effect on hematopoiesis, these data suggest that using phototherapy to inactivate the alloreactivity of T cells may provide an alternative to purging T cells from the donor marrow, thus suppressing both the incidence of graft-versus-host disease and the incidence of graft failure.
J Invest Dermatol 1991 Mar
PMID:Photoinactivation of T-cell function with psoralen and UVA radiation suppresses the induction of experimental murine graft-versus-host disease across major histocompatibility barriers. 200 50

The therapeutic spectrum for ultraviolet radiation treatment of skin disease has continued to be broadened. Psoralen photochemotherapy is beneficial in chronic lichenoid graft-versus-host disease and disseminated granuloma annulare. This treatment is now being found more useful in atopic eczema and chronic photosensitivity with some modifications of the therapy. UV phototherapy has also been found useful in mild to moderate atopic eczema. The nature of these treatments is also changing with greater use of selective UV phototherapy and definition of the required schedule for maintenance treatment with UVB phototherapy. The mechanism of therapeutic benefit remains unknown although one possibility is selective phototoxicity for inflammatory cells in the dermis. Nonmelanoma skin cancer, premature aging of the skin and freckling are the main long-term adverse effects of these treatments.
J Dermatol Sci 1990 May
PMID:Recent advances in phototherapy and photochemotherapy of skin disease. 208 2

A multitude of skin lesions that are seen following organ transplantation have been presented. Many of them, such as opportunistic infections, are related to the immunosuppressive agents used to prevent graft rejection and graft-versus-host disease. Corticosteroids and cyclosporine commonly produce other skin changes as well. A high index of suspicion for unusual infections and skin cancer should lead the dermatologist to initiate the proper diagnostic procedures in these patients.
Dermatol Clin 1990 Apr
PMID:Skin lesions in transplant patients. 214 6

We have used oral psoralen photochemotherapy (PUVA) to treat four patients with chronic graft-versus-host disease of the skin, oral mucosa, and liver, who had responded only partially to long-term immunosuppressive therapy (prednisolone, cyclosporine, azathioprine). PUVA therapy was delivered to the entire skin but not to the oral mucosa, and immunosuppressive therapy was continued in all patients. Two patients' skin lesions improved considerably; the oral lesions healed and did not recur in one. Immunosuppressive therapy could be reduced in these two patients. One patient with sicca signs did not improve. One patient had to interrupt PUVA therapy because of side effects attributed to 8-methoxypsoralen (nausea and vomiting). No flare of acute cutaneous graft-versus-host disease was noted during PUVA therapy. Chronic graft-versus-host disease of the liver did not improve in any patient.
J Am Acad Dermatol 1990 Aug
PMID:Photochemotherapy improves chronic cutaneous graft-versus-host disease. 221 17

Acute graft-versus-host reaction after allogeneic bone marrow transplantation has been reported to induce toxic epidermal necrolysis. To assess the respective role of acute graft-versus-host disease and of drug reaction in this setting, we retrospectively reviewed nine cases of toxic epidermal necrolysis that occurred in a series of 152 allogenic bone marrow recipients. In five cases visceral involvement was suggestive of acute graft-versus-host disease without any drug more than "doubtfully" suspected. In four cases extracutaneous symptoms were absent or mild and suspect drugs (mainly sulfonamides) had been administered with a timing suggestive of "possible" causality. All nine patients died, mainly from infection possibly aggravated by high doses of corticosteroids. We conclude that toxic epidermal necrolysis may be more frequent than generally thought after bone marrow transplantation and has a poor prognosis. It seems to be related to a drug reaction to sulfonamides as often as to acute graft-versus-host disease.
J Am Acad Dermatol 1990 Nov
PMID:Toxic epidermal necrolysis after bone marrow transplantation: study of nine cases. 225 72

Cutaneous graft-versus-host disease (GVHD) provides a unique model for studying the pathogenesis of several important lymphocyte-mediated skin diseases. Morphologic studies have suggested that Ia antigen (Ia)-bearing epidermal Langerhans cells (LC) may be specific targets for destruction in these conditions. Keratinocytes synthesize and express Ia in GVHD and some other lymphocyte-mediated skin disorders; Ia+ keratinocytes, constitutively able to secrete epidermal cell-derived thymocyte activating factor (ETAF)/interleukin 1, may possess antigen-presenting capacity, thus leading to enhanced cutaneous immune responses and disease chronicity. We therefore investigated the fate of Ia+ LC, and the potential antigen-presenting capacity of Ia+ keratinocytes, in a murine model of GVHD. Lethally irradiated C3H/He (H-2k) mice developed acute cutaneous GVHD, and expressed keratinocyte Iak, 8 days after injection of BALB/c (H-2d) bone marrow and spleen cells. Immunofluorescence studies showed a progressive decrease in the density of Ia+ epidermal LC during the evolution of GVHD. This decrease was paralleled by a progressive reduction in the allostimulatory capacity of GVHD epidermal cells (EC) in the allogeneic EC-lymphocyte reaction (ELR). The fall in the density of Ia+ LC, and in EC allostimulatory capacity in both primary and secondary ELRs, was consistently greater in GVHD mice than in mice treated only with x-irradiation. The allostimulatory capacity of GVHD and x-irradiated EC could not be restored by addition of indomethacin or exogenous ETAF to ELR cultures. The decreased allostimulatory capacity was not the result of inhibition of the ELR, since EC from GVHD and x-irradiated mice did not cause suppression when added to control ELR cultures. The capacity of EC to present ovalbumin, purified protein derivative of tuberculin, 2,4,6-trinitrobenzenesulfonic acid coupled to EC, and native cytochrome c (CYTc) to antigen-specific T-cell lines, clones, or hybridomas was reduced in x-irradiated mice and markedly decreased in GVHD mice. The capacity of EC from x-irradiated and GVHD mice to present CYTc fragment 81-104, which does not require further processing or catabolism by accessory cells, was similarly decreased. Taken together, the results indicate that: the function of LC is markedly and progressively impaired in acute GVHD; LC function is also decreased, but to a lesser extent, following x-irradiation alone; and Ia+ keratinocytes from lethally irradiated mice undergoing GVHD do not exhibit antigen-presenting capacity.
J Invest Dermatol 1986 Mar
PMID:Immunologic aspects of acute cutaneous graft-versus-host disease: decreased density and antigen-presenting function of Ia+ Langerhans cells and absent antigen-presenting capacity of Ia+ keratinocytes. 242 2

The presence of numerous keratin bodies in the upper dermis is a characteristic finding in skin lesions of patients with various dermatoses such as cutaneous graft-versus-host disease, lichen planus, or chronic discoid lupus erythematosus. These keratin bodies are generated by apoptotic keratinocyte death, consist largely of keratin intermediate filaments (KIF), and are constantly covered with immunoglobulins, mainly IgM. Apoptosis is also thought to occur under physiologic conditions in the skin as it does in other organs, but keratin bodies are not frequently reported as being found in nonlesional skin. In order to assess the frequency of keratin bodies in normal skin, we examined serial sections of 10 normal human skin specimens and 5 dermal sheets prepared from normal human skin for the presence of keratin bodies. They were visualized by direct immunofluorescence using a fluorescein isothiocyanate (FITC) rabbit antihuman IgM conjugate. In addition the KIF origin of keratin bodies was demonstrated by a double-staining immunofluorescence procedure using a FITC-conjugated rabbit antihuman IgM followed by a mouse monoclonal antibody against keratin and a sheep antimouse immunoglobulin conjugated with Texas Red. One specimen was also examined for keratin bodies at the ultrastructural level. In serial sections, all 10 normal human skin specimens had numerous keratin bodies as assessed by visualization of globular IgM deposits. Evaluated on dermal sheets, the number of keratin bodies ranged from 39-262 per mm2. Nearly all keratin bodies also stained with the antikeratin antibodies. Ultrastructurally the remarkable number of keratin bodies, which consist of filaments measuring approximately 10 nm in diameter or of more granular material, in normal human skin was confirmed. In order to investigate the capacity of KIF material in keratin bodies to function as autoantigen, we examined the sera of the 10 skin donors and, in addition, of 30 normal healthy individuals and 10 patients with rheumatoid arthritis for the occurrence and specificity of IgM-anti-KIF autoantibodies by an enzyme-linked immunosorbent assay and by immunoblot. IgM-anti-KIF autoantibodies were found in all 50 test sera. In the majority of the sera the specificity of these autoantibodies included the 51 kD and the 58 kD KIF protein, which are constituents of KIF in keratin bodies and basal keratinocytes. Quantitatively, the antibody activity of the IgM-anti-KIF autoantibodies varied from serum to serum, being highest in the sera of patients with rheumatoid arthritis.(ABSTRACT TRUNCATED AT 400 WORDS)
J Invest Dermatol 1986 Oct
PMID:Apoptotic keratin bodies as autoantigen causing the production of IgM-anti-keratin intermediate filament autoantibodies. 242 83

IgG-anti-keratin intermediate filament autoantibodies occur in low titers in all normal human sera. These same antibodies are present in high titers in the sera of patients who have diseases in which cells containing keratin intermediate filaments (KIF) have been damaged, such as systemic lupus erythematosus, graft-versus-host disease, and cutaneous tumors. Since some human autoantibodies are thought to function in part as opsonins promoting the removal of insoluble cellular proteins after tissue injury, we investigated the influence of IgG-anti-KIF autoantibodies on the phagocytosis of insoluble KIF aggregates by human monocytes and polymorphonuclear neutrophils (PMN). Keratin intermediate filaments assembled in vitro were reconstituted into dense spherical KIF aggregates 0.3-2.5 microns in diameter by dialysis against phosphate-buffered saline. Immunoelectron microscopy revealed that, as expected, human IgG-anti-KIF autoantibodies bound to the KIF aggregates. Human monocytes or PMN were incubated either with nonopsonized KIF aggregates or with KIF aggregates that had been reacted with IgG-anti-KIF autoantibodies. The uptake of KIF aggregates was visualized by indirect immunofluorescence, immunoperoxidase staining, and immunoelectron microscopy. Monocytes rapidly and efficiently bound and phagocytosed KIF aggregates that had been coated with IgG-anti-KIF autoantibodies. Nonopsonized KIF aggregates, in contrast, were taken up much less efficiently. Differences were most marked at 4 degrees C for 60 min with phagocytosis of opsonized KIF aggregates by 23 +/- 8% of monocytes in contrast to phagocytosis by only 0.2 +/- 3% monocytes when nonopsonized KIF aggregates were used. Similar results occurred at 37 degrees C for 5 min with phagocytosis by 38 +/- 28% vs 1.8 +/- 0.4% of monocytes of opsonized and nonopsonized KIF aggregates, respectively. A high percentage of PMN also phagocytosed opsonized KIF aggregates, whereas nonopsonized KIF aggregates were ingested less avidly. These data indicate that the opsonization of extracellular KIF aggregates by IgG-anti-KIF autoantibodies plays an important role in promoting the phagocytosis of KIF aggregates. The subsequent phagocytosis represents a rapid and very effective mechanism for the removal of insoluble KIF following keratinocyte cell death.
J Invest Dermatol 1987 Feb
PMID:Phagocytosis of keratin filament aggregates following opsonization with IgG-anti-keratin filament autoantibodies. 243 55

Because keratinocytes (KCs) express HLA-DR in a wide variety of skin diseases in which mononuclear leukocytes are observed in close apposition to KCs (i.e., graft-versus-host disease), and since gamma interferon (IFN-gamma) induces HLA-DR expression on KCs, we asked whether IFN-gamma treatment of KCs would influence the adherence of mononuclear leukocytes. When allogeneic peripheral blood mononuclear leukocytes (PBML) and a Leu-3+ T cell clone were coincubated with IFN-gamma-treated KCs (300 U/ml, 3 days), there was a marked increase in binding compared with nontreated KCs. Similar binding results were obtained using a cutaneous squamous carcinoma cell line (SCL-1) after IFN-gamma treatment. The IFN effect was relatively specific for IFN-gamma, as neither IFN-alpha nor -beta had any effect. Tumor necrosis factor exposure (500 U/ml, 3 days) increased the binding of the Leu-3+ T cell clone to both KCs and SCL-1 cells. Neutrophils displayed a less marked (but statistically significant) increase in binding to IFN-gamma-treated KCs. Using the Leu-3+ cell clone and SCL-1 cells, detailed kinetic analysis of the effect of IFN-gamma on binding was performed. The increased adherence between the cells began to appear after only 7 hours of treatment with r-IFN-gamma (300 U/ml) and reached a plateau at 48 hours, with significantly enhanced binding continuing for at least 48 hours after removal of IFN-gamma. The mechanism of binding was explored by preincubation of the PBML/Leu-3+ T cells with anti-LFA-1 (lymphocyte function-associated antigen) antibody (0.6-6.0 micrograms/ml), which totally inhibited the binding with no effect by anti-LFA-2 or -3 or class I or II antibodies despite documented binding of these antibodies to the cells. These results suggest that, after exposure to IFN-gamma, the ability of KCs to bind mononuclear leukocytes is strongly enhanced, and this adherence may be important in leukocyte trafficking in the skin as well as contributing to altered KC-leukocyte interaction, which may be of fundamental importance in a variety of skin disease.
J Invest Dermatol 1988 Jan
PMID:Recombinant gamma interferon increases the binding of peripheral blood mononuclear leukocytes and a Leu-3+ T lymphocyte clone to cultured keratinocytes and to a malignant cutaneous squamous carcinoma cell line that is blocked by antibody against the LFA-1 molecule. 244 90

Several of the cytokines that regulate the immune system have been tested for efficacy in the clinical setting. Of these, interleukin-2 shows particular potential for antitumor therapy when used in combination with autologous lymphokine-activated killer cells; the interferons have proved effective in the treatment of certain viral diseases and malignancies, particularly those of hematologic origin; and the colony-stimulating factors show great promise for treatment of diseases associated with bone marrow dysfunction. Heterologous monoclonal antibodies have proved effective in control of acute allograft rejection and prevention of graft versus host disease by selective elimination of cell types. Anti-idiotype antibodies are being investigated for their potential as vaccines. Many synthetic compounds possess immunomodulatory properties; one of these, inosiplex, may prove effective in enhancing immune function in patients with immune deficiencies such as AIDS.
Dermatol Clin 1988 Oct
PMID:Therapeutic immunomodulation. 246 56


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